Familial Melanoma


Literature Analysis

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

  • Molecular Sequence Data
  • Skin Cancer
  • CDKN2A Protein
  • CDKN2A
  • CDK4
  • Risk Factors
  • Receptor, Melanocortin, Type 1
  • Incidence
  • Cancer DNA
  • DNA Mutational Analysis
  • Childhood Cancer
  • Germ-Line Mutation
  • Sunlight
  • Pedigree
  • Polymorphism
  • Cyclin-Dependent Kinases
  • Melanoma
  • Phenotype
  • Tumor Suppressor Protein p14ARF
  • Hereditary Neoplastic Syndromes
  • Chromosome 9
  • Dysplastic Nevus Syndrome
  • Genetic Testing
  • Carrier Proteins
  • CDK6
  • Genetic Predisposition
  • Genetic Linkage
  • Multiple Primary Neoplasms
  • Recombinant Fusion Proteins
  • BAP1
  • Mutation
  • Point Mutation
  • Chromosome Mapping
  • Ultraviolet Rays
  • Base Sequence
  • Adolescents
  • Family Health
  • POT1
  • Proto-Oncogene Proteins
  • Familial Melanoma
  • Tumor Suppressor Proteins
  • Young Adult
  • Italy
Tag cloud generated 29 August, 2019 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'.

CDKN2A 9p21.3 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
MC1R 16q24.3 CMM5, MSH-R, SHEP2 -MC1R Polymorphisms and Melanoma
CDK4 12q14.1 CMM3, PSK-J3 Germline
-CDK4 Germline Mutations in Melanoma Prone Families
BAP1 3p21.1 UCHL2, hucep-6, HUCEP-13 Germline
-BAP1 and Melanoma
CDK6 7q21.2 MCPH12, PLSTIRE -CDK6 and Melanoma
POT1 7q31.33 GLM9, CMM10, HPOT1 Germline
-POT1 and Predisposition to Familial Melanoma

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

Latest Publications

He M, Chaurushiya MS, Webster JD, et al.
Intrinsic apoptosis shapes the tumor spectrum linked to inactivation of the deubiquitinase BAP1.
Science. 2019; 364(6437):283-285 [PubMed] Related Publications
Malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. For example,

Wong K, van der Weyden L, Schott CR, et al.
Cross-species genomic landscape comparison of human mucosal melanoma with canine oral and equine melanoma.
Nat Commun. 2019; 10(1):353 [PubMed] Free Access to Full Article Related Publications
Mucosal melanoma is a rare and poorly characterized subtype of human melanoma. Here we perform a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary canine oral and 28 primary equine melanoma cases from mucosal sites. Analysis of these data reveals recurrently mutated driver genes shared between species such as NRAS, FAT4, PTPRJ, TP53 and PTEN, and pathogenic germline alleles of BRCA1, BRCA2 and TP53. We identify a UV mutation signature in a small number of samples, including human cases from the lip and nasal mucosa. A cross-species comparative analysis of recurrent copy number alterations identifies several candidate drivers including MDM2, B2M, KNSTRN and BUB1B. Comparison of somatic mutations in recurrences and metastases to those in the primary tumor suggests pervasive intra-tumor heterogeneity. Collectively, these studies suggest a convergence of some genetic changes in mucosal melanomas between species but also distinctly different paths to tumorigenesis.

Visser M, van der Stoep N, Gruis N
Progress report on the major clinical advances in patient-oriented research into familial melanoma (2013-2018).
Fam Cancer. 2019; 18(2):267-271 [PubMed] Related Publications

Melzer C, Sharma A, Peters S, et al.
Basal cell carcinomas developing independently from BAP1-tumor predisposition syndrome in a patient with bilateral uveal melanoma: Diagnostic challenges to identify patients with BAP1-TPDS.
Genes Chromosomes Cancer. 2019; 58(6):357-364 [PubMed] Related Publications
Basal cell carcinomas (BCC) have been recently included into the spectrum of BAP1-tumor predisposition syndrome (TPDS). Uveal melanoma (UM) is also a tumor often observed in patients with this hereditary tumor syndrome, in particular bilateral UM is highly suspicious for BAP1-TPDS although no patient has been reported yet. Based on our index patient with BAP1-TPDS with bilateral UM (choroid OD, oculus dexter; iris OS, oculus sinister), several BCCs and thyroid cancer as well as a family history for cancer, this paper analyzes hints and pitfalls to diagnose this syndrome clinically and histologically. A previously undescribed germline variant, namely a heterozygous deletion of a single nucleotide on position 2001 (c.2001delG;p.[Thr668Profs*24] in exon 16 of the BAP1 gene), was identified. Structural changes in the C-terminal of the BAP1 protein were observed by in silico analysis. While the excised iris melanoma showed loss of BAP1 nuclear staining by immunohistochemical staining, the BCCs of our patient (and in the control group, n = 13) were BAP1 positive. Genetic analysis of the BCC of the ocular adnexae confirmed a remaining intact BAP1 copy. The constellation of (bilateral) UM in combination with BCC should raise suspicion for a BAP1-TPDS. As our BCCs probably developed independently from the BAP1-TPDS and UMs frequently show loss of nuclear BAP1 staining, genetic analysis is mandatory to diagnose this syndrome.

