Familial Melanoma

Overview

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Familial Melanoma
  • Tumor Suppressor Protein p14ARF
  • Phenotype
  • Genetic Testing
  • Skin Cancer
  • Polymorphism
  • Genetic Markers
  • Proto-Oncogene Proteins
  • Melanoma
  • CDK6
  • Hereditary Neoplastic Syndromes
  • Chromosome 9
  • Genetic Linkage
  • POT1
  • Mutation
  • Childhood Cancer
  • DNA Mutational Analysis
  • Family Health
  • Multiple Primary Neoplasms
  • Genetic Predisposition
  • Point Mutation
  • Tumor Suppressor Proteins
  • Italy
  • CDK4
  • Germ-Line Mutation
  • Risk Factors
  • Young Adult
  • BAP1
  • Alleles
  • Ultraviolet Rays
  • Cancer DNA
  • CDKN2A Protein
  • Spain
  • Dysplastic Nevus Syndrome
  • CDKN2A
  • Adolescents
  • Recombinant Fusion Proteins
  • Carrier Proteins
  • Base Sequence
  • Cyclin-Dependent Kinases
  • Pedigree
  • Chromosome Mapping
  • Molecular Sequence Data
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (6)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
CDKN2A 9p21 ARF, MLM, P14, P16, P19, CMM2, INK4, MTS1, TP16, CDK4I, CDKN2, INK4A, MTS-1, P14ARF, P19ARF, P16INK4, P16INK4A, P16-INK4A Germline
-CDKN2A and Familial Melanoma
266
MC1R 16q24.3 CMM5, MSH-R, SHEP2 -MC1R Polymorphisms and Melanoma
165
CDK4 12q14 CMM3, PSK-J3 Germline
-CDK4 Germline Mutations in Melanoma Prone Families
95
BAP1 3p21.1 UCHL2, hucep-6, HUCEP-13 Germline
-BAP1 and Melanoma
39
CDK6 7q21-q22 MCPH12, PLSTIRE -CDK6 and Melanoma
29
POT1 7q31.33 CMM10, HPOT1 Germline
GWS
-POT1 and Predisposition to Familial Melanoma
4

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Sargen MR, Kanetsky PA, Newton-Bishop J, et al.
Histologic features of melanoma associated with CDKN2A genotype.
J Am Acad Dermatol. 2015; 72(3):496-507.e7 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Inherited susceptibility genes have been associated with histopathologic characteristics of tumors.
OBJECTIVE: We sought to identify associations between histology of melanomas and CDKN2A genotype.
METHODS: This was a case-control study design comparing 28 histopathologic tumor features among individuals with sporadic melanomas (N = 81) and cases from melanoma families with (N = 123) and without (N = 120) CDKN2A germline mutations.
RESULTS: Compared with CDKN2A(-) cases, mutation carriers tended to have histologic features of superficial spreading melanoma subtype including higher pigmentation (Ptrend = .02) and increased pagetoid scatter (Ptrend = .07) after adjusting for age at diagnosis, sex, and American Joint Committee on Cancer thickness category. Similar associations were observed when comparing mutation carriers with a combined group of CDKN2A(-) (wild type) and sporadic melanomas. The presence of spindle cell morphology in the vertical growth phase was also an important predictor of genotype. Of the 15 cases with this phenotype, none were observed to harbor a CDKN2A mutation.
LIMITATIONS: Our study examined rare mutations and may have been underpowered to detect small, but biologically significant associations between histology and genotype.
CONCLUSION: Familial melanomas with CDKN2A mutations preferentially express a histologic phenotype of dense pigmentation, high pagetoid scatter, and a non-spindle cell morphology in the vertical growth phase.

Aoude LG, Pritchard AL, Robles-Espinoza CD, et al.
Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma.
J Natl Cancer Inst. 2015; 107(2) [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.
METHODS: Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction).
RESULTS: Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma.
CONCLUSIONS: Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.

Antonopoulou K, Stefanaki I, Lill CM, et al.
Updated field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma: the MelGene database.
J Invest Dermatol. 2015; 135(4):1074-9 [PubMed] Related Publications
We updated a field synopsis of genetic associations of cutaneous melanoma (CM) by systematically retrieving and combining data from all studies in the field published as of August 31, 2013. Data were available from 197 studies, which included 83,343 CM cases and 187,809 controls and reported on 1,126 polymorphisms in 289 different genes. Random-effects meta-analyses of 81 eligible polymorphisms evaluated in >4 data sets confirmed 20 single-nucleotide polymorphisms across 10 loci (TYR, AFG3L1P, CDK10, MYH7B, SLC45A2, MTAP, ATM, CLPTM1L, FTO, and CASP8) that have previously been published with genome-wide significant evidence for association (P<5 × 10(-8)) with CM risk, with certain variants possibly functioning as proxies of already tagged genes. Four other loci (MITF, CCND1, MX2, and PLA2G6) were also significantly associated with 5 × 10(-8)

