Supplemental Table 1. Selected ongoing clinical trials targeting RET aberrations Drug Phase
of the study
Types of RET aberrations being targeted
Types of cancer being enrolled
NCT identifier*
Cabozantinib II Fusion/Rearrangement Non-small cell lung cancer NCT01639508Apatinib II Fusion/Rearrangement Non-small cell lung cancer NCT02540824Vandetanib II Fusion/Rearrangement Non-small cell lung cancer NCT01823068Ponatinib II Fusion/Rearrangement Non-small cell lung cancer NCT01813734Lenvatinib II Fusion/Rearrangement Lung adenocarcinoma NCT01877083Sunitinib II Fusion/Rearrangement Lung adenocarcinoma NCT01829217Sunitinib II Fusion/Rearrangement Advanced solid tumors NCT02450123Sunitinib II Fusion/Rearrangement Advanced solid tumors NCT02691793Ponatinib II Any activating aberrations Advanced solid tumors NCT02272998MGCD516 I Fusion/Rearrangement Advanced solid tumors NCT02219711Regorafenib II Mutation or amplification Advanced solid tumors NCT02693535Vandetanib plus everolimus
I Any activating aberrations Advanced solid tumors NCT01582191
RXDX-105 I Mutation or Fusion/Rearrangement
Advanced solid tumors NCT01877811
* Please see http://clinicaltrials.gov for further detail. Last accessed 5/18/2016.
1
Supplemental Table 2. Cancer diagnosis that were negative for RET aberration (included cases with N ≥10).
Diagnosis Number of cases sequenced
Cholangiocarcinoma 159
Neuroendocrine carcinoma * 97
Renal cell carcinoma § 92
Glioblastoma 84
Head and neck adenoid cystic carcinoma 49
Astrocytoma 45
Small cell lung carcinoma 43
Mesothelioma 36
Squamous cell carcinoma (unknown primary) 35
Large cell lung carcinoma 30
Neuroblastoma 28
Head and neck carcinoma (histology unspecified) 24
Anal squamous cell carcinoma 23
Appendix adenocarcinoma 23
Cervical squamous cell carcinoma 22
Salivary gland carcinoma (histology unspecified) 22
Esophageal squamous cell carcinoma 21
Renal pelvis urothelial carcinoma 21
B-cell lymphoma 20
Peritoneal carcinoma 19
Metaplastic breast carcinoma 17
Oligodendroglioma 17
Small bowel adenocarcinoma 17
Thymic carcinoma 16
Malignant peripheral nerve sheath tumor 15
Chordoma 13
Glioma 13
Ovarian sex cord stromal tumor 12
Carcinoid tumor 11
Lung adenosquamous carcinoma 11
Mucoepidermoid carcinoma 11
Testis germ cell tumor (non-seminoma) 10
2
* Neuroendocrine carcinoma include neuroendocrine carcinoma (location unspecified) (N=44), neuroendocrine tumor of pancreas (N=22), cervical (N=7), head and neck (N=5), bladder (N=4), colorectal (N=4), prostate (N=4), ovarian (N=3), breast (N=2), gastric (N=1) and uterine (N=1).
§ Renal cell carcinoma include renal cell carcinoma (histology unspecified) (N=58), clear cell (N=23), papillary (N=8), collecting duct (N=2) and medullary (N=1).
3
Supplemental Table 3. Complete list of RET aberration with cancer diagnosis and co-occurring aberrations. ID
Diagnosis RET aberrations
Molecular effect of mutation Co-occurring aberrations
1 Medullary thyroid carcinoma
RET C634R Activating (S1) Not detected
2 Breast carcinoma RET C634R Activating (S1) Not detected
3 Endometrial adenocarcinoma
RET E511K Activating (S2) ARID1A F2141fs*59, Q1519fs*8NOTCH1 S2486fs*71+, S2329fs*7NRAS Q61RPIK3CA E545KPTEN D268fs*30, W274fs*2TP53 V157A, P152LTSC1 L203fs*7
4 Merkel cell carcinoma
RET E511K Activating (S2) ALK F1174C
5 Anaplastic thyroid carcinoma
RET E511K Activating (S2) ARID1A Q1334_R1335insQ BRAF V600ECDKN2A/B lossEMSY amplificationJAK2 amplificationPIK3CA H1047LTP53 R306*
6 Paraganglioma RET M918T Activating (S3) Not detected
7 Medullary thyroid carcinoma
RET M918T Activating (S3) ATM S978fs*12, L804fs*4
8 Medullary thyroid carcinoma
RET M918T Activating (S3) Not detected
9 Atypical lung carcinoid
RET M918T Activating (S3) Not detected
10 Medullary thyroid carcinoma
RET M918T Activating (S3) DDR2 R806Q
11 Pheochromocytoma
RET M918T Activating (S3) Not detected
12 Papillary thyroid carcinoma
RET M918T Activating (S3) Not detected
13 Colorectal adenocarcinoma
RET V804M Activating (S4) APC D1033fs*4, R1450*ATM C1045fs*3, Q2277*KRAS G12C MCL1 amplificationMYC amplificationSMAD2 S464*
14 Meningioma RET V804M Activating (S4) CDKN2A/B lossCDKN2C lossNF2 L117fs*6
15 GIST (Gastrointestinal
RET V804M Activating (S4) CDKN2A/B lossKIT S501_A502insAY
4
stromal tumor)16 Hepatocellular
carcinomaRET V804M Activating (S4) MYC amplification
17 Lung adenocarcinoma
RET R114H Unknown - predicted inactivating (S5).According to PolyPhen-2 (S6), it is predicted to be benign mutation.
ARID1A P1325fs*146EPHB1 amplificationMSH6 K1358fs*2NF2 Q410*
18 Uterine carcinosarcoma
RET R114H Unknown - predicted inactivating (S5).According to PolyPhen-2 (S6), it is predicted to be benign mutation.
KRAS amplificationPIK3CA amplificationSOX2 amplificationTP53 R248W
19 Gastric adenocarcinoma
RET R114H Unknown - predicted inactivating (S5).According to PolyPhen-2 (S6), it is predicted to be benign mutation.
FBXW7 R689Q
20 Hemangiopericytoma
RET R114H Unknown - predicted inactivating (S5).According to PolyPhen-2 (S6), it is predicted to be benign mutation.
Not detected
21 Ovarian epithelial carcinoma
RET R114H Unknown - predicted inactivating (S5).According to PolyPhen-2 (S6), it is predicted to be benign mutation.
CDKN2A A76fs*70KRAS G12D PTCH1 T416STP53 Y220C
22 Adrenal carcinoma
RET R114H Unknown - predicted inactivating (S5).According to PolyPhen-2 (S6), it is predicted to be benign mutation.
CTNNB1 T41A RB1 R73fs*36TP53 R337fs*4
23 Basal cell carcinoma
RET A756V Unknown. However, according to PolyPhen-2 (S6), it is predicted to be probably damaging mutation.
KDR G1145E PDGFRA E459KPIK3R1 G45*PTCH1 E237K, R770*TP53 R342*, S241P, R196*, Q317fs*21XPO1 E383K
24 Melanoma RET M1109I Unknown. CDKN2A R80*, T79T
5
According to PolyPhen-2 (S6), it is predicted to be benign mutation.
ERBB2 S310FFGFR3 F384LNF1 A1670fs*11 TP53 S241F, P60fs*63
25 Anaplastic thyroid carcinoma
RET M1109T Unknown (S7).According to PolyPhen-2 (S6), it is predicted to be benign mutation.
PTEN E40*, K267fs*9TP53 I254V
26 Lung adenocarcinoma
RET M255I Unknown.According to PolyPhen-2 (S6), it is predicted to be benign mutation.
CCNE1 amplification MCL1 amplificationMYC amplificationTP53 L206fs*3, K132_A138del, loss exon 2
27 Lung adenocarcinoma
RET R163Q Unknown.According to PolyPhen-2 (S6), it is predicted to be benign mutation.
CDKN2A P11fs*15CEBPA L155fs*10KRAS G12DTP53 R158L
28 Ovarian epithelial carcinoma
RET R525Q Unknown.According to PolyPhen-2 (S6), it is predicted to be benign mutation.
PIK3CA H1047RSMARCA4 splice site 760+1G>A
29 Ureter urothelial carcinoma
RET R525Q Unknown.According to PolyPhen-2 (S6), it is predicted to be benign mutation.
BCL2L2 amplificationCCND1 amplificationCCND2 G268RCDKN2A/B lossFGFR1 amplificationFGFR3 amplificationMDM2 amplificationMYC amplificationTP53 R280T, M246I
30 Sarcoma RET R600Q Unknown (S8).According to PolyPhen-2 (S6), it is predicted to be benign mutation.
RB1 loss
31 Colorectal adenocarcinoma
RET R600Q Unknown (S8).According to PolyPhen-2 (S6), it is predicted to be benign mutation.
APC S1214fs*51ARID1A Q1334_R1335insQ TP53 C176F
32 Pancreatic ductal adenocarcinoma
RET T636M Unknown, however preclinical data showed transforming potential including cell proliferation (S9).
KRAS G12RTP53 M237I
33 Cervical adenocarcinoma
RET V706M Unknown. However,
PIK3CA E545K, amplificationSOX2 amplification
6
according to PolyPhen-2 (S6), it is predicted to be probably damaging mutation.
34 Esophageal adenocarcinoma
RET V706M Unknown.However, according to PolyPhen-2 (S6), it is predicted to be probably damaging mutation.
