Predisposition of Melanoma Nelleke Gruis Department of Dermatology - PowerPoint PPT Presentation

Predisposition of Melanoma Nelleke Gruis Department of Dermatology Leiden University Medical Center The Netherlands OCTOBER 27TH 2017

Melanoma Risk Factors ?

Melanoma Predisposition 10% familial Manolio TA et al, Nature 2009

Melanoma Predisposition High risk genes 10% familial

Familial Melanoma (scientific definition) melanoma in 2 first degree relatives melanoma in ≥3 relatives on same side of family

Nevus phenotype of Familial Melanoma atypical nevus 20% melanoma

Melanoma gene; CDKN2A CDKN2A 3 Chr 9p21 p16 39% mutation in CDKN2A, 2 affecting both p16 and p14ARF 3 2 1 α 1 α p14ARF 1 β 24 23 22 1 β 3% mutations affecting p14ARF only 21 13 12 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 Kamb et al., Science. 1994;264:436-40.

CDKN2A gene structure and function p53 pathway RB pathway DNA repair response Cell cycle regulation

Melanoma gene; CDK4 CDK4 13.3 1 13.2 Chr 12q14 13.1 12.3 12.2 12.1 activating mutation 2 11.2 in exon 2 (R24C; R24H) 11.1 11 3 12 13.1 4 13.2 Since 1996 only reported 13.3 5 14 in 20 families worldwide 15 21.1 21.2 21.3 22 23 6 24.1 24.2 7 24.31 24.32 24.33 8 CHROMOSOME 12 Zuo et al., Nat Genet. 1996;12:97.

CDK4 function p53 pathway RB pathway DNA repair response Cell cycle regulation

CDKN2A mutations worldwide % families with CDKN2A mutations 45% 57% 39% 20% number of melanoma patients in family Goldstein et al., J Med Genet. 2007; 44:99-106

Penetrance of CDKN2A mutations AUS 67% at ALL age 80 USA EUR 30% at age 50 Bishop et al., J Natl Cancer Inst. 2002;94:894-903

CDKN2A and multiple primary melanoma

Risk of other tumors in CDKN2A mutation carriers (n=499) (n=1029) De Snoo et al., Clin Cancer Res 2008; 14, 7151 lifetime risk PC :15 % to 20%

CDKN2A mutations and pancreatic carc. % families with CDKN2A mutations number pancreatic carcinoma patients in family Goldstein et al., J Med Genet. 2007; 44:99-106

Pancreatic carcinoma and smoking Melanoma: RR 41 Pancreatic Carcinoma: RR 81 Current Smokers have 4 fold increased risk than former or never smokers Potjer et al., Eur J Hum Genet 2014, 1-4

Familial Melanoma (Clinical Practice) melanoma in 2 first degree relatives: <40 years or multiple primaries in one relative melanoma in ≥3 relatives on same side of family M,M M M M M

CDKN2A and moles CDKN2A non-carrier CDKN2A carrier CDKN2A does partly explain nevus phenotype

Melanoma gene; BAP1 BAP1, • BAP1 is BRCA1 binding partner-1, involved chr 3p21 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) α -MSH adenylate cyclase cAMP MITF MC1R DCT TYR TYRP1 eumelanin Chr 3p13 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

Melanoma gene; TERT (promoter mutation) Chr 5p15 -57 bp • 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 Horn et al., Science, 2013; 339:959

Melanoma genes; POT1 and Shelterin complex ACD, TERF2IP, POT1 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

High risk melanoma genes • CDKN2A: 39% BAP1 • 1% CDK4 • Less than 1% POT1 • Less than 1% TERT CDKN2A • 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 What are the implications for patients/treatment options?

Melanoma predisposition New (unique) high risk genes?? 10% familial 90% sporadic

Melanoma predisposition Germline mutations: Somatic mutations Low risk melanoma genes 90% sporadic

Somatic mutations in melanoma Whole exome analysis 121 melanoma/matched normal tissue - 15 primary - 30 metastatic - 76 short term cultures Hodis et al Cell. 2012; 150: 251–263 26 Insert > Header & footer 26-okt-17

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 Muñoz-Couselo et al., Ann Transl Med, 2015 27 Insert > Header & footer 26-okt-17

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 Shain et al., N Engl J Med 2015, 373, 1926 29 Cutaneous melanoma > Order of the Genetic alterations 26-Oct-17

Order of somatic mutations Shain et al., N Engl J Med 2015, 373, 1926 30 Insert > Header & footer 26-okt-17

Order of somatic mutations Shain et al., N Engl J Med 2015, 373, 1926 Met dank aan H. Suleiman 31 Insert > Header & footer 26-okt-17

Melanoma gene; TERT (promoter mutation) Chr 5p15 -57 bp • 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 Horn et al., Science, 2013; 339:959

BRAF –TERT interaction ETS Thr 38 P TERT gene 33 Insert > Header & footer 26-okt-17

Melanoma predisposition Germline mutations: Somatic mutations Low risk melanoma genes 90% sporadic

SNP-GWAS AA AG GG Bi-allelic – one of two nucleotide options ( allele 1 ) …..TAGCCATCGGTA A GTACTCAATGAT….. ( allele 2 ) …..TAGCCATCGGTA G GTACTCAATGAT….. Adapted from Hunter et al. NEJM 2008

Melanoma predisposition low risk genes Bishop et al. Nat Genet. 2009; 41:920-5 Brown et al., Nat Genet 2008; 40:838-40 Gene Chr OR 1.67 MC1R 16q24 1.29 TYR 11q14 TYRP1 9p23 1.15 ASIP 20q11 1.75

Melanoma susceptibility low risk genes SNP variant OR α -MSH ASIP 1.75 adenylate cyclase MC1R 1.67 cAMP TYR 1.29 X TYRP1 1.15 MITF MC1R MC1R DCT TYR TYRP1 pheomelanin eumelanin pheomelanin

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

Summary- low risk genes PIGMENTATION MELANOMA CHARACTERISTICS ?UVA  UVB BODY SITE SURVIVAL SOMATIC CNV, MUTATION etc… PROFILE ?UVA UVB NAEVI TERT ?UVA UVB TELOMERE LENGTH ?UVA UVB OTHER Slide provided courtesy of Tim Bishop, Leeds

Low risk genes and melanoma progression MC1R +/+ MC1R e/e Without ultraviolet radiation, Braf CA red mice have an increased rate of melanoma development relative to black and albino Braf CA animals. Mitra D, Nature. 2012; 491:449-53

Low risk genes and melanoma progression 1 or 2 MC1R R variants: increased ( UV related) DNA damage Disrupted MC1R: diminished removal CPD and 6-4PP Robles-Espinoza CD et al., Nat Commun. 2016;7:12064

Summary Predisposition of Melanoma . TERT .POT1 TERF2IP ACD BAP1 .BAP1 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