Ibarrola-Villava M, Kumar R, Nagore E, et al.
Genes involved in the WNT and vesicular trafficking pathways are associated with melanoma predisposition.
Int J Cancer. 2015; 136(9):2109-19 [PubMed] Related Publications
Multifactorial predisposition to melanoma includes genes involved in pigmentation, immunity and DNA repair. Nonetheless, missing heritability in melanoma is still important. We studied the role of 335 candidate SNPs in melanoma susceptibility by using a dedicated chip and investigating 110 genes involved in different pathways. A discovery set was comprised of 1069 melanoma patients and 925 controls from France. Data were replicated using validation phases II (1085 cases and 801 controls from Spain) and III (1808 cases and 1894 controls from Germany and a second set of Spanish samples). In addition, an exome sequencing study was performed in three high-risk French melanoma families. Nineteen SNPs in 17 genes were initially associated with melanoma in the French population. Six SNPs were replicated in phase II, including two new SNPs in the WNT3 (rs199524) and VPS41 (rs11773094) genes. The role of VPS41 and WNT3 was confirmed in a meta-analysis (3940 melanoma cases and 3620 controls) with two-side p values of 0.002, (OR = 0.86) and 4.07 × 10(-10) (OR = 0.80), respectively. Exome sequencing revealed a non-synonymous VPS41 variant in one family that was shown to be strongly associated with familial melanoma (OR = 4.46, p = 0.001) in an independent sample of 178 melanoma families. WNT3 belongs to WNT pathway known to play a crucial role in melanoma, whereas VPS41 regulates vesicular trafficking and is thought to play a role in pigmentation. Our work identified two new pathways involved in melanoma predisposition. These results may be useful in the future for identifying individuals highly predisposed to melanoma.

de Araújo É, Marchi FA, Rodrigues TC, et al.
Genome-wide DNA methylation profile of leukocytes from melanoma patients with and without CDKN2A mutations.
Exp Mol Pathol. 2014; 97(3):425-32 [PubMed] Related Publications
Melanoma is a highly aggressive cancer, accounting for up to 75% of skin cancer deaths. A small proportion of melanoma cases can be ascribed to the presence of highly penetrant germline mutations, and approximately 40% of hereditary melanoma cases are caused by CDKN2A mutations. The current study sought to investigate whether the presence of germline CDKN2A mutations or the occurrence of cutaneous melanoma would result in constitutive genome-wide DNA methylation changes. The leukocyte methylomes of two groups of melanoma patients (those with germline CDKN2A mutations and those without CDKN2A mutations) were analyzed together with the profile of a control group of individuals. A pattern of DNA hypomethylation was detected in the CDKN2A-negative patients relative to both CDKN2A-mutated patients and controls. Additionally, we delineated a panel of 90 CpG sites that were differentially methylated in CDKN2A-mutated patients relative to controls. Although we identified a possible constitutive epigenetic signature in CDKN2A-mutated patients, the occurrence of reported SNPs at the detected CpG sites complicated the data interpretation. Thus, further studies are required to elucidate the impact of these findings on melanoma predisposition and their possible effect on the penetrance of CDKN2A mutations.

Iles MM, Bishop DT, Taylor JC, et al.
The effect on melanoma risk of genes previously associated with telomere length.
J Natl Cancer Inst. 2014; 106(10) [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.

Chen T, Hemminki K, Kharazmi E, et al.
Multiple primary (even in situ) melanomas in a patient pose significant risk to family members.
Eur J Cancer. 2014; 50(15):2659-67 [PubMed] Related Publications
BACKGROUND: We aimed at assessing familial risk of melanoma by considering a detailed family history of multiple primary (invasive/in situ) melanomas (MPM), stratified by histology and location.
METHODS: Among 65,429 melanoma patients diagnosed in 1958-2010 in the Swedish Family-Cancer Database, there were 4248 patients with familial melanoma. A detailed family history of MPM was investigated by number of melanomas in one first-degree relative (FDR) and in ⩾2 FDRs. Familial melanoma risk was assessed by standardised incidence ratios (SIRs) comparing those with family history of melanoma to those without. Combining invasive/in situ melanoma was due to essentially identical familial risks.
RESULTS: For one affected FDR, familial risk increased from SIR=2.2 (95% confidence interval (CI)=2.2-2.3) for single melanoma to 16.3 (9.5-26.1) for ⩾5 melanomas, while for ⩾2 affected FDRs, the risk increased from 5.5 (4.8-6.2) for single melanoma to 23.9 (13.6-38.8) for ⩾2 melanomas. Significantly higher familial risks for superficial spreading melanoma (SSM) [2.5 (2.3-2.6)] than lentigo maligna melanoma (LMM) [1.8 (1.6-2.1)], and for multiple parts [5.3 (3.1-8.4)] and trunk [2.6 (2.5-2.8)] than head/neck [2.0 (1.8-2.2)] were observed. Only at head/neck, significantly higher risk for SSM [2.4 (1.9-3.0)] than LMM [1.6 (1.4-1.8)] was noted.
CONCLUSION: We found, for the first time, that familial risks were similar for two/three melanomas in one FDR or for a single melanoma in ⩾2 FDRs and, higher familial risks for SSM than LMM occurred only at head/neck. This study provides new evidence for genetic counselling in melanoma, suggesting the need for considering not only the number of affected family members but also the diagnosis of MPM (even in situ) in relatives.