CCND1 amplificationCDH1 R63*CDKN2A lossKRAS amplificationMITF amplificationMYC amplificationNKX2-1 amplificationTP53 C176Y
35 Lung adenocarcinoma
TRIM33-RET fusion
Activating (S10). CDKN2A/B loss CTNNB1 S33C
36 Salivary gland adenocarcinoma
NCOA4-RET fusion
Activating (S11). ARID1A truncation, exon EGFR amplificationFBXW7 W446fs*25MSH2 N924fs*1TP53 R209fs*6
37 Carcinoma unknown primary
NCOA4-RET fusion
Activating (S11). Not detected
38 Papillary thyroid carcinoma
NCOA4-RET fusion
Activating (S11). Not detected
39 Non-small cell lung carcinoma (NSCLC)
KIF5B-RET fusion
Activating (S12). RB1 deletion, exons 13-21STK11 lossTP53 R248L
40 Non-small cell lung carcinoma (NSCLC)
KIF5B-RET fusion
Activating (S12). MCL1 amplification RB1 deletion, exons 13-21TP53 R248L
41 Lung adenocarcinoma
KIF5B-RET fusion
Activating (S12). RB1 lossSTK11 lossTP53 R248L
42 Lung adenocarcinoma
KIF5B-RET fusion
Activating (S12). RPTOR amplificationTP53 E68*
43 Lung adenocarcinoma
KIF5B-RET fusion
Activating (S12). CDKN2A/B loss FGFR1 amplificationMDM2 amplificationPIK3CA amplification
44 Lung adenocarcinoma
KIF5B-RET fusion
Activating (S12). MDM2 amplification
45 Non-small cell lung carcinoma (NSCLC)
KIF5B-RET fusion
Activating (S12). RB1 deletion, intron 12-exon 21STK11 lossTP53 R248L
46 Lung adenocarcinoma
KIF5B-RET fusion
Activating (S12). BRCA2 T1354MMYC amplification
47 Lung adenocarcinoma
KIF5B-RET fusion
Activating (S12). CDKN2A/B loss
48 Non-small cell lung carcinoma
KIF5B-RET fusion
Activating (S12). NOTCH1 lossTP53 E68*
7
(NSCLC)49 Lung
adenocarcinomaKIF5B-RET fusion
Activating (S12). APC truncation, exon 6ARFRP1 amplificationAURKA amplificationCDKN2A/B lossTP53 Q165*
50 Lung adenocarcinoma
KIF5B-RET fusion
Activating (S12). APC I1307KCDKN2A/B lossTP53 S241T, C135F
51 Lung adenocarcinoma
KIF5B-RET fusion
Activating (S12). CDKN2A/B lossMDM2 amplification
52 Lung adenocarcinoma
KIF5B-RET fusion
Activating (S12). NFKBIA amplificationNKX2-1 amplification
53 Carcinoma unknown primary
KIF5B-RET fusion
Activating (S12). CDKN2A/B lossRICTOR amplificationTSC1 Q763*
54 Lung carcinosarcoma
KIF5B-RET fusion
Activating (S12). CDKN2A/B lossMYC amplificationTP53 I251N, S241Y
55 Ovarian epithelial carcinoma
KIF5B-RET fusion
Activating (S12). STK11 K84*
56 Lung adenocarcinoma
KIF5B-RET fusion
Activating (S12). TP53 R181C
57 Lung adenocarcinoma
CCDC6-RET fusion
Activating (S13). Not detected
58 Lung adenocarcinoma
CCDC6-RET fusion
Activating (S13). Not detected
59 Lung adenocarcinoma
CCDC6-RET fusion
Activating (S13). BRCA2 K3326*CDKN2A/B lossTP53 C242fs*5
60 Lung adenocarcinoma
CCDC6-RET fusion
Activating (S13). Not detected
61 Papillary thyroid carcinoma
SQSTM1-RET fusion
Unknown. Not detected
62 Sarcoma RET amplification
Activating. Not detected
63 Pancreatic ductal adenocarcinoma
RET amplification
Activating. BRAF N486_P490del JUN amplificationMCL1 amplificationTP53 C176G
64 Melanoma RET amplification
Activating. BRAF G469VCDKN2A R58*NF1 Q1070*RICTOR R1075QTP53 V218M
65 Breast carcinoma RET amplification
Activating. AURKA amplificationIRS2 amplificationMCL1 amplificationMYC amplificationPIK3CA amplificationSOX2 amplificationTP53 splice site 673-2A>G
66 Ovarian epithelial RET Activating. AURKA amplification8
carcinoma amplification BRCA1 S1253fs*10CCND2 amplificationCCNE1 amplificationCDK6 amplificationEGFR amplificationESR1 amplificationKDR amplificationKIT amplificationKRAS amplificationMCL1 amplificationMYC amplificationNRAS amplificationPDGFRA amplificationPIK3CA amplificationTP53 R273H
67 Lung adenocarcinoma
RET amplification
Activating. ATM R1150*, E277fs*37KRAS G13D MCL1 amplificationNFKBIA amplificationNKX2-1 amplification
68 Breast carcinoma RET amplification
Activating. CCNE1 amplificationLRP1B Q4392*PIK3CA H1047R PTEN LossTP53 A74fs*74
69 Fallopian tube adenocarcinoma
RET amplification
Activating. ESR1 amplificationFGFR3 amplificationTP53 S94*
70 Sarcoma RET amplification
Activating. CCNE1 amplificationNF1 L190*RB1 R251*TET2 R544*TP53 R248W, R175H
71 Uterine carcinosarcoma
RET amplification
Activating. FGFR2 N549K, amplificationNRAS amplificationTP53 C141Y
72 Head and neck squamous cell carcinoma (HNSCC)
RET amplification
Activating. LRP1B S1687*NF1 splice site 288+1G>T, splice site 1642-1G>TPTEN lossTET2 E81*TP53 splice site 560-1delG
73 Carcinoma unknown primary
RET amplification
Activating. JAK2 amplificationMCL1 amplificationMYC amplificationTP53 splice site 993+1G>A
74 Gastroesophageal junction carcinoma
RET amplification
Activating. CCNE1 amplificationCRKL amplificationSMAD4 lossTP53 C176F
75 Ovarian serous carcinoma
RET amplification
Activating. CRKL amplificationFGFR2 amplification
76 Salivary gland RET Activating. CDKN2A/B loss
9
adenocarcinoma amplification ERBB2 amplificationFANCA Y843*TP53 A84fs*39
77 Colorectal adenocarcinoma
RET amplification
Activating. APC R232*, E1295fs*8AURKA amplificationBRCA2 K3326*CCND1 amplificationCCND2 amplificationCCNE1 amplificationEMSY amplificationSRC amplificationTOP1 amplification TP53 splice site 782+1G>A
78 Prostate adenocarcinoma
RET amplification
Activating. ATM splice site 7933_8010+29delATAAATATTCCAGCAGACCAGCCAATTACTAAACTTAAGAATTTAGAAGATGTTGTTGTCCCTACTATGGAAATTAAGGTAATTTGCAATTAACTCTTGATTTTTTTBRAF-NUB1 fusionCDK6 amplificationCREBBP truncation, exon 31KMT2D rearrangement, intron 47PTEN lossTP53 Y220C
79 Duodenal adenocarcinoma
RET amplification
Activating. AKT2 amplificationCDKN2A M1fs*5MYC amplificationSMAD4 splice site 1308+1G>T TP53 H193L
80 Ovarian serous carcinoma
RET amplification
Activating. PTCH1 R571W TP53 R342*TSC2 truncation, exon 38
81 Bladder urothelial (transitional cell) carcinoma
RET amplification
Activating. CDKN2A/B lossFGFR1 amplificationMDM2 amplificationTP53 G105fs*18
82 Lung squamous cell carcinoma
RET amplification
Activating. FLT3 splice site 1310-1G>TNF1 H819fs*2NOTCH1 Y625*TP53 R249S
83 Lung adenocarcinoma
RET partial amplification
Unknown, possibly activating.
FGFR4 amplificationFLT4 amplificationPDGFRB amplification RICTOR amplification
84 Pancreatic ductal adenocarcinoma
RET rearrangement, intergenic
Unknown. BRCA1 G275D MCL1 amplificationMTOR L1460P
85 Lung adenocarcinoma
RET rearrangeme
Unknown. Not detected
10
nt, intron 1186 Lung
adenocarcinomaRET rearrangement, exon 11
Unknown. CDKN2A/B loss NF1 R1276Q
87 Uterine carcinosarcoma
RET duplication, intron 9-exon 17
Unknown. KRAS G12D TP53 V274F
88 Cutaneous squamous cell carcinoma
RET loss Inactivating. CDKN2A R58*TP53 F270L, Q192*TSC2 S1799*
11
Supplemental Table 4. List of 182 and 236 cancer-related genes.
Supplemental Table 4.A. List of 182 cancer-related genes (N=16).
12
Supplemental Table 4.B. List of 236 cancer-related genes (N=72).
13
Supplemental Table 5. RET aberrations reported in cBioPortal database (http://cbioportal.org)
cBioPortal Diagnosis
Number of cases reported
Any aberrations
N (%)
Fusion§
N (%)Mutation
N (%)Amplification
N (%)LossN (%)
All cBioPortal data 6011 181 (3.0) 28 (0.5) 109 (1.8) 23 (0.4) 19 (0.3)Cutaneous squamous cell carcinoma (DFCI, Clin Cancer Res 2015)
29 3 (10.3) 0 3 (10.3) 0 0
Skin Cutaneous Melanoma (TCGA, Provisional)
278 21 (7.6) 0 16 (5.8) 0 5 (1.8)
Bladder Urothelial Carcinoma (TCGA, Nature 2014)
127 9 (7.1) 0 5 (3.9) 3 (2.4) 1 (0.8)
Papillary Thyroid Carcinoma (TCGA, Cell 2014) ¶
399 23 (5.8) 21 (5.3) 0 0 0
Cholangiocarcinoma (TCGA, Provisional)
35 2 (5.7) 0 1 (2.9) 1 (2.9) 0
Uterine Corpus Endometrioid Carcinoma (TCGA, Nature 2013)
240 11 (4.6) 0 11 (4.6) 0 0
Small Cell Lung Cancer (U Cologne, Nature 2015) *
110 5 (4.5) 0 5 (4.5) 0 0
Lung Adenocarcinoma (TCGA, Nature 2014)
230 10 (4.3) 2 (0.9) 7 (3.0) 0 1 (0.4)
Poorly-Differentiated and Anaplastic Thyroid Cancers (MSKCC, JCI 2016)
117 5 (4.3) 5 (4.3) 0 0 0
Stomach Adenocarcinoma (TCGA, Nature 2014)
287 12 (4.2) 0 12 (4.2) 0 0
Pancreatic Adenocarcinoma (TCGA, Provisional)
145 6 (4.1) 0 5 (3.4) 1 (0.7) 0
Colorectal Adenocarcinoma (TCGA, Nature 2012)
212 8 (3.8) 0 8 (3.8) 0 0
Pheochromocytoma and Paraganglioma (TCGA, Provisional)
161 6 (3.7) 0 6 (3.7) 0 0
Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015)
279 10 (3.6) 0 8 (2.9) 1 (0.4) 1 (0.4)
Sarcoma (TCGA, Provisional)
240 7 (2.9) 0 2 (0.8) 2 (0.8) 3 (1.3)
Lung Squamous Cell Carcinoma (TCGA,
178 5 (2.8) 0 3 (1.7) 2 (1.1) 0
14
Nature 2012)Adrenocortical Carcinoma (TCGA, Provisional)
88 2 (2.3) 0 2 (2.3) 0 0
Esophageal Carcinoma (TCGA, Provisional)
184 4 (2.2) 0 0 3 (1.6) 1 (0.5)
Breast Invasive Carcinoma (TCGA, Cell 2015)
974 20 (2.1) 0 11 (1.1) 7 (0.7) 2 (0.2)
Prostate Adenocarcinoma (TCGA, Cell 2015)
333 6 (1.8) 0 1 (0.3) 1 (0.3) 4 (1.2)
Mesothelioma (TCGA, Provisional)
87 1 (1.1) 0 0 1 (1.1) 0
Liver Hepatocellular Carcinoma (TCGA, Provisional)
193 2 (1.0) 0 1 (0.5) 1 (0.5) 0
Glioblastoma (TCGA, Cell 2013)
281 2 (0.7) 0 1 (0.4) 0 1 (0.4)
Ovarian Serous Cystadenocarcinoma (TCGA, Nature 2011)
316 1 (0.3) 0 1 (0.3) 0 0
Uterine Carcinosarcoma (TCGA, Provisional)
56 0 0 0 0 0
Adenoid Cystic Carcinoma (MSKCC, Nat Genet 2013)
60 0 0 0 0 0
Clear Cell Renal Cell Carcinoma (U Tokyo, Nat Genet 2013) *
106 0 0 0 0 0
Esophageal Squamous Cell Carcinoma (UCLA, Nat Genet 2014) *
137 0 0 0 0 0
Gallbladder Carcinoma (Shanghai, Nat Genet 2014) *
32 0 0 0 0 0
Neuroblastoma (AMC Amsterdam, Nature 2012) *
87 0 0 0 0 0
Pancreatic Neuroendocrine Tumors (Johns Hopkins University, Science 2011) *
10 0 0 0 0 0
There was no reported case with duplication or rearrangement.§ Fusions without known fusion partner were also reported as fusion in cBioPortal. ¶ Among papillary Thyroid Carcinoma (TCGA, Cell 2014), there were 2 cases harboring both RET loss and fusion.* Data were available for mutation only.
