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