Potrony M, Puig-Butillé JA, Aguilera P, et al.
Increased prevalence of lung, breast, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: implications for genetic counseling.
J Am Acad Dermatol. 2014; 71(5):888-95 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: Cyclin-dependent kinase inhibitor 2A (CDKN2A) is the major high-risk susceptibility gene for melanoma.
OBJECTIVE: We sought to evaluate the effect of CDKN2A mutations in Spanish patients with a high risk of developing melanoma and the association with clinical and family history features.
METHODS: A cross-sectional study design was used to analyze the CDKN2A impact in 702 Spanish patients with a high risk of developing melanoma.
RESULTS: The CDKN2A mutation prevalence was 8.5% in patients with sporadic multiple primary melanoma and 14.1% in familial melanoma. Number of cases in the family, number of primary melanomas, and age of onset were associated with the presence of CDKN2A mutation. Having a CDKN2A mutation in the family increased the prevalence of other cancers (prevalence ratio [PR] 2.99, P=.012) and prevalence of pancreatic (PR 2.97, P=.006), lung (PR 3.04, P<.001), and breast (PR 2.19, P=.018) cancers but not nephrourologic or colon cancer.
LIMITATIONS: Smoking status was not assessed in the individuals with lung cancer.
CONCLUSIONS: Melanoma-prone families with mutations in CDKN2A have an increased prevalence of a broad spectrum of cancers including lung, pancreatic, and breast cancer. This information should be included in genetic counseling and cancer prevention programs for CDKN2A mutation carriers.

de Ávila AL, Krepischi AC, Moredo LF, et al.
Germline CDKN2A mutations in Brazilian patients of hereditary cutaneous melanoma.
Fam Cancer. 2014; 13(4):645-9 [PubMed] Related Publications
Approximately 10 % of all cutaneous melanoma cases occur in a familial context. The major susceptibility gene for familial melanoma is CDKN2A. In Latin America, genetic studies investigating melanoma predisposition are scarce. The aim of this work was to investigate germline CDKN2A point mutations and genomic rearrangements in a cohort of 59 Brazilian melanoma-prone patients. Screening of CDKN2A alterations was performed by sequencing and multiplex ligation probe amplification. Germline CDKN2A mutations affecting p16(INK4a) were detected in 8 unrelated probands (13.6 %), including 7 familial cases and one patient with multiple melanomas; 4 out of 8 mutation carriers met the criteria for familial melanoma and had multiple primary lesions. Although this study adds to the literature on melanoma susceptibility in Latin America, it is limited by the small size of the cohort. Our findings suggest that stringent inclusion criteria led to a substantially increased rate of CDKN2A mutation detection. This consideration should be taken into account when referring patients for genetic screening in a setting of limited budget, such as in developing countries.

Frigerio S, Disciglio V, Manoukian S, et al.
A large de novo 9p21.3 deletion in a girl affected by astrocytoma and multiple melanoma.
BMC Med Genet. 2014; 15:59 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: Association of melanoma, neural system tumors and germ line mutations at the 9p21 region in the CDKN2A, CDKN2B and CDKN2BAS genes has been reported in a small number of families worldwide and described as a discrete syndrome in melanoma families registered as a rare disease, the melanoma-astrocytoma syndrome.
CASE PRESENTATION: We here studied two young patients developing melanoma after radiotherapy for astrocytoma, both reporting lack of family history for melanoma or neural system tumors at genetic counselling. Patient A is a girl treated for anaplastic astrocytoma at 10 years and for multiple melanomas on the scalp associated to dysplastic nevi two years later. Her monozygotic twin sister carried dysplastic nevi and a slow growing, untreated cerebral lesion. Direct sequencing analysis showed no alterations in melanoma susceptibility genes including CDKN2A, CDK4, MC1R and MITF or in TP53. By microsatellite analysis, multiplex ligation-dependent probe amplification, and array comparative genomic hybridization a deletion including the CDKN2A, CDKN2B and CDKN2BAS gene cluster was detected in both twin sisters, encompassing a large region at 9p21.3 and occurring de novo after the loss of one paternal allele.Patient B is a boy of 7 years when treated for astrocytoma then developing melanoma associated to congenital nevi on the head 10 years later: sequencing and multiplex ligation-dependent probe amplification revealed a normal profile of the CDKN2A/CDKN2B/CDKN2BAS region. Array comparative genomic hybridization confirmed the absence of deletions at 9p21.3 and failed to reveal known pathogenic copy number variations.
CONCLUSIONS: By comparison with the other germ line deletions at the CDKN2A, CDKN2B and CDKN2BAS gene cluster reported in melanoma susceptible families, the deletion detected in the two sisters is peculiar for its de novo origin and for its extension, as it represents the largest constitutive deletion at 9p21.3 region identified so far.In addition, the two studied cases add to other evidence indicating association of melanoma with exposure to ionizing radiation and with second neoplasm after childhood cancer. Melanoma should be considered in the monitoring of pigmented lesions in young cancer patients.