15
Supplemental Table 6. Co-aberrant oncogenic pathways and the type of RET aberrations.
The term fusion was used when RET was rearranged with known fusion partner (e.g. KIF5B-RET).
16
RETAll
(N=88)Mutations
(N=34)Fusions *
(N=27)Amplification
(N=22)Cell cycle associated genes 35 (39.8%) 10 (29.4%) 13 (48.1%) 10 (45.5%)TP53-associated genes 52 (59.1%) 16 (47.1%) 15 (55.6%) 19 (86.4%)Tyrosine kinase families 19 (21.6%) 7 (20.6%) 2 (7.4%) 10 (45.5%)MAPK signaling pathway 20 (22.7%) 9 (26.5%) 0 (0%) 9 (40.9%)PI3K signaling pathway 27 (30.7%) 9 (26.5%) 7 (25.9%) 9 (40.9%)
Supplemental Table 7. Co-occurring aberrations associated with RET aberrations and examples of possible targeted therapies.
ID Co-occurring aberrations Possible targeted therapies 1 Not detected Not applicable.
2 Not detected Not applicable.
3 ARID1A F2141fs*59, Q1519fs*8NOTCH1 S2486fs*71+, S2329fs*7NRAS Q61RPIK3CA E545KPTEN D268fs*30, W274fs*2TP53 V157A, P152LTSC1 L203fs*7
ARID1A may be targetable with EZH2 inhibitor (EPZ-6438 *, NCT01897571) through a synthetic lethal mechanism (S14).
NOTCH1 may be targetable with a gamma-secretase inhibitor * (S15, 16).
RAS aberrations, including NRAS, have been challenging to target (S17). However, NRAS mutations are potentially targetable with a MEK inhibitor such as trametinib (S18).
PIK3CA and PTEN aberrations may be targetable with mTOR inhibitors such as everolimus (S19, 20).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
TSC1 aberrations are potentially targetable with mTOR inhibitors such as everolimus (S24).
4 ALK F1174C The ALK F1174C aberration has been associated with resistance to ALK inhibitors including crizotinib, ceritinib and alectinib. However, trials with third-generation ALK inhibitor such as lorlatinib (PF-06463922, NCT01970865) * are ongoing (S25).
5 ARID1A Q1334_R1335insQ BRAF V600ECDKN2A/B lossEMSY amplificationJAK2 amplificationPIK3CA H1047LTP53 R306*
ARID1A may be targetable with EZH2 inhibitor (EPZ-6438 *, NCT01897571) through a synthetic lethal mechanism (S14).
BRAF V600 mutation is targetable with vemurafenib and dabrafenib (S26, 27).
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this
17
aberration was not predictive of response (S29).
EMSY amplification abrogates BRCA2 function;, thus, it is potentially targetable with a PARP inhibitor (such as olaparib) or platinum (S30, 31).
JAK2 is targetable with ruxolitinib (S32).
PIK3CA may be targetable with mTOR inhibitors such as everolimus (S19, 20), or with PI3K inhibitors in clinical trials.
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
6 Not detected Not applicable.
7 ATM S978fs*12, L804fs*4 ATM aberrations are associated with defects in DNA double strand break repair. Thus, they are potentially targetable with a PARP inhibitor such as olaparib (S33).
8 Not detected Not applicable.
9 Not detected Not applicable.
10 DDR2 R806Q DDR2 aberration is targetable with dasatinib (S34).
11 Not detected Not applicable.
12 Not detected Not applicable.
13 APC D1033fs*4, R1450*ATM C1045fs*3, Q2277*KRAS G12C MCL1 amplificationMYC amplificationSMAD2 S464*
A preclinical study using an APC-mutated intestinal polyposis mouse model showed that treatment with a COX-2 inhibitor reduced the number of polyps (S35). Further investigation in a randomized clinical trial demonstrated that targeting COX-2 with celecoxib was effective for the prevention of colorectal adenomas (S36). Thus, APC aberration is potentially targetable with celecoxib.
ATM aberrations are associated with defects in DNA double strand break repair. Thus, they are potentially targetable with a PARP inhibitor such as olaparib (S33).
18
RAS mutations, including KRAS, have been challenging to target (S17). However, KRAS mutations are potentially targetable with a MEK inhibitor such as trametinib (S18).
In a preclinical model, sorafenib downregulated phospho-STAT3 and subsequently reduced the expression of MCL1, which led to the inhibition of tumor growth. Thus MCL1 amplification may be targetable with sorefenib (S37).
There is no therapy that directly targets MYC alterations. However, cell cycle checkpoints are associated with MYC synthetic lethal interactions and it is potentially targetable with an aurora kinase inhibitor (e.g. MLN8237 *) (S38) or CDK1 inhibitor (dinaciclib * [CDK1/2/5/9 inhibitor]) (S39). MYC is also known to induce a rapid increase in CDK4 and thus potentially targetable with CDK4/6 inhibitor, palbociclib. Additionally, BET inhibitors * are capable of downregulating MYC transcription (S40) (NCT01943851).
SMAD proteins are signal transducers and transcriptional modulators mediating multiple signaling pathways (S41). To our knowledge, there is no targeted therapy for SMAD2 aberrations.
14 CDKN2A/B lossCDKN2C lossNF2 L117fs*6
CDKN2A/B loss and CDKN2C loss are theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that these aberrations were not predictive of response (S29).
NF2 is a negative regulator of mTOR. Thus, it is potentially targetable with an mTOR inhibitor such as everolimus (S42, 43).
15 CDKN2A/B lossKIT S501_A502insAY
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
KIT aberrations may be targetable with imatinib (S44).
16 MYC amplification There is no therapy that directly targets MYC alterations. However, cell cycle checkpoints are associated with MYC synthetic lethal interactions and it is potentially targetable with an aurora kinase inhibitor (e.g. MLN8237 *) (S38) or CDK1 inhibitor (dinaciclib * [CDK1/2/5/9 inhibitor]) (S39). MYC is also known to induce a rapid increase in CDK4 and thus potentially targetable with CDK4/6 inhibitor, palbociclib. Additionally, BET inhibitors * are capable of downregulating MYC transcription (S40) (NCT01943851).
19
17 ARID1A P1325fs*146EPHB1 amplificationMSH6 K1358fs*2NF2 Q410*
ARID1A may be targetable with EZH2 inhibitor (EPZ-6438 *, NCT01897571) through a synthetic lethal mechanism (S14).
EPH is associated with tumor growth and progression (S45). EPH families may be targetable with a multi-kinase inhibitor that includes EPH inhibition such as MGCD516 * (NCT02219711).
Aberrations in mismatch repair machinery, including MSH6, result in high-level microsatellite instability which has been associated with significant response to anti-PD1 inhibitors such as pembrolizumab (S46).
NF2 is a negative regulator of mTOR. Thus, it is potentially targetable with an mTOR inhibitor such as everolimus (S42, 43).
18 KRAS amplificationPIK3CA amplificationSOX2 amplificationTP53 R248W
RAS mutations, including KRAS, have been challenging to target (S17). However, KRAS aberrations are potentially targetable with a MEK inhibitor such as trametinib (S18).
PIK3CA may be targetable with mTOR inhibitors such as everolimus (S19, 20), or with PI3K inhibitors in clinical trials.
SOX2 is a transcription factor associated with tumor initiation and progression (S47). To our knowledge, there is no targeted therapy for SOX2 aberrations.
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
19 FBXW7 R689Q Since FBXW7 targets mTOR for degradation, FBXW7 mutation may lead to increased mTOR signaling, which may be targetable with everolimus (S48).
20 Not detected Not applicable.
21 CDKN2A A76fs*70KRAS G12D PTCH1 T416STP53 Y220C
CDKN2A aberrations are theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that these aberrations were not predictive of response (S29).
20
RAS mutations, including KRAS, have been challenging to target (S17). However, KRAS mutations are potentially targetable with a MEK inhibitor such as trametinib (S18).
PTCH1 aberrations may be targetable with SMO inhibitors such as vismodegib (S49) or sonidegib (S50).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
22 CTNNB1 T41A RB1 R73fs*36TP53 R337fs*4
In a preclinical study using hepatocellular carcinoma cell lines, sorafenib was shown to inhibit Wnt/β-catenin signaling (S51). In addition, sulindac (NSAID) has been shown to suppress Wnt/β-catenin signaling in colon cancer cell line (S52). Since Notch is downstream of Wnt/β-catenin, Notch has also been implicated as a target for β-catenin dependent tumorigenesis (S53). Consistent with these preclinical data, sorafenib (S54), sulindac (S55) and a gamma-secretase inhibitor (PF-03084014 *) (S15) were all shown to have anti-tumor activity against patients with desmoid tumor, which is commonly associated with CTNNB1 mutation (S56). Moreover, CTNNB1 aberrations are potentially targetable with a β-catenin antagonist * that is currently in early phase clinical trial (CT02413853, NCT01764477).
RB1 is a tumor suppressor that regulates cell cycle progression. To our knowledge, there is no targeted therapy for RB1 aberrations.
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
23 KDR G1145E KDR aberration may be targeted with a VEGFR-2
21
PDGFRA E459KPIK3R1 G45*PTCH1 E237K, R770*TP53 R342*, S241P, R196*, Q317fs*21XPO1 E383K
inhibitor such as cabozantinib (S57).
PDGFR aberrations may be targeted with various multikinase inhibitors including imatinib (S58), dasatinib (S59) and sorafenib (S60).
