Predisposition of Melanoma

Nelleke Gruis

Department of Dermatology Leiden University Medical Center The Netherlands

OCTOBER 27TH 2017

Melanoma Risk Factors

?

Manolio TA et al, Nature 2009

Melanoma Predisposition

10% familial

10% familial

High risk genes

Melanoma Predisposition

melanoma in ≥3 relatives on same side of family

Familial Melanoma (scientific definition)

melanoma in 2 first degree relatives

Nevus phenotype of Familial Melanoma

atypical nevus

melanoma

20%

Melanoma gene; CDKN2A

3

2

1α

1β

p16

p14ARF

12 13 21 22 23 24

11 11 12 13

21.1 21.2 21.3 22.1 22.2 22.3

31 32 33

34.1 34.2 34.3

CHROMOSOME 9

1β

1α 2 3

3% mutations affecting p14ARF only

Kamb et al., Science. 1994;264:436-40.

39% mutation in CDKN2A, affecting both p16 and p14ARF

CDKN2A Chr 9p21

CDKN2A gene structure and function

RB pathway Cell cycle regulation

p53 pathway DNA repair response

Melanoma gene; CDK4

11.2

12.1 12.2 12.3 13.1

11.1 11 12

13.1 13.2 13.3

14

21.1 15

24.1

22 23

13.2 13.3

21.2 21.3

24.2 24.31

24.33 24.32

CHROMOSOME 12

2

3

1

4 5

6 7

8

activating mutation in exon 2 (R24C; R24H) Since 1996 only reported in 20 families worldwide

Zuo et al., Nat Genet. 1996;12:97.

CDK4 Chr 12q14

CDK4 function

RB pathway Cell cycle regulation

p53 pathway DNA repair response

CDKN2A mutations worldwide

Goldstein et al., J Med Genet. 2007; 44:99-106

% fa

mili

es w

ith C

DK

N2A

mut

atio

ns

number of melanoma patients in family

39%

45%

20%

57%

Penetrance of CDKN2A mutations

Bishop et al., J Natl Cancer Inst. 2002;94:894-903

67% at age 80

EUR

AUS

USA

ALL

30% at age 50

CDKN2A and multiple primary melanoma

Risk of other tumors in CDKN2A mutation carriers

De Snoo et al., Clin Cancer Res 2008; 14, 7151

(n=499) (n=1029)

lifetime risk PC :15 % to 20%

number pancreatic carcinoma patients in family

CDKN2A mutations and pancreatic carc.

Goldstein et al., J Med Genet. 2007; 44:99-106

% fa

mili

es w

ith C

DK

N2A

mut

atio

ns

Pancreatic carcinoma and smoking

Potjer et al., Eur J Hum Genet 2014, 1-4

Melanoma: RR 41 Pancreatic Carcinoma: RR 81 Current Smokers have 4 fold increased risk than former or never smokers

melanoma in ≥3 relatives on same side of family

M,M

M

M

M M

Familial Melanoma (Clinical Practice)

melanoma in 2 first degree relatives: <40 years or multiple primaries in one relative

CDKN2A and moles

CDKN2A non-carrier CDKN2A carrier

CDKN2A does partly explain nevus phenotype

Melanoma gene; BAP1

BAP1, chr 3p21

• BAP1 is BRCA1 binding partner-1, involved in DNA damage response

• BAP1 mutations in 16 families with mixed tumor phenotype, including cutaneous melanoma, mesothelioma, uveal melanoma and atypical melanocytic tumors

Wiesner et al. Nature Genetics 2011;43:1018; Abdel-Rahman M H et al. J Med Genet 2011;48:856.

Melanoma gene; MITF (E318K)

• MITF: transcription factor driving melanin biosynthesis and many other genes

• E318K mutation leads to higher MITF activity

• MITF E318K predisposes to melanoma and renal cell cancer

Bertolotto et al., Nature, 2011;480:94 Yokoyama et al., Nature, 2011;480:99

eumelanin

α-MSH

adenylate cyclase

cAMP

MITF

TYR TYRP1 DCT MC1R

Chr 3p13

Horn et al., Science, 2013; 339:959

Melanoma gene; TERT (promoter mutation)

• TERT encodes for catalytic subunit telomerase

• This prevents degradation of the chromosomal ends following

multiple rounds of replication

• TERT promotor mutations create a new binding motif for Ets

transcription factor

Chr 5p15

-57 bp

Melanoma genes; POT1 and Shelterin complex

Robles-Espinoza CD et al., Nat Genet. 2014;46:478-81 Aoude LG et al., J Natl Cancer Inst. 2014;107. Print 2015 Feb. Ramiro E et al., Nature 2007; 447, 924-931

ACD, TERF2IP, POT1

High risk melanoma genes

CDKN2A

BAP1

What are the implications for patients/treatment options?

