Predisposition of Melanoma

Transcription

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

2 Melanoma Risk Factors?

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

4 Melanoma Predisposition High risk genes 10% familial

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

6 Nevus phenotype of Familial Melanoma 20% atypical nevus melanoma

7 Melanoma gene; CDKN2A CDKN2A Chr 9p p % mutation in CDKN2A, affecting both p16 and p14arf 2 1α 1α β p14arf 1β 3% mutations affecting p14arf only CHROMOSOME 9 Kamb et al., Science. 1994;264:

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

9 Melanoma gene; CDK4 CDK4 Chr 12q activating mutation in exon 2 (R24C; R24H) Since 1996 only reported in 20 families worldwide CHROMOSOME 12 8 Zuo et al., Nat Genet. 1996;12:97.

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

11 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

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

13 CDKN2A and multiple primary melanoma

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

15 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

16 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

17 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

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

19 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.

20 Melanoma gene; MITF (E318K) α-msh adenylate cyclase camp MITF MC1R DCT TYR TYRP1 Chr 3p13 eumelanin 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

21 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

22 Melanoma genes; POT1 and Shelterin complex ACD, TERF2IP, POT1 Robles-Espinoza CD et al., Nat Genet. 2014;46: Aoude LG et al., J Natl Cancer Inst. 2014;107. Print 2015 Feb. Ramiro E et al., Nature 2007; 447,

23 High risk melanoma genes BAP1 CDKN2A 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 What are the implications for patients/treatment options?

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

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

26 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: Insert > Header & footer 26-okt-17

27 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, Insert > Header & footer 26-okt-17

28 Melanoma progression? BRAF, NRAS, NF1, P53, CDKN2A, PTEN

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

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

31 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

32 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

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

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

35 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

36 Melanoma predisposition low risk genes Bishop et al. Nat Genet. 2009; 41:920-5 Brown et al., Nat Genet 2008; 40: Gene Chr OR MC1R 16q TYR 11q TYRP1 9p ASIP 20q

37 Melanoma susceptibility low risk genes SNP variant OR ASIP 1.75 MC1R 1.67 α-msh adenylate cyclase TYR 1.29 TYRP camp MITF X MC1R pheomelanin DCT MC1R TYR TYRP1 pheomelanin eumelanin

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

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

40 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

41 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

42 Summary Predisposition of Melanoma. TERT.POT1 TERF2IP ACD BAP1.BAP1 Implications for clinical genetic management?

43 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