PIK3R1 aberration is potentially targetable with an mTOR inhibitor such as everolimus (S61).
PTCH1 aberrations may be targetable with SMO inhibitors such as vismodegib (S49) or sonidegib (S50).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
XPO1 mediates the nuclear export of specific molecules including small nuclear RNA. To our knowledge, there is no targeted therapy for XPO1 aberrations.
24 CDKN2A R80*, T79TERBB2 S310FFGFR3 F384LNF1 A1670fs*11 TP53 S241F, P60fs*63
CDKN2A aberrations are theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that these aberrations were not predictive of response (S29).
ERBB2 aberrations may be targetable with lapatinib, trastuzumab, or afatinib (S62).
FGFR3 aberration is potentially targetable with pazopanib and ponatinib (S63).
NF1 encodes neurofibromin, which is a RAS-GTPase activating protein. Therefore, NF1 aberration is associated with RAS activation leading to MEK dependency. Thus, it may be targetable with MEK inhibitors including trametinib (S64).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0
22
versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
25 PTEN E40*, K267fs*9TP53 I254V
PTEN aberrations may be targetable with mTOR inhibitors such as everolimus (S19, 20).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
26 CCNE1 amplification MCL1 amplificationMYC amplificationTP53 L206fs*3, K132_A138del, loss exon 2
A synthetic lethal screen showed that CCNE1 amplified cells required the ubiquitin pathway and were sensitive to the proteasome inhibitor bortezomib (S65).
In a preclinical model, sorafenib downregulated phospho-STAT3 and subsequently reduced the expression of MCL1, which led to the inhibition of tumor growth. Thus MCL1 amplification may be targetable with sorefenib (S37).
There is no therapy that directly targets MYC alterations. However, cell cycle checkpoints are associated with MYC synthetic lethal interactions and it is potentially targetable with an aurora kinase inhibitor (e.g. MLN8237 *) (S38) or CDK1 inhibitor (dinaciclib * [CDK1/2/5/9 inhibitor]) (S39). MYC is also known to induce a rapid increase in CDK4 and thus potentially targetable with CDK4/6 inhibitor, palbociclib. Additionally, BET inhibitors * are capable of downregulating MYC transcription (S40) (NCT01943851).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
27 CDKN2A P11fs*15CEBPA L155fs*10
CDKN2A aberrations are theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28);
23
KRAS G12DTP53 R158L
however, some publications indicate that these aberrations were not predictive of response (S29).
CEBPA encodes CCAAT/enhancer-binding protein-alpha, which functions as a tumor suppressor (S66). To our knowledge, there is no targeted therapy for CEBPA aberrations.
RAS mutations, including KRAS, have been challenging to target (S17). However, KRAS mutations are potentially targetable with a MEK inhibitor such as trametinib (S18).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
28 PIK3CA H1047RSMARCA4 splice site 760+1G>A
PIK3CA may be targetable with mTOR inhibitors such as everolimus (S19, 20), or with PI3K inhibitors in clinical trials.
SMARCA4 encodes a subunit of the SWI/SNF chromatin-remodeling complex. A preclinical study suggests BRM as a candidate target for synthetic lethal therapy (S67). However, to our knowledge, there is no direct targeted therapy for SMARCA4 aberrations.
29 BCL2L2 amplificationCCND1 amplificationCCND2 G268RCDKN2A/B lossFGFR1 amplificationFGFR3 amplificationMDM2 amplificationMYC amplificationTP53 R280T, M246I
BCL2L2 amplification may be targetable with a BCL-2 family inhibitor such as ABT-263 * (navitoclax) that is in clinical development (NCT02143401) (S68) or venetoclax (approved in CLL).
CCND1/2 aberrations as well as CDKN2A/B loss are theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that these aberrations were not predictive of response (S29).
FGFR aberrations are potentially targetable with pazopanib and ponatinib (S63).
MDM2 amplification may be targetable with an MDM2 inhibitor that is currently in clinical trials (DS-3032b *: NCT01877382 and ALRN-6924 *: NCT02264613).
24
There is no therapy that directly targets MYC alterations. However, cell cycle checkpoints are associated with MYC synthetic lethal interactions and it is potentially targetable with an aurora kinase inhibitor (e.g. MLN8237 *) (S38) or CDK1 inhibitor (dinaciclib * [CDK1/2/5/9 inhibitor]) (S39). MYC is also known to induce a rapid increase in CDK4 and thus potentially targetable with CDK4/6 inhibitor, palbociclib. Additionally, BET inhibitors * are capable of downregulating MYC transcription (S40) (NCT01943851).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
30 RB1 loss RB1 is a tumor suppressor that regulates cell cycle progression. To our knowledge, there is no targeted therapy for RB1 aberrations.
31 APC S1214fs*51ARID1A Q1334_R1335insQ TP53 C176F
A preclinical study using an APC-mutated intestinal polyposis mouse model showed that treatment with a COX-2 inhibitor reduced the number of polyps (S35). Further investigation in a randomized clinical trial demonstrated that targeting COX-2 with celecoxib was effective for the prevention of colorectal adenomas (S36). Thus, APC aberration is potentially targetable with celecoxib. ARID1A may be targetable with EZH2 inhibitor (EPZ-6438 *, NCT01897571) through a synthetic lethal mechanism (S14).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
32 KRAS G12RTP53 M237I
RAS mutations, including KRAS, have been challenging to target (S17). However, KRAS mutations are potentially targetable with a MEK inhibitor such as trametinib (S18).
25
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
33 PIK3CA E545K, amplificationSOX2 amplification
PIK3CA may be targetable with mTOR inhibitors such as everolimus (S19, 20), or with PI3K inhibitors in clinical trials.
SOX2 is a transcription factor associated with tumor initiation and progression (S47). To our knowledge, there is no targeted therapy for SOX2 aberrations.
34 CCND1 amplificationCDH1 R63*CDKN2A lossKRAS amplificationMITF amplificationMYC amplificationNKX2-1 amplificationTP53 C176Y
CCND1 amplification and CDKN2A loss are theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that these aberrations were not predictive of response (S29).
CDH1 aberration is associated with hereditary diffuse gastric cancer (S69). However, to our knowledge, there is no therapy targeting CDH1 aberrations.
RAS aberrations, including KRAS, have been challenging to target (S17). However, KRAS aberrations are potentially targetable with a MEK inhibitor such as trametinib (S18).
MITF is a transcription factor that regulates cell differentiation and development (S70). To our knowledge, there is no targeted therapy for MITF amplification.
There is no therapy that directly targets MYC alterations. However, cell cycle checkpoints are associated with MYC synthetic lethal interactions and it is potentially targetable with an aurora kinase inhibitor (e.g. MLN8237 *) (S38) or CDK1 inhibitor (dinaciclib * [CDK1/2/5/9 inhibitor]) (S39). MYC is also known to induce a rapid increase in CDK4 and thus potentially targetable with CDK4/6 inhibitor, palbociclib. Additionally, BET inhibitors * are capable of downregulating MYC transcription (S40) (NCT01943851).
NKX2-1 is a transcription factor that can have both
26
oncogenic and tumor suppressive functions in cancer (S71). To our knowledge, there is no targeted therapy for NKX2-1 amplification.
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
35 CDKN2A/B loss CTNNB1 S33C
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
In a preclinical study using hepatocellular carcinoma cell lines, sorafenib was shown to inhibit Wnt/β-catenin signaling (S51). In addition, sulindac (NSAID) has been shown to suppress Wnt/β-catenin signaling in colon cancer cell line (S52). Since Notch is downstream of Wnt/β-catenin, Notch has also been implicated as a target for β-catenin dependent tumorigenesis (S53). Consistent with these preclinical data, sorafenib (S54), sulindac (S55) and a gamma-secretase inhibitor (PF-03084014 *) (S15) were all shown to have anti-tumor activity against patients with desmoid tumor, which is commonly associated with CTNNB1 mutation (S56). Moreover, CTNNB1 aberrations are potentially targetable with a β-catenin antagonist * that is currently in early phase clinical trial (CT02413853, NCT01764477).
36 ARID1A truncation, exon EGFR amplificationFBXW7 W446fs*25MSH2 N924fs*1TP53 R209fs*6
ARID1A may be targetable with EZH2 inhibitor (EPZ-6438 *, NCT01897571) through a synthetic lethal mechanism (S14).
EGFR amplification may be targetable with anti-EGFR therapy such as cetuximab or panitumumab (S72).
Since FBXW7 targets mTOR for degradation, FBXW7 mutation may lead to increased mTOR signaling, which may be targetable with everolimus (S48).
Aberrations in mismatch repair machinery, including MSH2, result in high-level microsatellite instability which has been associated with significant response to anti-PD1 inhibitors such as
27
pembrolizumab (S46).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
37 Not detected Not applicable.
38 Not detected Not applicable.
39 RB1 deletion, exons 13-21STK11 lossTP53 R248L
RB1 is a tumor suppressor that regulates cell cycle progression. To our knowledge, there is no targeted therapy for RB1 aberrations.
STK11 activates adenine monophosphate (AMP)-activation protein kinase which leads to inhibition of mTOR. Thus, loss of STK11 leads to increased mTOR signaling and may be targetable with everolimus (S73).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
40 MCL1 amplification RB1 deletion, exons 13-21TP53 R248L
In a preclinical model, sorafenib downregulated phospho-STAT3 and subsequently reduced the expression of MCL1, which led to the inhibition of tumor growth. Thus MCL1 amplification may be targetable with sorefenib (S37).
RB1 is a tumor suppressor that regulates cell cycle progression. To our knowledge, there is no targeted therapy for RB1 aberrations.
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-
28
bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
41 RB1 lossSTK11 lossTP53 R248L
RB1 is a tumor suppressor that regulates cell cycle progression. To our knowledge, there is no targeted therapy for RB1 aberrations.
STK11 activates adenine monophosphate (AMP)-activation protein kinase which leads to inhibition of mTOR. Thus, loss of STK11 leads to increased mTOR signaling and may be targetable with everolimus (S73).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
42 RPTOR amplificationTP53 E68*
Raptor is potentially targetable with everolimus (mTORC1 inhibitor). However, mTORC1 inhibition alone can lead to increased AKT signaling through rictor (part of mTORC2) (S74). Thus inhibition of both mTORC1/2 with a dual inhibitor such as MLN0128 * that is currently in clinical trial may be suitable for targeting RPTOR amplification (NCT01899053).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
43 CDKN2A/B loss FGFR1 amplificationMDM2 amplificationPIK3CA amplification
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
FGFR1 amplification is potentially targetable with pazopanib and ponatinib (S63).
29
MDM2 amplification may be targetable with an MDM2 inhibitor that is currently in clinical trials (DS-3032b *: NCT01877382 and ALRN-6924 *: NCT02264613).
PIK3CA may be targetable with mTOR inhibitors such as everolimus (S19, 20), or with PI3K inhibitors in clinical trials.
