Familial Melanoma


Literature Analysis

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

  • Carrier Proteins
  • Hereditary Neoplastic Syndromes
  • Tumor Suppressor Proteins
  • Risk Factors
  • Genetic Predisposition
  • Germ-Line Mutation
  • Phenotype
  • Italy
  • CDK6
  • Adolescents
  • CDKN2A Protein
  • Cyclin-Dependent Kinases
  • POT1
  • Polymorphism
  • Lod Score
  • Chromosome 9
  • Mutation
  • BAP1
  • Multiple Primary Neoplasms
  • Melanoma
  • Alleles
  • Young Adult
  • Family Health
  • CDK4
  • Tumor Suppressor Protein p14ARF
  • Genetic Linkage
  • Ultraviolet Rays
  • Genetic Markers
  • Chromosome Mapping
  • DNA Mutational Analysis
  • Recombinant Fusion Proteins
  • Proto-Oncogene Proteins
  • Skin Cancer
  • Base Sequence
  • Genetic Testing
  • Familial Melanoma
  • Dysplastic Nevus Syndrome
  • Childhood Cancer
  • Point Mutation
  • CDKN2A
  • Cancer DNA
  • Molecular Sequence Data
  • Pedigree
Tag cloud generated 10 March, 2017 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 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-q22 MCPH12, PLSTIRE -CDK6 and Melanoma
POT1 7q31.33 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

Wang A, Papneja A, Hyrcza M, et al.
Gene of the month: BAP1.
J Clin Pathol. 2016; 69(9):750-3 [PubMed] Related Publications
The BAP1 gene (BRCA1-associated protein 1) is a tumour suppressor gene that encodes a deubiquitinating enzyme (DUB), regulating key cellular pathways, including cell cycle, cellular differentiation, transcription and DNA damage response. Germline BAP1 mutations cause a novel cancer syndrome characterised by early onset of multiple atypical Spitz tumours and increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma and various other malignancies. Recognising the clinicopathological features of specific BAP1-deficient tumours is crucial for early screening/tumour detection, with significant impact on patient outcome.

Fidalgo F, Rodrigues TC, Silva AG, et al.
Role of rare germline copy number variation in melanoma-prone patients.
Future Oncol. 2016; 12(11):1345-57 [PubMed] Related Publications
AIM: This work evaluates a possible causative role for germline copy number variants (CNVs) in melanoma predisposition.
PATIENTS & METHODS: A total of 41 melanoma-prone Brazilian patients were investigated for CNVs using 850K single nucleotide polymorphism arrays.
RESULTS: Ten rare CNVs were identified in nine patients, comprising 54 known genes, mostly related to cancer. In silico analyses revealed gene enrichment for cellular development and growth, and proliferation, highlighting five genes directly associated with the melanoma phenotype (ANGPT1, IDH1, PDE5A, HIST1H1B and GCNT2).
CONCLUSION: Patients harboring rare CNVs exhibited a decreased age of disease onset, in addition to an overall higher skin cancer predisposition. Our findings suggest that rare CNVs contribute to melanoma susceptibility, and should be taken into account when investigating cancer risk factors.

Soura E, Eliades PJ, Shannon K, et al.
Hereditary melanoma: Update on syndromes and management: Emerging melanoma cancer complexes and genetic counseling.
J Am Acad Dermatol. 2016; 74(3):411-20; quiz 421-2 [PubMed] Free Access to Full Article Related Publications
Recent advances in cancer genomics have enabled the discovery of many cancer-predisposing genes that are being used to classify new familial melanoma/cancer syndromes. In addition to CDKN2A and CDK4, germline variants in TERT, MITF, and BAP1 have been added to the list of genes harboring melanoma-predisposing mutations. These newer entities may have escaped earlier description in part because of more advanced technologies now being used and in part because of their mixed cancer phenotype as opposed to a melanoma-focused syndrome. Dermatologists should be aware of (and be able to recognize) the clinical signs in high-risk patients in different contexts. Personal and family histories of cancer should always be sought in patients with multiple nevi or a positive history for melanoma, and should be updated annually. Various features that are unique to specific disorders, such as the appearance of melanocytic BAP1-mutated atypical intradermal tumors in cases of BAP1 melanoma syndrome, should also be recognized early. These patients should be offered regular screenings with the use of dermoscopy and total body photography, as needed. More importantly, referral to other specialists may be needed if a risk for internal malignancy is suspected. It is important to have in mind that these patients tend to develop multiple melanomas, along with various internal organ malignancies, often at younger ages; a multidisciplinary approach to their cancer screening and treatment is ideal.