Appelqvist F, Yhr M, Erlandson A, et al.
Deletion of the MGMT gene in familial melanoma.
Genes Chromosomes Cancer. 2014; 53(8):703-11 [PubMed] Related Publications
The DNA repair gene MGMT (O-6-methylguanine-DNA methyltransferase) is important for maintaining normal cell physiology and genomic stability. Alterations in MGMT play a critical role in the development of several types of cancer, including glioblastoma, lung cancer, and colorectal cancer. The purpose of this study was to explore the function of genetic alterations in MGMT and their connection with familial melanoma (FM). Using multiplex ligation-dependent probe amplification, we identified a deletion that included the MGMT gene in one of 64 families with a melanoma predisposition living in western Sweden. The mutation segregated with the disease as a heterozygous deletion in blood-derived DNA, but a homozygous deletion including the promoter region and exon 1 was seen in tumor tissue based on Affymetrix 500K and 6.0 arrays. By sequence analysis of the MGMT gene in the other 63 families with FM from western Sweden, we identified four common polymorphisms, nonfunctional, as predominantly described in previous studies. We conclude that inherited alterations in the MGMT gene might be a rare cause of FM, and we suggest that MGMT contributes to melanoma predisposition.

Gromowski T, Masojć B, Scott RJ, et al.
Prevalence of the E318K and V320I MITF germline mutations in Polish cancer patients and multiorgan cancer risk-a population-based study.
Cancer Genet. 2014; 207(4):128-32 [PubMed] Related Publications
The E318K mutation in the MITF gene has been associated with a high risk of melanoma, renal cell carcinoma, and pancreatic cancer; the risk of other cancers has not been evaluated so far. Herein, we examined the possible association of E318K and a novel variant of the MITF gene, V320I, with the risk of cancers of different sites of origin in a Polish population. We assayed for the presence of the E318K and V320I missense mutations in 4,226 patients with one of six various cancers (melanoma or cancer of the kidney, lung, prostate, colon, or breast) and 2,114 controls from Poland. The E318K mutation was detected in 4 of 2,114 participants (0.19%) in the Polish control population, the V320I in 3 of 2,114 participants (0.14%) in the control group. We found no statistically significant differences in the prevalence of the E318K and V320I variants among cases and controls. We found two carriers of the E318K variant among melanoma patients (P = 0.95), one carrier among breast cancer patients (P = 0.77), one carrier among colorectal cancer patients (P = 0.82), and one carrier among kidney cancer patients (P = 0.64). Our study demonstrates a lack of strong association of E318K and V320I with increased risk of melanoma or cancers of the kidney, breast, prostate, lung, or colon.

Hyland PL, Burke LS, Pfeiffer RM, et al.
Constitutional promoter methylation and risk of familial melanoma.
Epigenetics. 2014; 9(5):685-92 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Constitutional epigenetic changes detected in blood or non-disease involving tissues have been associated with disease susceptibility. We measured promoter methylation of CDKN2A (p16 and p14ARF) and 13 melanoma-related genes using bisulfite pyrosequencing of blood DNA from 114 cases and 122 controls in 64 melanoma-prone families (26 segregating CDKN2A germline mutations). We also obtained gene expression data for these genes using microarrays from the same blood samples. We observed that CDKN2A epimutation is rare in melanoma families, and therefore is unlikely to cause major susceptibility in families without CDKN2A mutations. Although methylation levels for most gene promoters were very low (<5%), we observed a significantly reduced promoter methylation (odds ratio = 0.63, 95% confidence interval = 0.50, 0.80, P<0.001) and increased expression (fold change = 1.27, P = 0.048) for TNFRSF10C in melanoma cases. Future research in large prospective studies using both normal and melanoma tissues is required to assess the significance of TNFRSF10C methylation and expression changes in melanoma susceptibility.