Ewens KG, Lalonde E, Richards-Yutz J, et al.
Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma.
BMC Cancer. 2018; 18(1):1172 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma. Alternatively, somatic mutations in BAP1 in UM have been associated with high risk for metastasis. In this study, we compare the risk of metastasis in UM that carry germline versus somatic BAP1 mutations and mutation-negative tumors.
METHODS: DNA extracted from 142 UM and matched blood samples was sequenced using Sanger or next generation sequencing to identify BAP1 gene mutations.
RESULTS: Eleven of 142 UM (8%) carried germline BAP1 mutations, 43 (30%) had somatic mutations, and 88 (62%) were mutation-negative. All BAP1 mutations identified in blood samples were also present in the matched UM. There were 52 unique mutations in 54 tumors. All were pathogenic or likely pathogenic. A comparison of tumors carrying somatic vs. germline mutations, or no mutations, showed a higher frequency of metastasis in tumors carrying somatic mutations: 74% vs. 36%, P=0.03 and 74% vs. 26% P<0.001, respectively. Tumors with a somatic mutation compared to mutation-negative had an older age of diagnosis of (61.8 vs. 52.2 years, P=0.002), and shorter time to metastasis (16 vs. 26 months, P=0.04). Kaplan-Meier analysis further showed that tumors with somatic (vs. germline) mutations demonstrated a greater metastatic risk (P=0.03). Cox multivariate analysis showed in addition to chromosome-3 monosomy and larger tumor diameter, the presence of BAP1 somatic, but not germline mutations, was significantly associated with risk of metastasis(P=0.02). Personal or family history of BAP1-TPDS was available for 79 of the cases. All eight cases with germline mutations reported a history of BAP1-TPDS, which was significantly greater than what was observed in cases with somatic mutations (10 of 23, P=0.009) or mutation-negative cases (11 of 48, P<0.001).
CONCLUSIONS: Defining germline vs. somatic nature of BAP1 mutations in UM can inform the individual about both the risk of metastasis, and the time to metastasis, which are critically important outcomes for the individual. This information can also change the cascade screening and surveillance of family members.

Potjer TP, Bollen S, Grimbergen AJEM, et al.
Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non-CDKN2A/CDK4 melanoma families.
Int J Cancer. 2019; 144(10):2453-2464 [PubMed] Free Access to Full Article Related Publications
Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10-40% of melanoma-prone families. In our study we comprehensively characterized 488 melanoma cases from 451 non-CDKN2A/CDK4 families for mutations in 30 established and candidate melanoma susceptibility genes using a custom-designed targeted gene panel approach. We identified (likely) pathogenic variants in established melanoma susceptibility genes in 18 families (n = 3 BAP1, n = 15 MITF p.E318K; diagnostic yield 4.0%). Among the three identified BAP1-families, there were no reported diagnoses of uveal melanoma or malignant mesothelioma. We additionally identified two potentially deleterious missense variants in the telomere maintenance genes ACD and TERF2IP, but none in the POT1 gene. MC1R risk variants were strongly enriched in our familial melanoma cohort compared to healthy controls (R variants: OR 3.67, 95% CI 2.88-4.68, p <0.001). Several variants of interest were also identified in candidate melanoma susceptibility genes, in particular rare (pathogenic) variants in the albinism gene OCA2 were repeatedly found. We conclude that multigene panel testing for familial melanoma is appropriate considering the additional 4% diagnostic yield in non-CDKN2A/CDK4 families. Our study shows that BAP1 and MITF are important genes to be included in such a diagnostic test.

Dalmasso B, Pastorino L, Ciccarese G, et al.
CDKN2A germline mutations are not associated with poor survival in an Italian cohort of melanoma patients.
J Am Acad Dermatol. 2019; 80(5):1263-1271 [PubMed] Related Publications
BACKGROUND: Cyclin dependent kinase inhibitor 2A gene (CDKN2A) germline mutations have recently been associated with poor survival in patients with melanoma. Despite the high mutation rate in our cohort (up to 10% in patients with apparently sporadic melanoma), information on the impact of CDKN2A on survival in this cohort is lacking.
OBJECTIVE: To investigate whether poor survival associated with CDKN2A germline mutations was confirmed in a high mutation-prevalence cohort of Italian patients with melanoma undergoing a mutation-based follow-up.
METHODS: A total of 1239 patients with cutaneous melanoma were tested for CDKN2A mutational status and then assigned to a follow-up scheme according not only to family history but also to CDKN2A mutational status, as follow-up intervals were more frequent for CDKN2A germline mutation-positive (MUT
RESULTS: We found no difference in overall survival (hazard ratio, 0.85; 95% confidence interval, 0.48-1.52; P = .592,) or melanoma-specific survival (hazard ratio, 0.86; 95% confidence interval, 0.38-1.95; P = .718,) between MUT
LIMITATIONS: Retrospective study.
CONCLUSION: CDKN2A mutations were not associated with survival in our cohort.