Soura E, Eliades PJ, Shannon K, et al.
Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome.
J Am Acad Dermatol. 2016; 74(3):395-407; quiz 408-10 [PubMed] Free Access to Full Article Related Publications
Malignant melanoma is considered the most lethal skin cancer if it is not detected and treated during its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (ie, unilateral lineage, multigenerational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. These patients have a high risk of developing multiple primary melanomas and internal organ malignancies, especially pancreatic cancer; therefore, a multidisciplinary approach is necessary in many cases. The value of dermoscopic examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first-degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. This must be performed with care, however, and only by qualified individuals trained in cancer risk analysis.

Bruno W, Pastorino L, Ghiorzo P, et al.
Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup.
J Am Acad Dermatol. 2016; 74(2):325-32 [PubMed] Related Publications
BACKGROUND: Multiple primary melanoma (MPM), in concert with a positive family history, is a predictor of cyclin-dependent kinase (CDK) inhibitor 2A (CDKN2A) germline mutations. A rule regarding the presence of either 2 or 3 or more cancer events (melanoma and pancreatic cancer) in low or high melanoma incidence populations, respectively, has been established to select patients for genetic referral.
OBJECTIVE: We sought to determine the CDKN2A/CDK4/microphthalmia-associated transcription factor mutation rate among Italian patients with MPM to appropriately direct genetic counseling regardless of family history.
METHODS: In all, 587 patients with MPM and an equal number with single primary melanomas and control subjects were consecutively enrolled at the participating centers and tested for CDKN2A, CDK4, and microphthalmia-associated transcription factor.
RESULTS: CDKN2A germline mutations were found in 19% of patients with MPM versus 4.4% of patients with single primary melanoma. In familial MPM cases the mutation rate varied from 36.6% to 58.8%, whereas in sporadic MPM cases it varied from 8.2% to 17.6% in patients with 2 and 3 or more melanomas, respectively. The microphthalmia-associated transcription factor E318K mutation accounted for 3% of MPM cases altogether.
LIMITATIONS: The study was hospital based, not population based. Rare novel susceptibility genes were not tested.
CONCLUSION: Italian patients who developed 2 melanomas, even in situ, should be referred for genetic counseling even in the absence of family history.

Abdel-Rahman MH, Rai K, Pilarski R, et al.
Germline BAP1 mutations misreported as somatic based on tumor-only testing.
Fam Cancer. 2016; 15(2):327-30 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
We present three unrelated patients with germline mutations in BAP1 misreported as somatic mutations. All had strong family histories of cancer. One of these patients presented with an invasive breast cancer with the tumor tissue showing partial loss of the mutant rather than the wild type allele, suggesting that the germline BAP1 mutation didn't contribute to breast cancer development in this patient. This data highlights the importance of sequencing matching germline and tumor DNA for proper assessment of somatic versus germline mutation status. In patients with somatic mutations reported from laboratories carrying out tumor-only genomic testing, the possibility that a variant may be a germline mutation should be considered, especially if the personal and/or family history suggests hereditary cancer predisposition. Since tumor-only testing can reveal germline mutations, ethical issues for patients being tested should be considered including proper consent and genetic counseling.

Carbone M, Flores EG, Emi M, et al.
Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s.
PLoS Genet. 2015; 11(12):e1005633 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies).