Tuominen R, Jönsson G, Enerbäck C, et al.
Investigation of a putative melanoma susceptibility locus at chromosome 3q29.
Cancer Genet. 2014; 207(3):70-4 [PubMed] Related Publications
Malignant melanoma, the most fatal form of skin cancer, is currently increasing in incidence in many populations. Approximately 10% of all cases occur in families with an inherited predisposition for melanoma. In Sweden, only a minor portion of such melanoma families carry a mutation in the known melanoma gene CDKN2A, and there is a need to identify additional melanoma susceptibility genes. In a recently performed genome-wide linkage screen, novel loci with suggestive evidence of linkage to melanoma were detected. In this study, we have further analyzed one region on chromosome 3q29. In all, 89 affected and 15 nonaffected family members from 42 melanoma-prone families were genotyped for 34 genetic markers. In a pooled linkage analysis of all 42 families, we detected significant evidence of linkage, with a maximum heterogeneity logarithm of odds (HLOD) score of 3.1 with 83% of the families contributing to the linkage score. The minimum critical region of linkage (defined by a 1LOD score support interval) maps to chromosome 3q29, spans 3.5 Mb of genomic sequence, and harbors 44 identified genes. Sequence variants within this region have previously been associated with cancer susceptibility. This study reports the presence of a putative novel melanoma susceptibility locus in the Swedish population, a finding that needs to be replicated in an independent study on other individuals with familial melanoma. Sequencing of genes in the region may identify novel melanoma-associated mutations.

Yeh I, Mully TW, Wiesner T, et al.
Ambiguous melanocytic tumors with loss of 3p21.
Am J Surg Pathol. 2014; 38(8):1088-95 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Germline loss-of-function mutations in BAP1 are associated with the development of cutaneous melanocytic tumors with some histopathologic characteristics seen in Spitz nevi. Similar melanocytic tumors occurring in a sporadic setting have been demonstrated to have biallelic loss of BAP1. In some of these sporadic tumors, loss of BAP1 occurs through mutation of 1 allele and genomic loss of the other. We screened our database of comparative genomic hybridization profiles of ambiguous melanocytic tumors to identify cases with a single genomic event involving loss of the BAP1 locus. The prevalence of tumors with a single genomic event involving loss of BAP1 was 6.7% in our study population. We further characterized the BAP1 status in 17 of these tumors with available additional material, confirming loss of BAP1 in all cases. We describe BAP1 loss in a blue nevus-like melanoma and further expand the histopathologic spectrum of spitzoid melanocytic neoplasms with BAP1 loss.

Robles-Espinoza CD, Harland M, Ramsay AJ, et al.
POT1 loss-of-function variants predispose to familial melanoma.
Nat Genet. 2014; 46(5):478-81 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.

Shi J, Yang XR, Ballew B, et al.
Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.
Nat Genet. 2014; 46(5):482-6 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.

Scaini MC, Minervini G, Elefanti L, et al.
CDKN2A unclassified variants in familial malignant melanoma: combining functional and computational approaches for their assessment.
Hum Mutat. 2014; 35(7):828-40 [PubMed] Related Publications
CDKN2A codes for two oncosuppressors by alternative splicing of two first exons: p16INK4a and p14ARF. Germline mutations are found in about 40% of melanoma-prone families, and most of them are missense mutations mainly affecting p16INK4a. A growing number of p16INK4a variants of uncertain significance (VUS) are being identified but, unless their pathogenic role can be demonstrated, they cannot be used for identification of carriers at risk. Predicting the effect of these VUS by either a "standard" in silico approach, or functional tests alone, is rather difficult. Here, we report a protocol for the assessment of any p16INK4a VUS, which combines experimental and computational tools in an integrated approach. We analyzed p16INK4a VUS from melanoma patients as well as variants derived through permutation of conserved p16INK4a amino acids. Variants were expressed in a p16INK4a-null cell line (U2-OS) and tested for their ability to block proliferation. In parallel, these VUS underwent in silico prediction analysis and molecular dynamics simulations. Evaluation of in silico and functional data disclosed a high agreement for 15/16 missense mutations, suggesting that this approach could represent a pilot study for the definition of a protocol applicable to VUS in general, involved in other diseases, as well.