Gironi LC, Colombo E, Pasini B, et al.
Melanoma-prone families: new evidence of distinctive clinical and histological features of melanomas in CDKN2A mutation carriers.
Arch Dermatol Res. 2018; 310(10):769-784 [PubMed] Related Publications
Germline mutations on the CDKN2A gene, the most important known genetic factors associated with cutaneous melanomas (CMs), predispose carriers to multiple primary CMs (MPMs) with higher frequency and younger onset compared to non-carriers. Most of the largest published studies concerning clinical and histological characteristics of CMs with CDKN2A mutation carriers did not specify if the described CMs are first or subsequent to the first, and they used sporadic CMs from non-genotyped patients as controls. We conducted a single-centre observational study to compare clinical and histological CM features of 32 unrelated carriers (MUT) of 5 germline CDKN2A mutations (one of which was never previously described) compared to 100 genotyped wild-type (WT) patients. We stratified the data based on time of diagnosis, anatomical site and histological subtype of CMs, demonstrating several significant unreported differences between the two groups. MUT developed a higher number of dysplastic nevi and MPMs. We proved for the first time that anatomical distribution of CMs in MUT was independent of gender, unlike WTs. MUTs developed in situ and superficial spreading melanomas (SSMs) more frequently, with significantly higher number of SSMs on the head/neck. In MUTs, Breslow thickness was significantly lower for all invasive CMs. When CMs were stratified on the basis of the time of occurrence, statistical significance was maintained only for SSMs subsequent to the first. In WTs, Clark level was significantly higher, and ulceration was more prevalent than in MUTs. Significant differences in ulceration were observed only in SSMs. In nodular CMs, we did not find differences in terms of Breslow thickness or ulceration between WTs and MUTs. In situ CMs developed 10 years earlier in MUTs with respect to WTs, whereas no significant differences were observed in invasive CMs. In contrast to those reported previously by other authors, we did not find a difference in skin phototype.

Sá BCS, Moredo LF, Gomes EE, et al.
Hereditary melanoma: a five-year study of Brazilian patients in a cancer referral center - phenotypic characteristics of probands and pathological features of primary tumors.
An Bras Dermatol. 2018; 93(3):337-340 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Approximately five to 10% of all melanomas occur in families with hereditary predisposition and the main high-risk melanoma susceptibility gene is the CDKN2A.
OBJECTIVES: To describe, after a five-years study, the clinical data of patients (probands) from familial melanoma kindreds, and the pathological characteristics of their melanoma.
METHODS: The inclusion criteria were melanoma patients with a family history of melanoma or pancreatic cancer (first- or second-degree relatives) or patients with multiple primary melanomas (MPM).
RESULTS: A total of 124 probands were studied, where 64 were considered familial cases and 60 MPM. Mean age at diagnosis was 50 years. Our results show that the following characteristics were prevalent: skin phototype I/II (89.5%), sunburn during childhood (85.5%), total number of nevi ≥50 (56.5%), Breslow thickness ≤1.0mm (70.2%), tumors located on the trunk (53.2%) and superficial spreading melanomas (70.2%).
STUDY LIMITATIONS: Analyses of probands' relatives will be demonstrated in future publication.
CONCLUSIONS: Our findings are in agreement with previous familial melanomas reports. Fifteen new melanomas in 11 patients were diagnosed during follow up, all of which were ≤1.0 mm. This is the largest dataset of Brazilian melanoma prone kindreds to date, thus providing a complete database for future genetic studies.

Karagianni F, Njauw CN, Kypreou KP, et al.
CDKN2A/CDK4 Status in Greek Patients with Familial Melanoma and Association with Clinico-epidemiological Parameters.
Acta Derm Venereol. 2018; 98(9):862-866 [PubMed] Free Access to Full Article Related Publications
Approximately 5-10% of melanoma cases occur in a familial context. CDKN2A/CDK4 were the first high-penetrance melanoma genes identified. The aims of this study were to evaluate CDKN2A/CDK4 variants in Greek familial melanoma patients and to correlate the mutational status with specific clinico-epidemiological characteristics. A cross-sectional study was conducted by genotyping CDKN2A/CDK4 variants and selected MC1R polymorphisms in 52 melanoma-prone families. Descriptive statistics were calculated and comparisons were made using the χ2 test, Fisher's exact test and Student's t-test for statistical analysis, as appropriate. CDKN2A variants were detected in 46.2% of melanoma-prone families, while a CDK4 variant was found in only one family. This study confirmed that, in the Greek population, the age at melanoma diagnosis was lower in patients carrying a variant in CDKN2A compared with wild-type patients. No statistically significant associations were found between CDKN2A mutational status and MC1R polymorphisms.

