clasificación molecular del cáncer de próstataclasificación molecular del cáncer de próstata...
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Clasificación Molecular delCáncer de Próstata
Clasificación Molecular delCáncer de Próstata
JM Piulats
• The Gleason score is the major method for prostate cancer tissue grading and the mostimportant prognostic factor in this disease.
• However, the Gleason score does not provide information on therapy selection.
• Patients are currently grouped by clinical stage or treatment status.
• This approach does not have a mechanistic foundation that can guide the propersequences or combinations of molecularly targeted therapies.
Introduction
• The Gleason score is the major method for prostate cancer tissue grading and the mostimportant prognostic factor in this disease.
• However, the Gleason score does not provide information on therapy selection.
• Patients are currently grouped by clinical stage or treatment status.
• This approach does not have a mechanistic foundation that can guide the propersequences or combinations of molecularly targeted therapies.
Tumor HeterogeneityCS Cooper et al. Nature Genet 47, 367-372 (2015)
L Wei et al. Eur Urol 71, 183-192 (2017)
Tumor HeterogeneityCS Cooper et al. Nature Genet 47, 367-372 (2015)
L Wei et al. Eur Urol 71, 183-192 (2017)
• Mutations present at highlevels in morphologicallynormal tissue distant fromcancer.
• Existence of ongoingmutational processesconsistent with field effects.
• Earlier or separate clonalexpansions.
• Mutations present at highlevels in morphologicallynormal tissue distant fromcancer.
• Existence of ongoingmutational processesconsistent with field effects.
• Earlier or separate clonalexpansions.
Tumor HeterogeneityA Kumar et al. Nature Med 22, 369-378 (2016)
• There is limited diversity among metastases within an individual.
Basic Biology
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)D Robinson et al. Cell 161, 1215-1228 (2015)Basic Biology
Basic Biology
Basic Biology
114
57
17661
12
150
499
> 1800 patients
Prostate Cancer Datasets
112
57
477216
333
333 patientsPrimary Tumors
PSA Recurrence 11.74%Median Follow-up close to 2 years
150 patients (mostly pre-ABI/ENZA)Metastatic tumors
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)D Robinson et al. Cell 161, 1215-1228 (2015)Prostate Cancer Datasets
333 patientsPrimary Tumors
PSA Recurrence 11.74%Median Follow-up close to 2 years
DNA-based
RNA-based
Protein-based
TCGA (n) ECDT (n)
Whole-exome Seq Yes (333) Yes (150)
Copy-number Changes Yes (333) Yes (150)
DNA-methyla on Yes (333) No
Whole-genome Seq Low pass (100)High pass (19)
No
RNA-seq Yes (333) Yes (150)
microRNA-seq Yes (330) No
Reverse-phase Protein-array Yes (152) No
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)D Robinson et al. Cell 161, 1215-1228 (2015)Prostate Cancer Datasets
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)D Robinson et al. Cell 161, 1215-1228 (2015)Prostate Cancer Datasets
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)
TCGA Primary Tumor - HSPC
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)
TCGA Primary Tumor - HSPC
ETS p
ositi
veET
S neg
ativ
e
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)
TCGA Primary Tumor - HSPC
ETS p
ositi
ve
PI3K and TP53 mutations
TMPRSS2-ERG presence in:• TUR associated with risk of death from PCa.• Active surveillance associated with increased
risk of progression.• Associated with younger age at diagnosis.
ETS n
egat
ive
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)
TCGA Primary Tumor - HSPC
ETS p
ositi
ve
SPOP wt SPOP mutant
ETS n
egat
ive
CHD1 and SPINK1
• No clear association with clinical or pathologicalparameters.
• Tumors among highest androgen receptortranscriptional activity.
• Modulates DNA-Ds break repair, associated withgenomic instability, and sensitizes to PARPi.
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)
TCGA Primary Tumor - HSPC
ETS p
ositi
veET
S neg
ativ
e 10% SPINK1 • Mutually exclusive with ERG rearrangements.• Shorter time to BQ recurrence than SPINK1-.• Independent predictor for clinical recurrence.
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)
TCGA Primary Tumor - HSPC
ETS p
ositi
veET
S neg
ativ
e
Tumors among highest androgen receptortranscriptional activity.
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)
TCGA Primary Tumor - HSPC
ETS p
ositi
veET
S neg
ativ
e
• Methylator phenotype.• Actionable mutation.• Early age of onset.
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)
TCGA Primary Tumor - HSPCNo ERG
rearrangementWith ERG
rearrangement
Cancer Genome Atlas Research Network. Cell 163, 1011-1025 (2015)
TCGA Primary Tumor - HSPCNo ERG
rearrangementWith ERG
rearrangement
D Robinson et al. Cell 161, 1215-1228 (2015)
SU2C Metastases - CRPC
D Robinson et al. Cell 161, 1215-1228 (2015)
SU2C Metastases - CRPC
Expression Arrays
S You et al. Cancer Res 76, 4948-4958 (2016)
Expression Arrays
S You et al. Cancer Res 76, 4948-4958 (2016)
Expression Arrays
S You et al. Cancer Res 76, 4948-4958 (2016)
Expression Arrays
S You et al. Cancer Res 76, 4948-4958 (2016)
Expression Arrays
S You et al. Cancer Res 76, 4948-4958 (2016)
Expression Arrays
Investigate Gene SetsCurated Gene Sets
• Genes down-regulated upon IL6 deprivation.• BRCA2 network of transcripts.• Lung cancer poor survival.• High grade breast cancer.• NRAS signaling.• Cervical cancer proliferation.• Dividing cells.• CHECK2 network of transcripts.
• KRAS signaling.• Down-regulated after acute transplant
rejection.• Transport of inorganic cations and aa.• Up-regulated in GIST.• Good survival in HCC.
• KRAS signaling.• Down-regulated after acute transplant
rejection.• Transport of inorganic cations and aa.• Up-regulated in GIST.• Good survival in HCC.
• Down-regulated in PC.• Down-regulated during differentiation.• Up-regulated in CD31- stem cells.• Down-regulated in basal breast cancer .• Down-regulated in KRAS signal.
Conclusions:
• When comparing primary tumors, molecular classification might hint small differencesin prognostic between different groups.
• Molecular classification gets blurry when comparing samples from mCRPC. Importanceof tumor biopsies.
• Molecular classification still not useful to decide patient treatment. But close?.
• Intra-patient tumor heterogeneity seems not to be a problem when comparingbetween metastases. Liquid biopsy?.
• When comparing primary tumors, molecular classification might hint small differencesin prognostic between different groups.
• Molecular classification gets blurry when comparing samples from mCRPC. Importanceof tumor biopsies.
• Molecular classification still not useful to decide patient treatment. But close?.
• Intra-patient tumor heterogeneity seems not to be a problem when comparingbetween metastases. Liquid biopsy?.