Fallah M, Pukkala E, Sundquist K, et al.
Familial melanoma by histology and age: joint data from five Nordic countries.
Eur J Cancer. 2014; 50(6):1176-83 [PubMed] Related Publications
BACKGROUND: We aimed to estimate lifetime cumulative risk of melanoma (CRM) in relatives of patients with melanoma by histology and age at diagnosis in patients and relatives.
METHODS: A population-based cohort of 238724 first-degree relatives of 46091 melanoma patients diagnosed in 1955-2010 in Nordic countries was followed for cancer incidence.
FINDINGS: The CRM (0-79 years) in first-degree relatives of a patient with superficial spreading (SSM), nodular (NM), or lentigo maligna melanoma was quite similar, ranging from 2.5% to about 3%, which represents about 2-fold increase over the general population risk. When one melanoma patient in the family was diagnosed before age 30, the CRM was about 3%. When there were > or =2 melanoma patients diagnosed before age 30 in a family, CRM for relatives was about 14%, 6% for diagnoses at age 30-59, and 5% for diagnoses at age 60 or older. Depending on age at diagnosis of same-sex twins (not known whether monozygotic/dizygotic), their CRM was about 7-21%. Although no familial case of concordant histological types of acral lentiginous/desmoplastic/compound nevus/spindle cell melanomas or malignant blue nevus was found, familial risks of discordant histological types of melanoma were interchangeably high for most of the types, e.g. higher risk of SSM when a first-degree relative had NM [standardized incidence ratios (SIR)=2.6, 95% confidence interval (CI)=2.1-3.3, n=72] or acral lentiginous (4.0, 95% CI=1.5-8.8, n=6) and vice versa. There was a tendency toward concordant age at diagnosis of melanoma among relatives of melanoma patients.
INTERPRETATION: Findings of this study may help clinicians to find subjects at high melanoma risk for the genetic counseling. The risk was highest when melanoma occurred in a same-sex twin, one first-degree relative diagnosed at young age (<30), or > or =2 first-degree relatives. Histological type of melanoma does not seem to play an important role in familial melanoma.
FUNDING: This work was supported by the Nordic Cancer Union, Swedish Council for Working Life and Social Research, and German Cancer Aid.

Paillerets BB, Lesueur F, Bertolotto C
A germline oncogenic MITF mutation and tumor susceptibility.
Eur J Cell Biol. 2014 Jan-Feb; 93(1-2):71-5 [PubMed] Related Publications
MITF (Microphthalmia-associated transcription factor) is a lineage specific transcription factor that plays a critical role in melanocyte homeostasis and whose deregulation has been shown to contribute to melanoma disease. A germline mutation in MITF, impairing SUMOylation and predisposing to cutaneous malignant melanoma, was recently identified. Interestingly, an association of the MITF mutation with coexisting melanoma and renal cell carcinoma was also shown. Collectively, these data suggest that MITF has an important oncogenic function in tumorigenesis of multiple tissues/melanocytes and kidney cells.

Marzuka-Alcalá A, Gabree MJ, Tsao H
Melanoma susceptibility genes and risk assessment.
Methods Mol Biol. 2014; 1102:381-93 [PubMed] Related Publications
Familial melanoma accounts for approximately a tenth of all melanoma cases. The most commonly known melanoma susceptibility gene is the highly penetrant CDKN2A (p16INK4a) locus, which is transmitted in an autosomal dominant fashion and accounts for approximately 20-50 % of familial melanoma cases. Mutated p16INK4a shows impaired capacity to inhibit the cyclin D1-CDK4 complex, allowing for unchecked cell cycle progression. Mutations in the second protein coded by CDKN2A, p14ARF, are much less common and result in proteasomal degradation of p53 with subsequent accumulation of DNA damage as the cell progresses through the cell cycle without a functional p53-mediated DNA damage response. Mutations in CDK4 that impair the inhibitory interaction with p16INK4a also increase melanoma risk but these mutations are extremely rare. Genes of the melanin biosynthetic pathway, including MC1R and MITF, have also been implicated in melanomagenesis. MC1R variants were traditionally thought to increase risk for melanoma secondary to intensified UV-mediated DNA damage in the setting of absent photoprotective eumelanin. Accumulation of pheomelanin, which appears to have a carcinogenic effect regardless of UV exposure, may be a more likely mechanism. Impaired SUMOylation of the E318K variant of MITF results in increased transcription of genes that confer melanocytes with a pro-malignant phenotype. Mutations in the tumor suppressor BAP1 enhance the metastatic potential of uveal melanoma and predispose to cutaneous/ocular melanoma, atypical melanocytic tumors, and other internal malignancies (COMMON syndrome). Genome-wide association studies have identified numerous low-risk alleles. Although several melanoma susceptibility genes have been identified, risk assessment tools have been developed only for the most common gene implicated with hereditary melanoma, CDKN2A. MelaPRO, a validated model that relies on Mendelian inheritance and Bayesian probability theories, estimates carrier probability for CDKN2A and future risk of melanoma taking into account a patient's family and past medical history of melanoma. Genetic testing for CDKN2A mutations is currently available but the Melanoma Genetics Consortium recommends offering such testing to patients only in the context of research protocols because clinical utility is uncertain.

Pilarski R, Cebulla CM, Massengill JB, et al.
Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases.
Genes Chromosomes Cancer. 2014; 53(2):177-82 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1. We also studied four additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome. We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1. Two of these three patients presented with UM and the third with a metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Reported family histories included UM, mesothelioma, RCC, CM, and several other internal malignancies. The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC. However, other cancers, such as cholangiocarcinoma and breast carcinoma may be part of the phenotype of this hereditary cancer predisposition syndrome. In addition, the results support the existence of other candidate genes in addition to BAP1 contributing to hereditary predisposition to UM.