Dębniak T, Scott RJ, Lea RA, et al.
Founder Mutations for Early Onset Melanoma as Revealed by Whole Exome Sequencing Suggests That This is Not Associated with the Increasing Incidence of Melanoma in Poland.
Cancer Res Treat. 2019; 51(1):337-344 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Germline mutations within melanoma susceptibility genes are present only in minority of melanoma patients and it is expected that additional genes will be discovered with next generation sequence technology and whole-exome sequencing (WES).
Materials and Methods: Herein we performed WES on a cohort of 96 unrelated Polish patients with melanoma diagnosed under the age of 40 years who all screened negative for the presence of CDKN2Avariants. A replication study using a set of 1,200 melanoma patient DNA samples and similarly large series of healthy controls was undertaken.
RESULTS: We selected 21 potentially deleterious variants in 20 genes (VRK1, MYCT1, DNAH14, CASC3, MS4A12, PRC1, WWOX, CARD6, EXO5, CASC3, CASP8AP2, STK33, SAMD11, CNDP2, CPNE1, EFCAB6, CABLES1, LEKR1, NUDT17, and RRP15), which were identified by WES and confirmed by Sanger sequencing for an association study. Evaluation of the allele distribution among carriers and their relatives in available family trios revealed that these variants were unlikely to account for many familial cases of melanoma. Replication study revealed no statistically significant differences between cases and controls.
CONCLUSION: Although most of the changes seemed to be neutral we could not exclude an association between variants in VRK1, CREB3L3, EXO5, and STK33 with melanoma risk.

Rodrigues M, Mobuchon L, Houy A, et al.
Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors.
Nat Commun. 2018; 9(1):1866 [PubMed] Free Access to Full Article Related Publications
Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors.

Garfield EM, Walton KE, Quan VL, et al.
Histomorphologic spectrum of germline-related and sporadic BAP1-inactivated melanocytic tumors.
J Am Acad Dermatol. 2018; 79(3):525-534 [PubMed] Related Publications
BACKGROUND: BRCA1-associated protein 1 (BAP1)-inactivated melanocytic tumors (BIMTs) are often the earliest sign of the BAP1 tumor predisposition syndrome. Identification of BIMTs and selection of patients for germline testing affect the lives of patients with germline BAP1 mutations.
OBJECTIVE: To describe the spectrum of histomorphologic findings in BAP1-inactivated melanocytic lesions to improve their recognition. We determined the frequency of sporadic versus germline cases in our cohort, assessing whether any features were statistically linked to germline status.
METHODS: Histomorphologic features of BAP1-inactivated melanocytic lesions were analyzed by comparing cases with germline mutations with those with unknown or negative status. Available clinical follow-up data were reported.
RESULTS: The histomorphologic spectrum of BAP1-inactivated melanocytic lesions is broad; it includes cases with spitzoid cytomorphology (69%), smaller epithelioid cells without spitzoid features (31%), and rhabdoid cytologic features (58%). BIMTs from patients with germline mutations were statistically more likely to have an extensive junctional component of BAP1-inactivated melanocytes (P = .0177). All 11 patients with suspected or confirmed germline mutations had a history of cutaneous melanoma or multiple BIMTs.
LIMITATIONS: The unknown germline status of 77 patients.
CONCLUSION: Approximately 12% of patients with BIMTs have germline mutations. Extensive junctional involvement in a BIMT and a personal history of melanoma or previous BIMT may be additional indications for germline testing.

Potrony M, Puig-Butille JA, Farnham JM, et al.
Genome-wide linkage analysis in Spanish melanoma-prone families identifies a new familial melanoma susceptibility locus at 11q.
Eur J Hum Genet. 2018; 26(8):1188-1193 [PubMed] Free Access to Full Article Related Publications
The main genetic factors for familial melanoma remain unknown in >75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain <3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3, and 6 families with 2, 3, and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4, and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD >1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family-specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409), and 11q13.3-q21 (max. TLOD 2.654). Future next-generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.

Shukla SA, Bachireddy P, Schilling B, et al.
Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade.
Cell. 2018; 173(3):624-633.e8 [PubMed] Free Access to Full Article Related Publications
CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.