44 MDM2 amplification MDM2 amplification may be targetable with an MDM2 inhibitor that is currently in clinical trials (DS-3032b *: NCT01877382 and ALRN-6924 *: NCT02264613).
45 RB1 deletion, intron 12-exon 21STK11 lossTP53 R248L
RB1 is a tumor suppressor that regulates cell cycle progression. To our knowledge, there is no targeted therapy for RB1 aberrations.
STK11 activates adenine monophosphate (AMP)-activation protein kinase which leads to inhibition of mTOR. Thus, loss of STK11 leads to increased mTOR signaling and may be targetable with everolimus (S73).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
46 BRCA2 T1354MMYC amplification
BRCA2 mutations may be targetable with a PARP inhibitor, such as olaparib (S75).
There is no therapy that directly targets MYC alterations. However, cell cycle checkpoints are associated with MYC synthetic lethal interactions and it is potentially targetable with an aurora kinase inhibitor (e.g. MLN8237 *) (S38) or CDK1 inhibitor (dinaciclib * [CDK1/2/5/9 inhibitor]) (S39). MYC is also known to induce a rapid increase in CDK4 and thus potentially targetable with CDK4/6 inhibitor, palbociclib. Additionally, BET inhibitors * are capable of downregulating MYC transcription (S40) (NCT01943851).
47 CDKN2A/B loss CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
48 NOTCH1 lossTP53 E68*
Although NOTCH1 may be targetable with gamma-secretase inhibitor * (S15, 16), to our knowledge, loss of NOTCH1 is not targetable.
30
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
49 APC truncation, exon 6ARFRP1 amplificationAURKA amplificationCDKN2A/B lossTP53 Q165*
A preclinical study using an APC-mutated intestinal polyposis mouse model showed that treatment with a COX-2 inhibitor reduced the number of polyps (S35). Further investigation in a randomized clinical trial demonstrated that targeting COX-2 with celecoxib was effective for the prevention of colorectal adenomas (S36). Thus, APC aberration is potentially targetable with celecoxib.
ADP-ribosylation factor related protein 1 (ARFRP1) encodes a protein that functions as a GTP-ase. To our knowledge, there is no targeted therapy for ARFRP1 amplification.
AURKA amplification may be targetable with aurora kinase inhibitors, such as alisertib, * that are in clinical trials (NCT02187991) (S76).
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
50 APC I1307KCDKN2A/B lossTP53 S241T, C135F
A preclinical study using an APC-mutated intestinal polyposis mouse model showed that treatment with a COX-2 inhibitor reduced the number of polyps (S35). Further investigation in a randomized clinical trial demonstrated that targeting COX-2 with celecoxib was effective for the prevention of colorectal adenomas (S36). Thus, APC aberration is potentially targetable with celecoxib.
31
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
51 CDKN2A/B lossMDM2 amplification
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
MDM2 amplification may be targetable with an MDM2 inhibitor that is currently in clinical trials (DS-3032b *: NCT01877382 and ALRN-6924 *: NCT02264613).
52 NFKBIA amplificationNKX2-1 amplification
NFKBIA amplification is potentially targetable with a proteasome inhibitor, such as bortezomib (S77).
NKX2-1 is a transcription factor that can have both oncogenic and tumor suppressive functions in cancer (S71). To our knowledge, there is no targeted therapy for NKX2-1 amplification.
53 CDKN2A/B lossRICTOR amplificationTSC1 Q763*
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
Rictor, which is a part of mTORC2, is targetable with a dual mTORC1/2 inhibitor such as MLN0128 *, which is currently in clinical trials (NCT01899053).
TSC1 aberrations are potentially targetable with mTOR inhibitors such as everolimus (S24).
54 CDKN2A/B lossMYC amplificationTP53 I251N, S241Y
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
There is no therapy that directly targets MYC alterations. However, cell cycle checkpoints are associated with MYC synthetic lethal interactions and it is potentially targetable with an aurora
32
kinase inhibitor (e.g. MLN8237 *) (S38) or CDK1 inhibitor (dinaciclib * [CDK1/2/5/9 inhibitor]) (S39). MYC is also known to induce a rapid increase in CDK4 and thus potentially targetable with CDK4/6 inhibitor, palbociclib. Additionally, BET inhibitors * are capable of downregulating MYC transcription (S40) (NCT01943851).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
55 STK11 K84* STK11 activates adenine monophosphate (AMP)-activation protein kinase which leads to inhibition of mTOR. Thus, loss of STK11 leads to increased mTOR signaling and may be targetable with everolimus (S73).
56 TP53 R181C TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
57 Not detected Not applicable.
58 Not detected Not applicable.
59 BRCA2 K3326*CDKN2A/B lossTP53 C242fs*5
BRCA2 mutations may be targetable with a PARP inhibitor, such as olaparib (S75).
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0
33
versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
60 Not detected Not applicable.
61 Not detected Not applicable.
62 Not detected Not applicable.
63 BRAF N486_P490del JUN amplificationMCL1 amplificationTP53 C176G
Although BRAF V600 mutations are targetable with BRAF inhibitors (e.g. vemurafenib) (S78), the functional effect of BRAF N486_P490del is unknown. Low-activity BRAF mutations may activate the MEK pathway via RAF1 activation, and may therefore be targetable with MEK inhibitors. Although the functional significance of BRAF N486_P490del is unknown (S79), it is worth targeting in the clinical trial setting.
c-JUN is a component of a transcription factor that plays an important role in carcinogenesis and cancer progression (S80). However, to our knowledge, there is no targeted therapy for JUN amplification.
In a preclinical model, sorafenib downregulated phospho-STAT3 and subsequently reduced the expression of MCL1, which led to the inhibition of tumor growth. Thus MCL1 amplification may be targetable with sorefenib (S37).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
64 BRAF G469VCDKN2A R58*NF1 Q1070*RICTOR R1075QTP53 V218M
Although BRAF V600 mutations are targetable with BRAF inhibitors (e.g. vemurafenib) (S78), the functional effect of BRAF G469V is unknown. Low-activity BRAF mutations may activate the MEK pathway via RAF1 activation, and may therefore be targetable with MEK inhibitors. Although the functional significance of BRAF G469V is unknown (S79), it is worth targeting in the clinical trial setting.
CDKN2A aberrations are theoretically targetable
34
with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that these aberrations were not predictive of response (S29).
NF1 encodes neurofibromin, which is a RAS-GTPase activating protein. Therefore, NF1 aberration is associated with RAS activation leading to MEK dependency. Thus, it may be targetable with MEK inhibitors including trametinib (S64).
Rictor, which is a part of mTORC2, is targetable with a dual mTORC1/2 inhibitor such as MLN0128 *, which is currently in clinical trials (NCT01899053).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
65 AURKA amplificationIRS2 amplificationMCL1 amplificationMYC amplificationPIK3CA amplificationSOX2 amplificationTP53 splice site 673-2A>G
AURKA amplification may be targetable with aurora kinase inhibitors, such as alisertib, * that are in clinical trials (NCT02187991) (S76).
IRS2 is a cytoplasmic adapter protein that docks to IGFR and is capable of activating the phosphoinositide 3-kinase (PI3K) pathway (S81). Consistent with this functional role of IRS2, one patient with advanced breast cancer harboring IRS2 amplification experienced a complete response with everolimus containing regimen (S82).
In a preclinical model, sorafenib downregulated phospho-STAT3 and subsequently reduced the expression of MCL1, which led to the inhibition of tumor growth. Thus MCL1 amplification may be targetable with sorefenib (S37).
There is no therapy that directly targets MYC alterations. However, cell cycle checkpoints are associated with MYC synthetic lethal interactions and it is potentially targetable with an aurora kinase inhibitor (e.g. MLN8237 *) (S38) or CDK1 inhibitor (dinaciclib * [CDK1/2/5/9 inhibitor]) (S39). MYC is also known to induce a rapid increase in CDK4 and thus potentially targetable with CDK4/6
35
inhibitor, palbociclib. Additionally, BET inhibitors * are capable of downregulating MYC transcription (S40) (NCT01943851).
PIK3CA may be targetable with mTOR inhibitors such as everolimus (S19, 20), or with PI3K inhibitors in clinical trials.
SOX2 is a transcription factor associated with tumor initiation and progression (S47). To our knowledge, there is no targeted therapy for SOX2 aberrations.
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
66 AURKA amplificationBRCA1 S1253fs*10CCND2 amplificationCCNE1 amplificationCDK6 amplificationEGFR amplificationESR1 amplificationKDR amplificationKIT amplificationKRAS amplificationMCL1 amplificationMYC amplificationNRAS amplificationPDGFRA amplificationPIK3CA amplificationTP53 R273H
AURKA amplification may be targetable with aurora kinase inhibitors, such as alisertib, * that are in clinical trials (NCT02187991) (S76).
BRCA1 mutations may be targetable with a PARP inhibitor, such as olaparib (S75).
CCND2 and CDK6 amplification are theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that these aberrations were not predictive of response (S29).
A synthetic lethal screen showed that CCNE1 amplified cells required the ubiquitin pathway and were sensitive to the proteasome inhibitor bortezomib (S65).
EGFR amplification may be targetable with anti-EGFR therapy such as cetuximab or panitumumab (S72).
ESR1 amplification may be targetable with anti-estrogen such as tamoxifen (S83).
KDR amplification may be targeted with a VEGFR-2 inhibitor such as cabozantinib (S57).
KIT amplification may be targetable with imatinib (S44).
36
RAS mutations, including NRAS and KRAS, have been challenging to target (S17). However, NRAS and KRAS mutations are potentially targetable with a MEK inhibitor such as trametinib (S18).
In a preclinical model, sorafenib downregulated phospho-STAT3 and subsequently reduced the expression of MCL1, which led to the inhibition of tumor growth. Thus MCL1 amplification may be targetable with sorefenib (S37).
There is no therapy that directly targets MYC alterations. However, cell cycle checkpoints are associated with MYC synthetic lethal interactions and it is potentially targetable with an aurora kinase inhibitor (e.g. MLN8237 *) (S38) or CDK1 inhibitor (dinaciclib * [CDK1/2/5/9 inhibitor]) (S39). MYC is also known to induce a rapid increase in CDK4 and thus potentially targetable with CDK4/6 inhibitor, palbociclib. Additionally, BET inhibitors * are capable of downregulating MYC transcription (S40) (NCT01943851).
PDGFR aberrations may be targeted with various multikinase inhibitors including imatinib (S58), dasatinib (S59) and sorafenib (S60).
PIK3CA may be targetable with mTOR inhibitors such as everolimus (S19, 20), or with PI3K inhibitors in clinical trials.
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
Hypermutated tumors, as in this case with 17 aberrations (including RET), may benefit from immune checkpoint inhibitors such as pembrolizumab (S84).