Vredenborg A, Böhringer S, Boonk SE, et al.
Acquired melanocytic nevi in childhood and familial melanoma.
JAMA Dermatol. 2014; 150(1):35-40 [PubMed] Related Publications
IMPORTANCE: In the surveillance of familial melanoma, the identification of children at greater risk of developing melanoma later in life would serve as a helpful tool.
OBJECTIVE: To determine whether acquired melanocytic nevi in childhood are an indicator of risk of melanoma in children from families with familial melanoma.
DESIGN, SETTING, AND PARTICIPANTS: A 20-year follow-up study of a cohort of children from families with familial melanoma. Phenotypical data on melanocytic nevi were collected from a random sample of 133 members of families with familial melanoma 2 to 18 years of age with variable risks of being a mutation carrier. More than 20 years of follow-up data (gene-carrier status, diagnosis of melanoma, and excisions of nevi) were collected. In a subgroup of 40 people, childhood phenotypical data were compared with data on nevus numbers in adulthood. Survival analyses, correlation analyses, and t tests were calculated to examine associations.
MAIN OUTCOMES AND MEASURES: Nevus count and distribution in childhood were correlated with the occurrence of melanoma and mutation carrier status.
RESULTS: Significant risk factors for melanoma were found, specifically in the group with the highest risk of being a mutation carrier: total number of atypical nevi in childhood (hazard ratio [HR], 1.21; 95% CI, 1.02-1.44; P = .03), the nevus count of atypical nevi on the buttocks (HR, 14.00; 95% CI, 2.94-66.55; P = .001), and the number of excisions during follow-up (HR, 1.27; 95% CI, 1.23-1.31; P < .001). The analysis also found a correlation between the distribution of nevi in childhood and adulthood and the distribution of melanomas (correlation, 0.89; 95% CI, 0.67-0.96; and correlation, 0.99; 95% CI, 0.98-1.00; P < .001, respectively for both).
CONCLUSIONS AND RELEVANCE: Numbers and distribution of melanocytic nevi in childhood are major indicators of the risk of melanoma in patients from families with familial melanoma.

Li WQ, Han J, Widlund HR, et al.
CXCR4 pathway associated with family history of melanoma.
Cancer Causes Control. 2014; 25(1):125-32 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
PURPOSE: Genetic predisposition plays a major role in the etiology of melanoma, but known genetic markers only account for a limited fraction of family-history-associated melanoma cases. Expression microarrays have offered the opportunity to identify further genomic profiles correlated with family history of melanoma. We aimed to distinguish mRNA expression signatures between melanoma cases with and without a family history of melanoma.
METHODS: Based on the Nurses' Health Study, family history was defined as having one or more first-degree family members diagnosed with melanoma. Melanoma diagnosis was confirmed by reviewing pathology reports, and tumor blocks were collected by mail from across the USA. Genomic interrogation was accomplished through evaluating expression profiling of formalin-fixed paraffin-embedded tissues from 78 primary cutaneous invasive melanoma cases, on either a 6K or whole-genome (24K) Illumina gene chip. Gene set enrichment analysis was performed for each batch to determine the differentially enriched pathways and key contributing genes.
RESULTS: The CXC chemokine receptor 4 (CXCR4) pathway was consistently up-regulated within cases of familial melanoma in both platforms. Leading edge analysis showed four genes from the CXCR4 pathway, including MAPK1, PLCG1, CRK, and PTK2, were among the core members that contributed to the enrichment of this pathway. There was no association between the enrichment of CXCR4 pathway and NRAS, BRAF mutation, or Breslow thickness of the primary melanoma cases.
CONCLUSIONS: We found that the CXCR4 pathway might constitute a novel susceptibility pathway associated with family history of melanoma in first-degree relatives.

Cheng YP, Chiu HY, Hsiao TL, et al.
Scalp melanoma in a woman with LEOPARD syndrome: possible implication of PTPN11 signaling in melanoma pathogenesis.
J Am Acad Dermatol. 2013; 69(4):e186-7 [PubMed] Related Publications

Burke LS, Hyland PL, Pfeiffer RM, et al.
Telomere length and the risk of cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations.
PLoS One. 2013; 8(8):e71121 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
INTRODUCTION: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations.
MATERIALS AND METHODS: We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT.
RESULTS: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02-7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction.
DISCUSSION: Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.