• CDKN2A: 39% • 1% CDK4 • Less than 1% POT1 • Less than 1% TERT • Less than 1% other mutations in

Shelterin complex genes • Less than 1% BAP 1 ˜60% still unexplained • inheritance of many low risk genes • ‘boutique’ mutations • ‘mixed cancer’ syndromes

Melanoma predisposition

10% familial 90% sporadic

New (unique) high risk genes??

Melanoma predisposition

90% sporadic

Germline mutations: Low risk melanoma genes Somatic mutations

Whole exome analysis 121 melanoma/matched normal tissue - 15 primary - 30 metastatic - 76 short term cultures

26-okt-17 26 Insert > Header & footer

Hodis et al Cell. 2012; 150: 251–263

Somatic mutations in melanoma

BRAF mutation in melanoma

BRAF gene encodes for BRAF protein kinase: Regulates MAPkinase/ERK signal transduction Specific T1796A, V600E mutation in ~ 60% melanoma MAPK pathway hyperactivated - Increased proliferation 26-okt-17 27 Insert > Header & footer

Muñoz-Couselo et al., Ann Transl Med, 2015

Melanoma progression

BRAF, NRAS, NF1, P53, CDKN2A, PTEN ?

Order of somatic mutations

Sequencing analyses of 293 cancer related genes in 150 areas of 37 primary melanomas and their precursor lesions

26-Oct-17 29 Cutaneous melanoma > Order of the Genetic alterations

Shain et al., N Engl J Med 2015, 373, 1926

26-okt-17 30 Insert > Header & footer

Shain et al., N Engl J Med 2015, 373, 1926

Order of somatic mutations

26-okt-17 31 Insert > Header & footer

Met dank aan H. Suleiman Shain et al., N Engl J Med 2015, 373, 1926

Order of somatic mutations

Horn et al., Science, 2013; 339:959

Melanoma gene; TERT (promoter mutation)

• TERT encodes for catalytic subunit telomerase

• This prevents degradation of the chromosomal ends following

multiple rounds of replication

• TERT promotor mutations create a new binding motif for Ets

transcription factor

Chr 5p15

-57 bp

BRAF –TERT interaction

26-okt-17 33 Insert > Header & footer

Thr 38P

ETS

TERT gene

Melanoma predisposition

90% sporadic

Germline mutations: Low risk melanoma genes Somatic mutations

SNP-GWAS

Bi-allelic – one of two nucleotide options

(allele 1) …..TAGCCATCGGTA A GTACTCAATGAT….. (allele 2) …..TAGCCATCGGTA G GTACTCAATGAT…..

AA

AG

GG

Adapted from Hunter et al. NEJM 2008

Bishop et al. Nat Genet. 2009; 41:920-5 Brown et al., Nat Genet 2008; 40:838-40

Melanoma predisposition low risk genes

Gene Chr OR MC1R 16q24 1.67

TYR 11q14 1.29

TYRP1 9p23 1.15 ASIP 20q11 1.75

SNP variant OR

ASIP 1.75

MC1R 1.67

TYR 1.29

TYRP1 1.15

eumelanin

α-MSH

adenylate cyclase

cAMP

MITF

TYR TYRP1 DCT MC1R

pheomelanin

pheomelanin

MC1R

X

Melanoma susceptibility low risk genes

Latest GWA results- 2015

Slide provided courtesy of Tim Bishop, Leeds and based on Law, M et al., Nat Genet. 2015; 47: 987–995

PIGMENTATION

OTHER

NAEVI

TERT

TELOMERE LENGTH ?UVA UVB

?UVA UVB

?UVA UVB

MELANOMA CHARACTERISTICS

BODY SITE

SOMATIC MUTATION PROFILE

SURVIVAL

CNV, etc…

?UVA UVB

Summary- low risk genes

Slide provided courtesy of Tim Bishop, Leeds

Mitra D, Nature. 2012; 491:449-53

Low risk genes and melanoma progression

MC1R e/e

MC1R +/+

Without ultraviolet radiation, BrafCA red mice have an increased rate of melanoma development relative to black and albino BrafCA animals.

Low risk genes and melanoma progression

Robles-Espinoza CD et al., Nat Commun. 2016;7:12064

1 or 2 MC1R R variants: increased ( UV related) DNA damage

Disrupted MC1R: diminished removal CPD and 6-4PP

Summary Predisposition of Melanoma

BAP1 .BAP1

. TERT .POT1

ACD TERF2IP

Implications for clinical genetic management?

Acknowledgements Team 113, Sanger Institute - David Adams St. James’ Hospital, Leeds - Mark Harland - Julia Newton-Bishop QIMR, Brisbane - Nick Hayward Leiden University Medical Center - Mijke Visser - Remco van Doorn - Eirini Christodoulou - Catarina Salgado - Nienke van der Stoep - Jeroen Laros