67 ATM R1150*, E277fs*37KRAS G13D MCL1 amplificationNFKBIA amplificationNKX2-1 amplification
ATM aberrations are associated with defects in DNA double strand break repair. Thus, they are potentially targetable with a PARP inhibitor such as olaparib (S33).
RAS mutations, including KRAS, have been
37
challenging to target (S17). However, KRAS mutations are potentially targetable with a MEK inhibitor such as trametinib (S18).
In a preclinical model, sorafenib downregulated phospho-STAT3 and subsequently reduced the expression of MCL1, which led to the inhibition of tumor growth. Thus MCL1 amplification may be targetable with sorefenib (S37).
NFKBIA amplification is potentially targetable with a proteasome inhibitor, such as bortezomib (S77).
NKX2-1 is a transcription factor that can have both oncogenic and tumor suppressive functions in cancer (S71). To our knowledge, there is no targeted therapy for NKX2-1 amplification.
68 CCNE1 amplificationLRP1B Q4392*PIK3CA H1047R PTEN LossTP53 A74fs*74
A synthetic lethal screen showed that CCNE1 amplified cells required the ubiquitin pathway and were sensitive to the proteasome inhibitor bortezomib (S65).
LRP1B is a tumor suppressor that is associated with chemotherapy resistance (S85). However, to our knowledge, there is no targeted therapy for LRP1B aberrations.
PIK3CA mutations and PTEN loss may be targetable with mTOR inhibitors such as everolimus (S19, 20), or with PI3K inhibitors in clinical trials.
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
69 ESR1 amplificationFGFR3 amplificationTP53 S94*
ESR1 amplification may be targetable with anti-estrogen such as tamoxifen (S83).
FGFR3 amplification is potentially targetable with pazopanib and ponatinib (S63).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-
38
containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
70 CCNE1 amplificationNF1 L190*RB1 R251*TET2 R544*TP53 R248W, R175H
A synthetic lethal screen showed that CCNE1 amplified cells required the ubiquitin pathway and were sensitive to the proteasome inhibitor bortezomib (S65).
NF1 encodes neurofibromin, which is a RAS-GTPase activating protein. Therefore, NF1 aberration is associated with RAS activation leading to MEK dependency. Thus, it may be targetable with MEK inhibitors including trametinib (S64).
RB1 is a tumor suppressor that regulates cell cycle progression. To our knowledge, there is no targeted therapy for RB1 aberrations.
TET2 is a tumor suppressor gene that is associated with myeloid cancers (S86). The use of DNA methyltransferase (DNMT) inhibitors is one strategy under investigation to address inactivating mutation or loss of TET2 in human cancer (S86).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
71 FGFR2 N549K, amplificationNRAS amplificationTP53 C141Y
FGFR2 aberrations are potentially targetable with pazopanib and ponatinib (S63).
RAS aberrations, including NRAS, have been challenging to target (S17). However, NRAS mutations are potentially targetable with a MEK inhibitor such as trametinib (S18).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0
39
versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
72 LRP1B S1687*NF1 splice site 288+1G>T, splice site 1642-1G>TPTEN lossTET2 E81*TP53 splice site 560-1delG
LRP1B is a tumor suppressor that is associated with chemotherapy resistance (S85). However, to our knowledge, there is no targeted therapy for LRP1B aberrations.
NF1 encodes neurofibromin, which is a RAS-GTPase activating protein. Therefore, NF1 aberration is associated with RAS activation leading to MEK dependency. Thus, it may be targetable with MEK inhibitors including trametinib (S64).
PTEN aberrations may be targetable with mTOR inhibitors such as everolimus (S19, 20).
TET2 is a tumor suppressor gene that is associated with myeloid cancers (S86). The use of DNA methyltransferase (DNMT) inhibitors is one strategy under investigation to address inactivating mutation or loss of TET2 in human cancer (S86).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
73 JAK2 amplificationMCL1 amplificationMYC amplificationTP53 splice site 993+1G>A
JAK2 is targetable with ruxolitinib (S32).
In a preclinical model, sorafenib downregulated phospho-STAT3 and subsequently reduced the expression of MCL1, which led to the inhibition of tumor growth. Thus MCL1 amplification may be targetable with sorefenib (S37).
There is no therapy that directly targets MYC alterations. However, cell cycle checkpoints are associated with MYC synthetic lethal interactions and it is potentially targetable with an aurora kinase inhibitor (e.g. MLN8237 *) (S38) or CDK1 inhibitor (dinaciclib * [CDK1/2/5/9 inhibitor]) (S39). MYC is also known to induce a rapid increase in CDK4 and thus potentially targetable with CDK4/6 inhibitor, palbociclib. Additionally, BET inhibitors * are capable of downregulating MYC transcription
40
(S40) (NCT01943851).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
74 CCNE1 amplificationCRKL amplificationSMAD4 lossTP53 C176F
A synthetic lethal screen showed that CCNE1 amplified cells required the ubiquitin pathway and were sensitive to the proteasome inhibitor bortezomib (S65).
CRKL encodes an adaptor protein of BCR-ABL kinase, functioning in signaling transduction (S87). However, to our knowledge, there is no targeted therapy for CRKL aberration.
SMAD proteins are signal transducers and transcriptional modulators mediating multiple signaling pathways (S41). To our knowledge, there is no targeted therapy for SMAD4 aberrations.
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
75 CRKL amplificationFGFR2 amplification
CRKL encodes an adaptor protein of BCR-ABL kinase, functioning in signaling transduction (S87). However, to our knowledge, there is no targeted therapy for CRKL aberration.
FGFR2 aberrations are potentially targetable with pazopanib and ponatinib (S63).
76 CDKN2A/B lossERBB2 amplificationFANCA Y843*TP53 A84fs*39
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
ERBB2 aberrations may be targetable with lapatinib, trastuzumab, or afatinib (S62).
41
FANCA is a Fanconi’s anemia gene, which functions in DNA repair. FANCA aberrations are potentially targetable with PARP inhibitors such as olaparib (S88).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
77 APC R232*, E1295fs*8AURKA amplificationBRCA2 K3326*CCND1 amplificationCCND2 amplificationCCNE1 amplificationEMSY amplificationSRC amplificationTOP1 amplification TP53 splice site 782+1G>A
A preclinical study using an APC-mutated intestinal polyposis mouse model showed that treatment with a COX-2 inhibitor reduced the number of polyps (S35). Further investigation in a randomized clinical trial demonstrated that targeting COX-2 with celecoxib was effective for the prevention of colorectal adenomas (S36). Thus, APC aberration is potentially targetable with celecoxib.
AURKA amplification may be targetable with aurora kinase inhibitors, such as alisertib, * that are in clinical trials (NCT02187991) (S76).
BRCA2 mutations may be targetable with a PARP inhibitor, such as olaparib (S75).
CCND1/2 amplification are theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that these aberrations were not predictive of response (S29).
A synthetic lethal screen showed that CCNE1 amplified cells required the ubiquitin pathway and were sensitive to the proteasome inhibitor bortezomib (S65).
EMSY amplification abrogates BRCA2 function;, thus, it is potentially targetable with a PARP inhibitor (such as olaparib) or platinum (S30, 31).
SRC amplification may be targetable with dasatinib (S89).
TPO1 amplification is potentially targetable with a topoisomerase I inhibitor such as topotecan (S90).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21).
42
Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
Hypermutated tumors, as in this case with 12 aberrations (including RET), may benefit from immune checkpoint inhibitors such as pembrolizumab (S84).
78 ATM splice site 7933_8010+29delATAAATATTCCAGCAGACCAGCCAATTACTAAACTTAAGAATTTAGAAGATGTTGTTGTCCCTACTATGGAAATTAAGGTAATTTGCAATTAACTCTTGATTTTTTTBRAF-NUB1 fusionCDK6 amplificationCREBBP truncation, exon 31KMT2D rearrangement, intron 47PTEN lossTP53 Y220C
ATM aberrations are associated with defects in DNA double strand break repair. Thus, they are potentially targetable with a PARP inhibitor such as olaparib (S33).
BRAF fusions may be targetable with a MEK inhibitor such as trametinib (S91).
CDK6 amplification is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
CREB binding protein has histone acetyltransferase activity. CREBBP aberration is potentially targetable with histone deacetylase inhibitors such as vorinostat (S92).
KMT2D encodes a lysine-specific methyltransferase 2D that functions as a histone methyltransferase. To our knowledge, there is no targeted therapy for KMT2D aberration.
PTEN aberrations may be targetable with mTOR inhibitors such as everolimus (S19, 20).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
79 AKT2 amplificationCDKN2A M1fs*5MYC amplification
AKT amplification may be targetable with mTOR inhibitors such as everolimus or with Akt inhibitors in clinical trials (S19, 20).
43
SMAD4 splice site 1308+1G>T TP53 H193L CDKN2A aberrations are theoretically targetable
with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
There is no therapy that directly targets MYC alterations. However, cell cycle checkpoints are associated with MYC synthetic lethal interactions and it is potentially targetable with an aurora kinase inhibitor (e.g. MLN8237 *) (S38) or CDK1 inhibitor (dinaciclib * [CDK1/2/5/9 inhibitor]) (S39). MYC is also known to induce a rapid increase in CDK4 and thus potentially targetable with CDK4/6 inhibitor, palbociclib. Additionally, BET inhibitors * are capable of downregulating MYC transcription (S40) (NCT01943851).
SMAD proteins are signal transducers and transcriptional modulators mediating multiple signaling pathways (S41). To our knowledge, there is no targeted therapy for SMAD4 aberrations.
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
80 PTCH1 R571W TP53 R342*TSC2 truncation, exon 38
PTCH1 aberrations may be targetable with SMO inhibitors such as vismodegib (S49) or sonidegib (S50).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
TSC2 aberrations are potentially targetable with mTOR inhibitors such as everolimus (S24).
81 CDKN2A/B lossFGFR1 amplification
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28);
44
MDM2 amplificationTP53 G105fs*18
however, some publications indicate that this aberration was not predictive of response (S29).
FGFR aberrations are potentially targetable with pazopanib and ponatinib (S63).
MDM2 amplification may be targetable with an MDM2 inhibitor that is currently in clinical trials (DS-3032b *: NCT01877382 and ALRN-6924 *: NCT02264613).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
82 FLT3 splice site 1310-1G>TNF1 H819fs*2NOTCH1 Y625*TP53 R249S
FLT3 aberration is potentially targetable with sorafenib (S93).
NF1 encodes neurofibromin, which is a RAS-GTPase activating protein. Therefore, NF1 aberration is associated with RAS activation leading to MEK dependency. Thus, it may be targetable with MEK inhibitors including trametinib (S64).
NOTCH1 may be targetable with a gamma-secretase inhibitor * (S15, 16).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
83 FGFR4 amplificationFLT4 amplificationPDGFRB amplification RICTOR amplification
FGFR4 aberration is potentially targetable with ponatinib (S63).