Pritchard AL, Johansson PA, Nathan V, et al.
Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers.
PLoS One. 2018; 13(4):e0194098 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: While a number of autosomal dominant and autosomal recessive cancer syndromes have an associated spectrum of cancers, the prevalence and variety of cancer predisposition mutations in patients with multiple primary cancers have not been extensively investigated. An understanding of the variants predisposing to more than one cancer type could improve patient care, including screening and genetic counselling, as well as advancing the understanding of tumour development.
METHODS: A cohort of 57 patients ascertained due to their cutaneous melanoma (CM) diagnosis and with a history of two or more additional non-cutaneous independent primary cancer types were recruited for this study. Patient blood samples were assessed by whole exome or whole genome sequencing. We focussed on variants in 525 pre-selected genes, including 65 autosomal dominant and 31 autosomal recessive cancer predisposition genes, 116 genes involved in the DNA repair pathway, and 313 commonly somatically mutated in cancer. The same genes were analysed in exome sequence data from 1358 control individuals collected as part of non-cancer studies (UK10K). The identified variants were classified for pathogenicity using online databases, literature and in silico prediction tools.
RESULTS: No known pathogenic autosomal dominant or previously described compound heterozygous mutations in autosomal recessive genes were observed in the multiple cancer cohort. Variants typically found somatically in haematological malignancies (in JAK1, JAK2, SF3B1, SRSF2, TET2 and TYK2) were present in lymphocyte DNA of patients with multiple primary cancers, all of whom had a history of haematological malignancy and cutaneous melanoma, as well as colorectal cancer and/or prostate cancer. Other potentially pathogenic variants were discovered in BUB1B, POLE2, ROS1 and DNMT3A. Compared to controls, multiple cancer cases had significantly more likely damaging mutations (nonsense, frameshift ins/del) in tumour suppressor and tyrosine kinase genes and higher overall burden of mutations in all cancer genes.
CONCLUSIONS: We identified several pathogenic variants that likely predispose to at least one of the tumours in patients with multiple cancers. We additionally present evidence that there may be a higher burden of variants of unknown significance in 'cancer genes' in patients with multiple cancer types. Further screens of this nature need to be carried out to build evidence to show if the cancers observed in these patients form part of a cancer spectrum associated with single germline variants in these genes, whether multiple layers of susceptibility exist (oligogenic or polygenic), or if the occurrence of multiple different cancers is due to random chance.

De Unamuno B, García-Casado Z, Bañuls J, et al.
CDKN2A germline alterations in melanoma patients with personal or familial history of pancreatic cancer.
Melanoma Res. 2018; 28(3):246-249 [PubMed] Related Publications
CDKN2A germline mutations increase the risk of melanoma development and are present in 20 and 10% of familial and multiple melanoma cases, respectively. Pancreatic cancer has been associated with CDKN2A in some populations and, accordingly, its presence in first-degree or second-degree relatives of a melanoma patient is considered as a criterion for genetic testing. In this study, we show that in an area with low melanoma incidence, CDKN2A germline mutations in patients with melanoma and personal or family history of pancreatic cancer are mainly present in the setting of familial or multiple melanoma cases. In addition, a relatively young age (≤52 years) at pancreatic diagnosis is an additional single criterion that might also be considered.

Nabil R, Plasmeijer E, van Doorn R, et al.
Unscheduled Visits of Patients with Familial Melanoma to a Pigmented Lesion Clinic: Evaluation of Patients' Characteristics and Suspicious Lesions.
Acta Derm Venereol. 2018; 98(7):667-670 [PubMed] Related Publications
Approximately 10% of all melanomas occur in subjects with a family history of melanoma. This retrospective follow-up study investigated the characteristics of patients with familial melanoma who made unscheduled visits to our pigmented lesions clinic, and the diagnosis of excised lesions. A total of 110 (9%) out of 1,267 patients made at least one unscheduled visit between May 2011 and February 2016. Histopathology was taken from 59 patients. Thirty-four naevi, 7 melanomas and 3 basal cell carcinomas were detected. All patients with melanoma were CDKN2A carriers and all melanomas were discovered at a very early stage. In this patient population it appears to be safe to limit visits to once or twice yearly, provided patients are easily able to make an unscheduled extra visit if they have a worrisome lesion. We recommend supporting patients' self-reliance by stimulating them to carry out self-examination of their skin.

Müller C, Krunic M, Wendt J, et al.
Germline Variants in the POT1-Gene in High-Risk Melanoma Patients in Austria.
G3 (Bethesda). 2018; 8(5):1475-1480 [PubMed] Free Access to Full Article Related Publications
Risk of melanoma is in part determined by genetic factors. Currently the only established high penetrance familial melanoma genes are CDKN2A and CDK4. Recent studies reported germline variants in POT1 in melanoma families. In the present study, we sequenced the entire POT1 gene in 694 patients from the M3-study. Patients with multiple primary melanomas (n = 163) or with a positive family history (n = 133) were classified as high-risk melanoma patients. Additionally, 200 single primary melanoma patients and 198 non-melanoma controls were sequenced. For prediction analysis 10 different tools were used.In total 53 different variants were found, of which 8 were detected in high-risk melanoma patients, only. Two out of these 8 variants were located in exons and were non-synonymous: g.124510982 G>A (p.R80C) and g.124491977 T>G (p.N300H). While g.124491977 T>G was predicted to be neutral, 80% of the prediction tools classified g.124510982 G>A as deleterious. The variant, g.124467236 T>C, which possibly causes a change in the splice site was identified in a case with a positive family history in the present study. Another variant in the 5-UTR, g.124537261 A>G, was found in 2 high-risk patients. So, in conclusion, melanoma associated POT1 germline variants seem to be rare. Further studies are required to evaluate the role of POT1 for genetic counseling.