Hu HH, Kannengiesser C, Lesage S, et al.
PARKIN Inactivation Links Parkinson's Disease to Melanoma.
J Natl Cancer Inst. 2016; 108(3) [PubMed] Related Publications
BACKGROUND: Melanoma incidence is higher in patients affected by Parkinson's disease (PD) and vice versa, but the genetic link shared by both diseases is unknown. As PARK2 is both a tumor suppressor gene and frequently mutated in young onset PD, we evaluated the role of PARK2 in melanoma predisposition and progression.
METHODS: An in-depth PARK2 gene dosage analysis and sequencing was performed on 512 French case patients and 562 healthy control patients, as well as sporadic tumors and melanoma cell lines. The frequency of genetic alterations was compared between case patients and control patients using two-sided Fisher's exact tests and odds ratio (OR) calculations. We used western blotting to determine PARKIN expression in melanocytes and melanoma cell lines and transfection followed by clonogenic assays to evaluate the effect of PARKIN expression on cellular proliferation. All statistical tests were two-sided.
RESULTS: Germline PARK2 mutations (including copy number variations, splicing, and putative deleterious missense mutations) were present in 25 case patients but only four control patients (OR = 3.95, 95% confidence interval = 1.34 to 15.75). Copy number variations (CNVs) and loss of heterozygosity were present in 60% and 74%, respectively, of primary tumors. PARKIN protein was expressed in melanocytes but not in most melanoma cell lines, and its expression decreased following melanocyte transformation by oncogenic NRAS. Re-expression of PARKIN in melanoma cell lines resulted in a drastic reduction of cell proliferation and inhibition of PARKIN in melanocytes stimulated their proliferation.
CONCLUSION: Our results show an important role for PARK2 as a tumor suppressor both in melanoma predisposition and progression, which could explain the epidemiological association of these diseases.

Di Lorenzo S, Fanale D, Corradino B, et al.
Absence of germline CDKN2A mutation in Sicilian patients with familial malignant melanoma: Could it be a population-specific genetic signature?
Cancer Biol Ther. 2016; 17(1):83-90 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Germline CDKN2A mutations have been described in 25% to 40% of melanoma families from several countries. Sicilian population is genetically different from the people of Europe and Northern Italy because of its historical background, therefore familial melanoma could be due to genes different from high-penetrance CDKN2A gene. Four hundred patients with cutaneous melanoma were observed in a 6-years period at the Plastic Surgery Unit of the University of Palermo. Forty-eight patients have met the criteria of the Italian Society of Human Genetics (SIGU) for the diagnosis of familial melanoma and were screened for CDKN2A and CDK4 mutations. Mutation testing revealed that none of the families carried mutations in CDK4 and only one patient harboured the rare CDKN2A p.R87W mutation. Unlike other studies, we have not found high mutation rate of CDKN2A in patients affected by familial melanoma or multiple melanoma. This difference could be attributed to different factors, including the genetic heterogeneity of the Sicilian population. It is likely that, as in the Australian people, the inheritance of familial melanoma in this island of the Mediterranean Sea is due to intermediate/low-penetrance susceptibility genes, which, together with environmental factors (as latitude and sun exposure), could determine the occurrence of melanoma.

Weiss S, Darvishian F, Tadepalli J, et al.
Somatic and germline analyses of a long term melanoma survivor with a recurrent brain metastasis.
BMC Cancer. 2015; 15:926 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Median overall survival (OS) of patients with melanoma brain metastases (MBM) is usually 6 months or less. There are rare reports of patients with treated MBM who survived for years. These outlier cases represent valuable opportunities to study the somatic and germline factors that may have influenced patient outcome and led to extended survival.
CASE PRESENTATION: Here we report the clinical scenario of a 67 year old man with a recurrent brain metastasis from melanoma who has survived over 12 years post-resection. We review the literature relating to clinical and molecular variables associated with long term survival post-brain metastasis. We present the somatic characteristics of this individual patient's tumor as well as an analysis of inherited genetic variants related to immune function. The patient's resected brain tumor is BRAF V600E mutated, NRAS wild type (WT), and TERT C250T mutated. The patient is a carrier of germline variants in immunomodulatory loci associated with prolonged survival.
CONCLUSIONS: Our data suggest that genetic variants in immunomodulatory loci may partially contribute to this patient's unusually favorable outcome and should not be overlooked. With further and future investigation, knowledge of inherited single nucleotide polymorphisms (SNPs) may provide clinicians with more individualized prognostic information for melanoma patients, with potential implications for surveillance strategies and therapeutic interventions.