FLT4 amplification is potentially targetable with VEGFR3 inhibitors such as sorafenib, pazopanib and sunitinib (S94).
PDGFRB amplification may be targetable with
45
imatinib (S95), dasatinib (S96) and sorafenib (S97).
Rictor, which is a part of mTORC2, is targetable with a dual mTORC1/2 inhibitor such as MLN0128 *, which is currently in clinical trials (NCT01899053).
84 BRCA1 G275D MCL1 amplificationMTOR L1460P
BRCA1 mutations may be targetable with a PARP inhibitor, such as olaparib (S75).
In a preclinical model, sorafenib downregulated phospho-STAT3 and subsequently reduced the expression of MCL1, which led to the inhibition of tumor growth. Thus MCL1 amplification may be targetable with sorefenib (S37).
MTOR aberration is targetable with everolimus (S98).
85 Not detected Not applicable.
86 CDKN2A/B loss NF1 R1276Q
CDKN2A/B loss is theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
NF1 encodes neurofibromin, which is a RAS-GTPase activating protein. Therefore, NF1 aberration is associated with RAS activation leading to MEK dependency. Thus, it may be targetable with MEK inhibitors including trametinib (S64).
87 KRAS G12D TP53 V274F
RAS mutations, including KRAS, have been challenging to target (S17). However, KRAS mutations are potentially targetable with a MEK inhibitor such as trametinib (S18).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21). Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
88 CDKN2A R58*TP53 F270L, Q192*TSC2 S1799*
CDKN2A aberrations are theoretically targetable with a CDK4/6 inhibitor such as palbociclib (S28); however, some publications indicate that this aberration was not predictive of response (S29).
TP53 mutations are reported to be associated with higher VEGF-A expression (p = 0.006) (S21).
46
Consistent with this association, retrospective data suggest that patients with TP53 mutations had longer progression-free survival with bevacizumab-containing regimens as compared to non-bevacizumab-containing regimens (median 11.0 versus 4.0 months [p < 0.0001]) (S22). In addition, TP53 may be targetable with a WEE1 inhibitor that is currently under clinical investigation (AZ1775 *, NCT01748825) (S23).
TSC2 aberrations are potentially targetable with mTOR inhibitors such as everolimus (S24).
* Therapies currently on clinical trial.
47
SUPPLEMENTAL FIGURE LEGEND
Supplemental Figure 1. Comparison of RET aberrations between current report and cBioPortal.
From current report, diagnoses with RET aberrations were included in figure when RET was aberrant in ≥ 5% of cases and if at least 5 cancer diagnosis were tested for the aberration (Table 1).
From cBioPortal, all diagnoses with RET aberrations were included in the figure when RET was aberrant in ≥ 5% of cases (Supplemental Table 4).
In addition, when available, corresponding cancer diagnoses from both reports were included for comparison.
Cancer diagnosis with uterine carcinosarcoma, papillary thyroid carcinoma, ovarian epithelial carcinoma, lung adenocarcinoma, cutaneous squamous cell carcinoma, melanoma, bladder urothelial carcinoma and cholangiocarcinoma were available for direct comparison between current report and cBioPortal.
The following diagnoses were not available from cBioPortal dataset for the direct comparison with current report;
Medullary thyroid carcinoma Anaplastic thyroid carcinoma Lung carcinosarcoma Ureter urothelial carcinoma Basal cell carcinoma Merkel cell carcinoma Atypical lung carcinoid Fallopian tube adenocarcinoma Salivary gland adenocarcinoma Meningioma Duodenal adenocarcinoma
Papillary thyroid carcinoma from cBioPortal had N=2 with multiple RET aberrations (both cases had loss and fusion) which was not described in the figure.
SCC; squamous cell carcinoma.
48
Supplemental Figure 1. Comparison of RET aberrations between current report and cBioPortal.
49
Supplemental References: S1. Cuccuru G, Lanzi C, Cassinelli G, Pratesi G, Tortoreto M, Petrangolini G, et al. Cellular effects and antitumor activity of RET inhibitor RPI-1 on MEN2A-associated medullary thyroid carcinoma. J Natl Cancer Inst. 2004;96:1006-14.S2. Muzza M, Cordella D, Bombled J, Bressac-de Paillerets B, Guizzardi F, Francis Z, et al. Four novel RET germline variants in exons 8 and 11 display an oncogenic potential in vitro. Eur J Endocrinol. 2010;162:771-7.S3. Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995;267:381-3.S4. Houvras Y. Completing the Arc: targeted inhibition of RET in medullary thyroid cancer. J Clin Oncol. 2012;30:200-2.S5. Garcia-Barcelo M, Sham MH, Lee WS, Lui VC, Chen BL, Wong KK, et al. Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung disease. Clin Chem. 2004;50:93-100.S6. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013;Chapter 7:Unit7 20.S7. Starr JS, Attia S, Joseph RW, Menke D, Casler J, Smallridge RC. Follicular Dendritic Cell Sarcoma Presenting As a Thyroid Mass. J Clin Oncol. 2015;33:e74-6.S8. Saez ME, Ruiz A, Cebrian A, Morales F, Robledo M, Antinolo G, et al. A new germline mutation, R600Q, within the coding region of RET proto-oncogene: a rare polymorphism or a MEN 2 causing mutation? Hum Mutat. 2000;15:122.S9. Silva AL, Carmo F, Moura MM, Domingues R, Espadinha C, Leite V, et al. Identification and characterization of two novel germline RET variants associated with medullary thyroid carcinoma. Endocrine. 2015;49:366-72.S10. Kohno T, Tsuta K, Tsuchihara K, Nakaoku T, Yoh K, Goto K. RET fusion gene: translation to personalized lung cancer therapy. Cancer Sci. 2013;104:1396-400.S11. Wang R, Hu H, Pan Y, Li Y, Ye T, Li C, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012;30:4352-9.S12. Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 2012;18:375-7.S13. Matsubara D, Kanai Y, Ishikawa S, Ohara S, Yoshimoto T, Sakatani T, et al. Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-2/ad. J Thorac Oncol. 2012;7:1872-6.S14. Bitler BG, Aird KM, Garipov A, Li H, Amatangelo M, Kossenkov AV, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med. 2015;21:231-8.S15. Messersmith WA, Shapiro GI, Cleary JM, Jimeno A, Dasari A, Huang B, et al. A Phase I, dose-finding study in patients with advanced solid malignancies of the oral gamma-secretase inhibitor PF-03084014. Clin Cancer Res. 2015;21:60-7.S16. Tolcher AW, Messersmith WA, Mikulski SM, Papadopoulos KP, Kwak EL, Gibbon DG, et al. Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol. 2012;30:2348-53.S17. Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci. 2014;39:91-100.S18. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:773-81.S19. Janku F, Hong DS, Fu S, Piha-Paul SA, Naing A, Falchook GS, et al. Assessing PIK3CA and PTEN in early-phase trials with PI3K/AKT/mTOR inhibitors. Cell Rep. 2014;6:377-87.S20. Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, Tsimberidou AM, et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol. 2012;30:777-82.S21. Schwaederle M, Lazar V, Validire P, Hansson J, Lacroix L, Soria JC, et al. VEGF-A Expression Correlates with TP53 Mutations in Non-Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy. Cancer Res. 2015;75:1187-90.S22. Said R, Hong DS, Warneke CL, Lee JJ, Wheler JJ, Janku F, et al. P53 mutations in advanced cancers: clinical characteristics, outcomes, and correlation between progression-free survival and bevacizumab-containing therapy. Oncotarget. 2013;4:705-14.S23. Mueller S, Haas-Kogan DA. WEE1 Kinase As a Target for Cancer Therapy. J Clin Oncol. 2015;33:3485-7.
50
S24. Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338:221.S25. Wu J, Savooji J, Liu D. Second- and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol. 2016;9:19.S26. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-16.S27. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379:1893-901.S28. Sherr CJ, Beach D, Shapiro GI. Targeting CDK4 and CDK6: From Discovery to Therapy. Cancer Discov. 2016;6:353-67.S29. DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res. 2015;21:995-1001.S30. Dedes KJ, Wilkerson PM, Wetterskog D, Weigelt B, Ashworth A, Reis-Filho JS. Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations. Cell Cycle. 2011;10:1192-9.S31. Michels J, Vitale I, Saparbaev M, Castedo M, Kroemer G. Predictive biomarkers for cancer therapy with PARP inhibitors. Oncogene. 2014;33:3894-907.S32. Harry BL, Eckhardt SG, Jimeno A. JAK2 inhibition for the treatment of hematologic and solid malignancies. Expert Opin Investig Drugs. 2012;21:637-55.S33. Weston VJ, Oldreive CE, Skowronska A, Oscier DG, Pratt G, Dyer MJ, et al. The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood. 2010;116:4578-87.S34. Hammerman PS, Sos ML, Ramos AH, Xu C, Dutt A, Zhou W, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011;1:78-89.S35. Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell. 1996;87:803-9.S36. Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006;355:873-84.S37. Tai WT, Shiau CW, Chen HL, Liu CY, Lin CS, Cheng AL, et al. Mcl-1-dependent activation of Beclin 1 mediates autophagic cell death induced by sorafenib and SC-59 in hepatocellular carcinoma cells. Cell Death Dis. 2013;4:e485.S38. Yang D, Liu H, Goga A, Kim S, Yuneva M, Bishop JM. Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase. Proc Natl Acad Sci U S A. 2010;107:13836-41.S39. Goga A, Yang D, Tward AD, Morgan DO, Bishop JM. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat Med. 2007;13:820-7.S40. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146:904-17.S41. Massague J, Seoane J, Wotton D. Smad transcription factors. Genes Dev. 2005;19:2783-810.S42. Moulder S, Helgason T, Janku F, Wheler J, Moroney J, Booser D, et al. Inhibition of the phosphoinositide 3-kinase pathway for the treatment of patients with metastatic metaplastic breast cancer. Ann Oncol. 2015;26:1346-52.S43. Subbiah V, Slopis J, Hong DS, Ketonen LM, Hamilton J, McCutcheon IE, et al. Treatment of patients with advanced neurofibromatosis type 2 with novel molecularly targeted therapies: from bench to bedside. J Clin Oncol. 2012;30:e64-8.S44. Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011;29:2904-9.S45. Boyd AW, Bartlett PF, Lackmann M. Therapeutic targeting of EPH receptors and their ligands. Nat Rev Drug Discov. 2014;13:39-62.S46. Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite Instability as a Biomarker for PD-1 Blockade. Clin Cancer Res. 2016;22:813-20.S47. Boumahdi S, Driessens G, Lapouge G, Rorive S, Nassar D, Le Mercier M, et al. SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature. 2014;511:246-50.S48. Mao JH, Kim IJ, Wu D, Climent J, Kang HC, DelRosario R, et al. FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science. 2008;321:1499-502.