Artomov M, Stratigos AJ, Kim I, et al.
Rare Variant, Gene-Based Association Study of Hereditary Melanoma Using Whole-Exome Sequencing.
J Natl Cancer Inst. 2017; 109(12) [PubMed] Free Access to Full Article Related Publications
Background: Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we performed an exome-wide, gene-based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM).
Methods: Using 11 990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by large-scale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Four models were used to estimate the association among different types of variants. In vitro functional validation was performed using three human melanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of human melanoma A375 melanoma cells in nude mice (eight mice per group). All statistical tests were two-sided.
Results: Strong signals were detected for CDKN2A (Pmin = 6.16 × 10-8) in the CM cohort (n = 273) and BAP1 (Pmin = 3.83 × 10-6) in the OM (n = 99) cohort. Eleven genes that exhibited borderline association (P < 10-4) were independently validated using The Cancer Genome Atlas melanoma cohort (379 CM, 47 OM) and a matched set of 3563 European controls with CDKN2A (P = .009), BAP1 (P = .03), and EBF3 (P = 4.75 × 10-4), a candidate risk locus, all showing evidence of replication. EBF3 was then evaluated using germline data from a set of 132 familial melanoma cases and 4769 controls of UK origin (joint P = 1.37 × 10-5). Somatically, loss of EBF3 expression correlated with progression, poorer outcome, and high MITF tumors. Functionally, induction of EBF3 in melanoma cells reduced cell growth in vitro, retarded tumor formation in vivo, and reduced MITF levels.
Conclusions: The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene.

Arbesman J, Ravichandran S, Funchain P, Thompson CL
Melanoma cases demonstrate increased carrier frequency of phenylketonuria/hyperphenylalanemia mutations.
Pigment Cell Melanoma Res. 2018; 31(4):529-533 [PubMed] Free Access to Full Article Related Publications
Identifying novel melanoma genetic risk factors informs screening and prevention efforts. Mutations in the phenylalanine hydroxylase gene (the causative gene in phenylketonuria) lead to reduced pigmentation in untreated phenylketonuria patients, and reduced pigmentation is associated with greater melanoma risk. Therefore, we sought to characterize the relationship between phenylketonuria carrier status and melanoma risk. Using National Newborn Screening Reports, we determined the United States phenylketonuria/hyperphenylalanemia carrier frequency in Caucasians to be 1.76%. We examined three publically available melanoma datasets for germline mutations in the phenylalanine hydroxylase gene associated with classic phenylketonuria and/or hyperphenylalanemia. Mutations were identified in 29/814 melanoma patients, with a carrier frequency of 3.56%. There was a twofold enrichment (p-value = 3.4 × 10

Star P, Goodwin A, Kapoor R, et al.
Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy.
Eur J Cancer. 2018; 92:48-53 [PubMed] Related Publications
The germline BAP1 (BRCA1-associated protein-1) mutation and associated cancer pre-disposition syndrome was first described in 2011. Since then, physicians have considered this diagnosis for patients with a characteristic personal or family history of BAP1-associated tumours (mainly uveal and cutaneous melanoma, pleural/peritoneal mesothelioma, renal cell carcinoma and BAP1-deficient melanocytic lesions). However, a positive germline BAP1 mutation detection creates significant uncertainty in terms of appropriate cancer surveillance. A number of groups have proposed surveillance plans but important management dilemmas remain unresolved. The lifetime risk of developing cancer is not known and it is not clear if surveillance would lead to detecting cancer at an earlier stage or change survival outcomes. A consensus monitoring strategy was initially proposed at the Melanoma Institute Australia Melanoma Multidisciplinary Team meeting and later discussed with specialists in the field of cancer genetics, pathology, radiology, medical oncology, ophthalmology and dermatology. The objectives were to facilitate early diagnosis, incorporating where possible, clinically based and low/non-ionising radiation imaging modalities, applying the principles of a good screening test and a multidisciplinary focus.

Huerta C, Garcia-Casado Z, Bañuls J, et al.
Characteristics of Familial Melanoma in Valencia, Spain, Based on the Presence of CDKN2A Mutations and MC1R Variants.
Acta Derm Venereol. 2018; 98(5):512-516 [PubMed] Related Publications
Melanoma results from a complex interplay between environmental factors and individual genetic susceptibility. Familial melanoma is attributable to predisposition genes with variable penetrance. The aim of this study was to identify differences between familial melanoma and sporadic cases in our population, based on the presence of CDKN2A mutations and MC1R variants. Comparing 107 patients with familial melanoma from 87 families (17% CDKN2A mutated) with 1,390 cases of sporadic melanomas, the former were younger and exhibited an increased prevalence of atypical naevi and squamous cell carcinoma (SCC). CDKN2A mutation carriers presented more atypical naevi, multiple melanomas, and basal cell carcinoma, while non-carriers were more likely to have light-coloured hair, atypical naevi, and SCC. MC1R variants decreased the age at diagnosis in all groups and were associated with an increased prevalence of SCC, especially in patients with familial melanoma without CDKN2A mutations. These characteristics may help to establish prevention measures targeting patients with familial melanoma in the Mediterranean area.