Harland M, Petljak M, Robles-Espinoza CD, et al.
Germline TERT promoter mutations are rare in familial melanoma.
Fam Cancer. 2016; 15(1):139-44 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology.

Cheung M, Kadariya Y, Talarchek J, et al.
Germline BAP1 mutation in a family with high incidence of multiple primary cancers and a potential gene-environment interaction.
Cancer Lett. 2015; 369(2):261-5 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
We report a high-risk cancer family with multiple mesotheliomas, cutaneous melanomas, basal cell carcinomas, and meningiomas segregating with a germline nonsense mutation in BAP1 (c.1938T>A; p.Y646X). Notably, most (four of five) mesotheliomas were peritoneal rather than the usually more common pleural form of the disease, and all five mesothelioma patients also developed second or third primary cancers, including two with meningiomas. Another family member developed both cutaneous melanoma and breast cancer. Two family members had basal cell carcinomas, and six others had melanocytic tumors, including four cutaneous melanomas, one uveal melanoma, and one benign melanocytic tumor. The family resides in a subtropical area, and several members had suspected exposure to asbestos either occupationally or in the home. We hypothesize that the concurrence of a genetic predisposing factor and environmental exposure to asbestos and UV irradiation contributed to the high incidence of multiple cancers seen in this family, specifically mesothelioma and various uveal/skin tumors, respectively.

Bennett DC
Genetics of melanoma progression: the rise and fall of cell senescence.
Pigment Cell Melanoma Res. 2016; 29(2):122-40 [PubMed] Related Publications
There are many links between cell senescence and the genetics of melanoma, meaning both familial susceptibility and somatic-genetic changes in sporadic melanoma. For example, CDKN2A, the best-known melanoma susceptibility gene, encodes two effectors of cell senescence, while other familial melanoma genes are related to telomeres and their maintenance. This article aimed to analyze our current knowledge of the genetic or epigenetic driver changes necessary to generate a cutaneous metastatic melanoma, the commonest order in which these occur, and the relation of these changes to the biology and pathology of melanoma progression. Emphasis is laid on the role of cell senescence and the escape from senescence leading to cellular immortality, the ability to divide indefinitely.

Gironi LC, Colombo E, Farinelli P, et al.
Germline CDKN2A mutations in childhood melanoma: a case of melanoma-pancreatic cancer syndrome.
Int J Dermatol. 2015; 54(12):e553-5 [PubMed] Related Publications

Read J, Wadt KA, Hayward NK
Melanoma genetics.
J Med Genet. 2016; 53(1):1-14 [PubMed] Related Publications
Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence of heritable melanoma risk genes is an important component of disease occurrence. Susceptibility for some families is due to mutation in one of the known high penetrance melanoma predisposition genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP and TERT. However, despite such mutations being implicated in a combined total of approximately 50% of familial melanoma cases, the underlying genetic basis is unexplained for the remainder of high-density melanoma families. Aside from the possibility of extremely rare mutations in a few additional high penetrance genes yet to be discovered, this suggests a likely polygenic component to susceptibility, and a unique level of personal melanoma risk influenced by multiple low-risk alleles and genetic modifiers. In addition to conferring a risk of cutaneous melanoma, some 'melanoma' predisposition genes have been linked to other cancers, with cancer clustering observed in melanoma families at rates greater than expected by chance. The most extensively documented association is between CDKN2A germ line mutations and pancreatic cancer, and a cancer syndrome including cutaneous melanoma, uveal melanoma and mesothelioma has been proposed for BAP1 germ line mutations. Other medium to high penetrance melanoma predisposition genes have been associated with renal cell carcinoma (MITF, BAP1) and glioma (POT1). These associations between melanoma and other cancers hint at the possibility of common pathways for oncogenesis, and better knowledge of these pathways may improve understanding of the genetic basis underpinning familial melanoma. It is likely that 'melanoma' risk genes will impact on mutation screening and genetic counselling not only for melanoma but also a range of other cancers.