Silva AG, Lisboa BC, Achatz MI, et al.
Germline BAX deletion in a patient with melanoma and gastrointestinal stromal tumor.
Am J Gastroenterol. 2013; 108(8):1372-5 [PubMed] Related Publications

Oike T, Ogiwara H, Nakano T, et al.
Inactivating mutations in SWI/SNF chromatin remodeling genes in human cancer.
Jpn J Clin Oncol. 2013; 43(9):849-55 [PubMed] Related Publications
Chromosomal deoxyribonucleic acid and histone proteins form a highly condensed structure known as chromatin. Chromatin remodeling proteins regulate deoxyribonucleic acid transcription, synthesis and repair by changing nucleosomal composition in an adenosine triphosphate-dependent manner and mediate access of deoxyribonucleic acid-binding proteins to deoxyribonucleic acid double strands. Recently, large-scale genome sequencing studies identified somatic mutations in genes encoding chromatin remodeling proteins in a variety of human solid cancers. Notably, inactivating mutations in genes encoding the catalytic and regulatory subunits of the switch/sucrose non-fermenting chromatin remodeling complex have been detected in several solid cancers: sucrose non-fermenting/switch/sucrose non-fermenting-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1/Brahma-related gene 1-associated factor 47/integrase interactor 1 mutations in rhabdoid tumors; AT-rich interactive domain-containing protein 1 A/Brahma-related gene 1-associated factor 250a mutations in ovarian clear cell carcinoma, hepatocellular carcinoma and gastric adenocarcinoma; polybromo 1/Brahma-related gene 1-associated factor 180 mutations in renal clear cell carcinoma; Brahma-related gene 1/switch/sucrose non-fermenting-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 mutations in non-small-cell lung carcinoma and AT-rich interactive domain-containing protein 2/Brahma-related gene 1-associated factor 200 mutations in hepatocellular carcinoma and malignant melanoma. This suggests that the switch/sucrose non-fermenting complex has a tumor-suppressive function, and that switch/sucrose non-fermenting gene deficiencies may affect the properties of cancer cells, which could be of value for the development of novel therapeutic strategies.

van der Rhee JI, Boonk SE, Putter H, et al.
Surveillance of second-degree relatives from melanoma families with a CDKN2A germline mutation.
Cancer Epidemiol Biomarkers Prev. 2013; 22(10):1771-7 [PubMed] Related Publications
BACKGROUND: Lifetime melanoma risk of mutation carriers from families with a germline mutation in the CDKN2A gene is estimated to be 67%. The necessity to include family members in a melanoma surveillance program is widely endorsed, but there is no consensus on which family members should be invited.
METHODS: In a retrospective follow-up study, we investigated the yield of surveillance of first- and second-degree relatives of melanoma and pancreatic cancer patients from 21 families with the "p16-Leiden" CDKN2A mutation. Melanoma incidence rates were compared with the general population.
RESULTS: Three-hundred and fifty-four first-degree relatives and 391 second-degree relatives were included. Forty-five first-degree relatives and 11 second-degree relatives were diagnosed with melanoma. Most (72%) of second-degree relatives diagnosed with melanoma had become a first-degree relative before diagnosis, due to the occurrence of a melanoma in a parent or sibling. Overall, melanoma incidence rate was 2.1 per 1,000 person years [95% confidence interval (CI), 1.2-3.8] in family members still being second-degree relatives at diagnosis, compared with 9.9 per 1,000 person years (95% CI, 7.4-13.3) in first-degree relatives. The standardized morbidity ratio for melanoma of second-degree relatives compared with the general population was 12.9 (95% CI, 7.2-23.4).
CONCLUSION: Second-degree relatives from families with the p16-Leiden mutation in CDKN2A have a considerably increased melanoma risk compared with the general population.
IMPACT: This study provides justification for the surveillance of second-degree relatives from families with a CDKN2A germline mutation.

Cheung M, Talarchek J, Schindeler K, et al.
Further evidence for germline BAP1 mutations predisposing to melanoma and malignant mesothelioma.
Cancer Genet. 2013; 206(5):206-10 [PubMed] Related Publications
We describe a new family with a novel germline BAP1 nonsense mutation, c.723T>G, which leads to a predicted truncated protein, p.Y241*, or nonsense-mediated decay of the BAP1 mRNA. The proband had uveal melanoma (UM), and his paternal family has a remarkable history of multiple cancers. The proband's father had both pleural malignant mesothelioma (MM) and cutaneous melanoma (CM); a paternal uncle had lung cancer, CM, and UM; and a grandmother had CM. The findings in this family provide further support for the existence of a BAP1 cancer syndrome that predisposes to MM, various melanocytic neoplasms, and potentially other cancers. The fact that several members of the family manifested two or more different types of cancer suggests widespread BAP1-related tumor susceptibility targeting tissues of multiple organs. In addition, a review of BAP1 cancer syndrome families reported to date indicates that the location of the BAP1 mutation does not have any bearing on the spectrum of cancer types observed, either for mesothelial or melanocytic tumors.

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