Aspinwall LG, Stump TK, Taber JM, et al.
Genetic test reporting of CDKN2A provides informational and motivational benefits for managing melanoma risk.
Transl Behav Med. 2018; 8(1):29-43 [PubMed] Free Access to Full Article Related Publications
A CDKN2A/p16 mutation confers 28%-67% lifetime melanoma risk, a risk that may be moderated by ultraviolet radiation exposure. The aim of this study was to test whether melanoma genetic counseling and test disclosure conferred unique informational, motivational, or emotional benefits compared to family history-based counseling. Participants included were 114 unaffected members of melanoma-prone families, ages 16-69, 51.8% men, 65.8% with minor children or grandchildren. Carriers (n = 28) and noncarriers (n = 41) from families with a CDKN2A mutation were compared to no-test controls (n = 45) from melanoma-prone families without an identifiable CDKN2A mutation. All participants received equivalent counseling about melanoma risk and management; only CDKN2A participants received genetic test results. Using newly developed inventories, participants rated perceived costs and benefits for managing their own and their children's or grandchildren's melanoma risk 1 month and 1 year after counseling. Propensity scores controlled for baseline family differences. Compared to no-test controls, participants who received test results (carriers and noncarriers) reported feeling significantly more informed and prepared to manage their risk, and carriers reported greater motivation to reduce sun exposure. All groups reported low negative emotions about melanoma risk. Parents reported high levels of preparedness to manage children's risk regardless of group. Carrier parents reported greater (but moderate) worry about their children's risk than no-test control parents. Women, older, and more educated respondents reported greater informational and motivational benefits regardless of group. Genetic test results were perceived as more informative and motivating for personal sun protection efforts than equivalent counseling based on family history alone.

Yu Y, Hu H, Chen JS, et al.
Integrated case-control and somatic-germline interaction analyses of melanoma susceptibility genes.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(6 Pt B):2247-2254 [PubMed] Free Access to Full Article Related Publications
While a number of genes have been implicated in melanoma susceptibility, the role of protein-coding variation in melanoma development and progression remains underexplored. To better characterize the role of germline coding variation in melanoma, we conducted a whole-exome case-control and somatic-germline interaction study involving 322 skin cutaneous melanoma cases from The Cancer Genome Atlas and 3607 controls of European ancestry. We controlled for cross-platform technological stratification using XPAT and conducted gene-based association tests using VAAST 2. Four established melanoma susceptibility genes achieved nominal statistical significance, MC1R (p = .0014), MITF (p = .0165) BRCA2 (p = .0206), and MTAP (p = .0393). We also observed a suggestive association for FANCA (p = .002), a gene previously implicated in melanoma survival. The association signal for BRCA2 was driven primarily by likely gene disrupting (LGD) variants, with an Odds Ratio (OR) of 5.62 (95% Confidence Interval (CI) 1.03-30.1). In contrast, the association signals for MC1R and MITF were driven primarily by predicted pathogenic missense variants, with estimated ORs of 1.4 to 3.0 for MC1R and 4.1 for MITF. MTAP exhibited an excess of both LGD and predicted damaging missense variants among cases, with ORs of 5.62 and 3.72, respectively, although neither category was significant. For individuals with known or predicted damaging variants, age of disease onset was significantly lower for two of the four genes, MC1R (p = .005) and MTAP (p = .035). In an analysis of germline carrier status and overlapping copy number alterations, we observed no evidence to support a two-hit model of carcinogenesis in any of the four genes. Although MC1R carriers were represented proportionally among the four molecular tumor subtypes, these individuals accounted for 69% of ultraviolet (UV) radiation mutational signatures among triple-wild type tumors (p = .040), highlighting the increased sensitivity to UV exposure among individuals with loss-of-function variants in MC1R.

Helgadottir H, Olsson H, Tucker MA, et al.
Phenocopies in melanoma-prone families with germ-line CDKN2A mutations.
Genet Med. 2018; 20(9):1087-1090 [PubMed] Related Publications
PURPOSE: Carriers of CDKN2A mutations have high risks of melanoma and certain other cancers. In this study we examined the occurrence of tumors among CDKN2A wild type (wt) members of melanoma-prone families with CDKN2A mutations.
METHODS: Swedish and US melanoma-prone families with CDKN2A mutations were included. Data was collected on tumors diagnosed among family members. Among the CDKN2A mutated families, members with CDKN2A wt status who were diagnosed with melanoma were designated phenocopies.
RESULTS: Of patients with melanoma in the CDKN2A mutated families (n = 266), 7.1%, were seen among members with CDKN2A wt status (phenocopy rate). Among the CDKN2A wt family members of the CDKN2A mutated families (n = 256), 7.4% were diagnosed with melanoma. The prospective relative risk for melanomas was significantly higher among the CDKN2A wt subjects compared with population-based controls (7.4 (95% confidence interval 1.7-33.2)), while no elevated risks of nonmelanoma cancers were seen and their offspring did not have significantly elevated risks of melanoma or other cancers.
CONCLUSION: Members of CDKN2A mutation carrying families who test negative for their family's mutation have moderately increased risk for melanoma and should, in addition to being considered for continuing dermatologic surveillance, be encouraged to follow sun safety recommendations and practice skin self-exams.