51
S49. LoRusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ, Borad MJ, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res. 2011;17:2502-11.S50. Migden MR, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16:716-28.S51. Lachenmayer A, Alsinet C, Savic R, Cabellos L, Toffanin S, Hoshida Y, et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin Cancer Res. 2012;18:4997-5007.S52. Li N, Xi Y, Tinsley HN, Gurpinar E, Gary BD, Zhu B, et al. Sulindac selectively inhibits colon tumor cell growth by activating the cGMP/PKG pathway to suppress Wnt/beta-catenin signaling. Mol Cancer Ther. 2013;12:1848-59.S53. Rodilla V, Villanueva A, Obrador-Hevia A, Robert-Moreno A, Fernandez-Majada V, Grilli A, et al. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Natl Acad Sci U S A. 2009;106:6315-20.S54. Gounder MM, Lefkowitz RA, Keohan ML, D'Adamo DR, Hameed M, Antonescu CR, et al. Activity of Sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res. 2011;17:4082-90.S55. Hansmann A, Adolph C, Vogel T, Unger A, Moeslein G. High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors. Cancer. 2004;100:612-20.S56. Le Guellec S, Soubeyran I, Rochaix P, Filleron T, Neuville A, Hostein I, et al. CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics. Mod Pathol. 2012;25:1551-8.S57. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298-308.S58. Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005;23:5357-64.S59. Dewaele B, Wasag B, Cools J, Sciot R, Prenen H, Vandenberghe P, et al. Activity of dasatinib, a dual SRC/ABL kinase inhibitor, and IPI-504, a heat shock protein 90 inhibitor, against gastrointestinal stromal tumor-associated PDGFRAD842V mutation. Clin Cancer Res. 2008;14:5749-58.S60. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7:3129-40.S61. Cheung LW, Hennessy BT, Li J, Yu S, Myers AP, Djordjevic B, et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011;1:170-85.S62. Greulich H, Kaplan B, Mertins P, Chen TH, Tanaka KE, Yun CH, et al. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci U S A. 2012;109:14476-81.S63. Shaw AT, Hsu PP, Awad MM, Engelman JA. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer. 2013;13:772-87.S64. Nissan MH, Pratilas CA, Jones AM, Ramirez R, Won H, Liu C, et al. Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res. 2014;74:2340-50.S65. Etemadmoghadam D, Weir BA, Au-Yeung G, Alsop K, Mitchell G, George J, et al. Synthetic lethality between CCNE1 amplification and loss of BRCA1. Proc Natl Acad Sci U S A. 2013;110:19489-94.S66. Tada Y, Brena RM, Hackanson B, Morrison C, Otterson GA, Plass C. Epigenetic modulation of tumor suppressor CCAAT/enhancer binding protein alpha activity in lung cancer. J Natl Cancer Inst. 2006;98:396-406.S67. Oike T, Ogiwara H, Tominaga Y, Ito K, Ando O, Tsuta K, et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res. 2013;73:5508-18.S68. Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68:3421-8.S69. Graziano F, Humar B, Guilford P. The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice. Ann Oncol. 2003;14:1705-13.S70. Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature. 2007;445:851-7.
52
S71. Winslow MM, Dayton TL, Verhaak RG, Kim-Kiselak C, Snyder EL, Feldser DM, et al. Suppression of lung adenocarcinoma progression by Nkx2-1. Nature. 2011;473:101-4.S72. Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009;27:5924-30.S73. Klumpen HJ, Queiroz KC, Spek CA, van Noesel CJ, Brink HC, de Leng WW, et al. mTOR inhibitor treatment of pancreatic cancer in a patient With Peutz-Jeghers syndrome. J Clin Oncol. 2011;29:e150-3.S74. Breuleux M, Klopfenstein M, Stephan C, Doughty CA, Barys L, Maira SM, et al. Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther. 2009;8:742-53.S75. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235-44.S76. Falchook GS, Bastida CC, Kurzrock R. Aurora Kinase Inhibitors in Oncology Clinical Trials: Current State of the Progress. Semin Oncol. 2015;42:832-48.S77. Baud V, Karin M. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov. 2009;8:33-40.S78. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med. 2015;373:726-36.S79. Zheng G, Tseng LH, Chen G, Haley L, Illei P, Gocke CD, et al. Clinical detection and categorization of uncommon and concomitant mutations involving BRAF. BMC Cancer. 2015;15:779.S80. Vleugel MM, Greijer AE, Bos R, van der Wall E, van Diest PJ. c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer. Hum Pathol. 2006;37:668-74.S81. Shaw LM. Identification of insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the alpha6beta4 integrin-dependent activation of phosphoinositide 3-OH kinase and promotion of invasion. Mol Cell Biol. 2001;21:5082-93.S82. Wheler JJ, Moulder SL, Naing A, Janku F, Piha-Paul SA, Falchook GS, et al. Anastrozole and everolimus in advanced gynecologic and breast malignancies: activity and molecular alterations in the PI3K/AKT/mTOR pathway. Oncotarget. 2014;5:3029-38.S83. Kim C, Tang G, Pogue-Geile KL, Costantino JP, Baehner FL, Baker J, et al. Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer. J Clin Oncol. 2011;29:4160-7.S84. Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, et al. Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency. J Clin Oncol. 2016.S85. Cowin PA, George J, Fereday S, Loehrer E, Van Loo P, Cullinane C, et al. LRP1B deletion in high-grade serous ovarian cancers is associated with acquired chemotherapy resistance to liposomal doxorubicin. Cancer Res. 2012;72:4060-73.S86. Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011;25:1147-52.S87. Kim YH, Kwei KA, Girard L, Salari K, Kao J, Pacyna-Gengelbach M, et al. Genomic and functional analysis identifies CRKL as an oncogene amplified in lung cancer. Oncogene. 2010;29:1421-30.S88. Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med. 2015;373:1697-708.S89. Montero JC, Seoane S, Ocana A, Pandiella A. Inhibition of SRC family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors. Clin Cancer Res. 2011;17:5546-52.S90. Rasheed ZA, Rubin EH. Mechanisms of resistance to topoisomerase I-targeting drugs. Oncogene. 2003;22:7296-304.S91. Hutchinson KE, Lipson D, Stephens PJ, Otto G, Lehmann BD, Lyle PL, et al. BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition. Clin Cancer Res. 2013;19:6696-702.S92. Lunning MA, Green MR. Mutation of chromatin modifiers; an emerging hallmark of germinal center B-cell lymphomas. Blood Cancer J. 2015;5:e361.S93. Zhang W, Konopleva M, Shi YX, McQueen T, Harris D, Ling X, et al. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst. 2008;100:184-98.S94. Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer. 2014;14:159-72.
53
S95. David M, Cross NC, Burgstaller S, Chase A, Curtis C, Dang R, et al. Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders. Blood. 2007;109:61-4.S96. Giles FJ, O'Dwyer M, Swords R. Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia. 2009;23:1698-707.S97. Lierman E, Lahortiga I, Van Miegroet H, Mentens N, Marynen P, Cools J. The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica. 2007;92:27-34.S98. Grabiner BC, Nardi V, Birsoy K, Possemato R, Shen K, Sinha S, et al. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 2014;4:554-63.
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Supplemental MethodsData from cBio Cancer Genomics Portal (cBioPortal) was obtained from http://cbioportal.org to investigate RET aberrations among diverse cancer type and to compare with current study (accessed on 5/25/2016).
Following datasets from cBioPortal were used with URL listed below:
1.Adenoid Cystic Carcinoma (MSKCC, Nat Genet 2013)http://bit.ly/1WOp4sC
2.Adrenocortical Carcinoma (TCGA, Provisional)http://bit.ly/1WMY9gM
3.Bladder Urothelial Carcinoma (TCGA, Nature 2014)http://bit.ly/1qHM9PZ
4.Breast Invasive Carcinoma (TCGA, Cell 2015)http://bit.ly/1qHN4A1
5.Cholangiocarcinoma (TCGA, Provisional)http://bit.ly/1WOoLya
6.Clear Cell Renal Cell Carcinoma (U Tokyo, Nat Genet 2013) * http://bit.ly/1szPK3O
7.Colorectal Adenocarcinoma (TCGA, Nature 2012)http://bit.ly/1qHMCl6
8.Cutaneous squamous cell carcinoma (DFCI, Clin Cancer Res 2015)http://bit.ly/1qHK0nx
9.Esophageal Carcinoma (TCGA, Provisional)http://bit.ly/1qHLkqm
10. Esophageal Squamous Cell Carcinoma (UCLA, Nat Genet 2014) * http://bit.ly/1WOpfUW
11. Gallbladder Carcinoma (Shanghai, Nat Genet 2014) * http://bit.ly/1szPYYH
12. Glioblastoma (TCGA, Cell 2013)http://bit.ly/1WOpJdC
13. Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015)http://bit.ly/1qHMWAl
14. Liver Hepatocellular Carcinoma (TCGA, Provisional)http://bit.ly/1qHL2zC
15. Lung Adenocarcinoma (TCGA, Nature 2014)http://bit.ly/1qHJaXF
16. Lung Squamous Cell Carcinoma (TCGA, Nature 2012)
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http://bit.ly/1WMZILL
17. Mesothelioma (TCGA, Provisional)http://bit.ly/1szPPEI
18. Neuroblastoma (AMC Amsterdam, Nature 2012) *
http://bit.ly/1WOpY8L
19. Ovarian Serous Cystadenocarcinoma (TCGA, Nature 2011)http://bit.ly/1qHJhm0
20. Pancreatic Adenocarcinoma (TCGA, Provisional)http://bit.ly/1WMYosd
21. Pancreatic Neuroendocrine Tumors (Johns Hopkins University, Science 2011)*
http://bit.ly/1szQ56v
22. Papillary Thyroid Carcinoma (TCGA, Cell 2014)http://bit.ly/1XCRIMY
23. Pheochromocytoma and Paraganglioma (TCGA, Provisional)http://bit.ly/1qx0azV
24. Poorly-Differentiated and Anaplastic Thyroid Cancers (MSKCC, JCI 2016)http://bit.ly/1qx1Glz
25. Prostate Adenocarcinoma (TCGA, Cell 2015)http://bit.ly/1qHKSsa
26. Sarcoma (TCGA, Provisional)http://bit.ly/1WN0oAP
27. Skin Cutaneous Melanoma (TCGA, Provisional)http://bit.ly/1WMZfsW
28. Small Cell Lung Cancer (U Cologne, Nature 2015) * http://bit.ly/1WOqRhi
29. Stomach Adenocarcinoma (TCGA, Nature 2014)http://bit.ly/1WN0c4B
30. Uterine Carcinosarcoma (TCGA, Provisional)http://bit.ly/1qx2syY
31. Uterine Corpus Endometrioid Carcinoma (TCGA, Nature 2013) http://bit.ly/1WMZGUc
* Data were available for mutation only.
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