Pellegrini C, Di Nardo L, Cipolloni G, et al.
Heterogeneity of BRAF, NRAS, and TERT Promoter Mutational Status in Multiple Melanomas and Association with MC1R Genotype: Findings from Molecular and Immunohistochemical Analysis.
J Mol Diagn. 2018; 20(1):110-122 [PubMed] Related Publications
Data on somatic heterogeneity and germline-somatic interaction in multiple primary melanoma (MPM) patients are limited. We investigated the mutational status of BRAF, NRAS, and TERT promoter genes in 97 melanomas of 44 MPM patients and compared molecular and immunohistochemical findings. We further evaluated the association of somatic alterations with the germline MC1R genotype. Mutations in BRAF gene were identified in 41.2% (40/97) of melanomas, in NRAS in 2.1% (2/97), and in TERT promoter in 19.6% (19/97). Distribution of BRAF mutations did not differ across multiple melanomas (P = 0.85), whereas TERT promoter changes decreased from first to subsequent melanomas (P = 0.04). Intrapatient discrepancy of BRAF mutations among multiple tumors was detected in 14 of 44 MPM patients (32%) and of BRAF/NRAS/TERT promoter genes in 20 of 44 (45%). We observed a high rate of agreement between allele-specific TaqMan assay and immunohistochemistry in BRAF

Goldstein AM, Xiao Y, Sampson J, et al.
Rare germline variants in known melanoma susceptibility genes in familial melanoma.
Hum Mol Genet. 2017; 26(24):4886-4895 [PubMed] Free Access to Full Article Related Publications
Known high-risk cutaneous malignant melanoma (CMM) genes account for melanoma risk in <40% of melanoma-prone families, suggesting the existence of additional high-risk genes or perhaps a polygenic mechanism involving multiple genetic modifiers. The goal of this study was to systematically characterize rare germline variants in 42 established melanoma genes among 144 CMM patients in 76 American CMM families without known mutations using data from whole-exome sequencing. We identified 68 rare (<0.1% in public and in-house control datasets) nonsynonymous variants in 25 genes. We technically validated all loss-of-function, inframe insertion/deletion, and missense variants predicted as deleterious, and followed them up in 1, 559 population-based CMM cases and 1, 633 controls. Several of these variants showed disease co-segregation within families. Of particular interest, a stopgain variant in TYR was present in five of six CMM cases/obligate gene carriers in one family and a single population-based CMM case. A start gain variant in the 5'UTR region of PLA2G6 and a missense variant in ATM were each seen in all three affected people in a single family, respectively. Results from rare variant burden tests showed that familial and population-based CMM patients tended to have higher frequencies of rare germline variants in albinism genes such as TYR, TYRP1, and OCA2 (P < 0.05). Our results suggest that rare nonsynonymous variants in low- or intermediate-risk CMM genes may influence familial CMM predisposition, warranting further investigation of both common and rare variants in genes affecting functionally important pathways (such as melanogenesis) in melanoma risk assessment.

Taylor NJ, Mitra N, Goldstein AM, et al.
Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families.
J Invest Dermatol. 2017; 137(12):2606-2612 [PubMed] Free Access to Full Article Related Publications
Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.

Helgadottir H, Tuominen R, Olsson H, et al.
Cancer risks and survival in patients with multiple primary melanomas: Association with family history of melanoma and germline CDKN2A mutation status.
J Am Acad Dermatol. 2017; 77(5):893-901 [PubMed] Related Publications
BACKGROUND: Worse outcomes have been noted in patients with multiple primary melanomas (MPMs) than in patients with single primary melanomas.
OBJECTIVE: We investigated how family history of melanoma and germline CDKN2A mutation status of MPM patients affects risks of developing subsequent melanomas and other cancers and survival outcomes.
METHODS: Comprehensive data on cancer diagnoses and deaths of MPM patients, their first-degree relatives, and matched controls were obtained through Swedish national health care and population registries.
RESULTS: Familial MPM cases with germline CDKN2A mutations were youngest at the diagnosis of their second melanoma (median age 42 years) and had among the MPM cohorts the highest relative risks (RR) compared to controls of developing >2 melanomas (RR 238.4, 95% CI 74.8-759.9). CDKN2A mutated MPM cases and their first-degree relatives were the only cohorts with increased risks of nonskin cancers compared to controls (RR 3.6, 95% CI 1.9-147.1 and RR 3.2, 95% CI 1.9-5.6, respectively). In addition, CDKN2A mutated MPM cases had worse survival compared with both cases with familial (HR 3.0, 95% CI 1.3-8.1) and sporadic wild-type MPM (HR 2.63, 95% CI 1.3-5.4).
LIMITATIONS: Our study examined outcomes in subgroups of MPM patients, which affected the sample size of the study groups.
CONCLUSION: This study demonstrates that CDKN2A mutation status and family history of melanoma significantly affects outcomes of MPM patients.

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Cite this page: Cotterill SJ. Familial Melanoma, Cancer Genetics Web: http://www.cancer-genetics.org/familial_melanoma Accessed:

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