Iles MM, Bishop DT, Barrett JH,
J Natl Cancer Inst. 2015; 107(10) [PubMed] Related Publications

Shen X, Zhan Y
RE: The Effect on Melanoma Risk of Genes Previously Associated With Telomere Length.
J Natl Cancer Inst. 2015; 107(10) [PubMed] Related Publications

Aoude LG, Heitzer E, Johansson P, et al.
POLE mutations in families predisposed to cutaneous melanoma.
Fam Cancer. 2015; 14(4):621-8 [PubMed] Related Publications
Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol ε mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer.

Burgstaller-Muehlbacher S, Marko M, Müller C, et al.
Novel CDKN2A mutations in Austrian melanoma patients.
Melanoma Res. 2015; 25(5):412-20 [PubMed] Related Publications
CDKN2A is the most prominent familial melanoma gene, with mutations occurring in up to 40% of the families. Numerous mutations in the gene are known, several of them representing regional founder mutations. We sought to determine, for the first time, germline mutations in CDKN2A in Austria to identify novel mutations. In total, 700 individuals (136 patients with a positive family history and 164 with at least two primary melanomas as the high-risk groups; 200 with single primary melanomas; and 200 healthy individuals as the control groups) were Sanger sequenced for CDKN2A exon 1α, 1β, and 2. The 136 patients with affected relatives were also sequenced for CDK4 exon 2. We found the disease-associated mutations p.R24P (8×), p.N71T (1×), p.G101W (1×), and p.V126D (1×) in the group with affected relatives and p.R24P (2×) in the group with several primary melanomas. Furthermore, we discovered four mutations of unknown significance, two of which were novel: p.A34V and c.151-4 G>C, respectively. Computational effect prediction suggested p.A34V as conferring a high risk for melanoma, whereas c.151-4 G>C, although being predicted as a splice site mutation by MutationTaster, could not functionally be confirmed to alter splicing. Moreover, computational effect prediction confirmed accumulation of high-penetrance mutations in high-risk groups, whereas mutations of unknown significance were distributed across all groups. p.R24P is the most common high-risk mutation in Austria. In addition, we discovered two new mutations in Austrian melanoma patients, p.A34V and c.151-4 G>C, respectively.

DePeralta DK, Boland GM
Melanoma: Advances in Targeted Therapy and Molecular Markers.
Ann Surg Oncol. 2015; 22(11):3451-8 [PubMed] Related Publications
PURPOSE AND DESIGN: In recent years, there have been dramatic improvements in the diagnosis and treatment of patients with melanoma. The development of molecular markers and associated targeted therapies have given new hope to subsets of patients with advanced disease. Here we discuss the most important advances in molecular targeted therapy and how these developments are likely to affect the practice of the clinical surgeon.
RESULTS AND CONCLUSIONS: Germ-line and somatic mutations are common in melanoma and provide prognostic information that can now be harnessed to provide a more personalized approach to cancer treatment. BRAF mutation at the V600 position is the most commonly identified mutation in patients with melanoma. Treatment with targeted inhibitors in patients with BRAF-mutant melanoma has afforded dramatic responses in about half of selected patients. Unfortunately, disease control is not durable and recurrences are common. We predict an increasing role for the surgeon in the multidisciplinary treatment of patients with metastatic disease, as well as a role for molecular profiling in patients with high-risk early stage disease. Further, we are only beginning to understand the prognostic significance of various gene mutations in patients with melanoma.

Gerami P, Yélamos O, Lee CY, et al.
Multiple Cutaneous Melanomas and Clinically Atypical Moles in a Patient With a Novel Germline BAP1 Mutation.
JAMA Dermatol. 2015; 151(11):1235-9 [PubMed] Related Publications
IMPORTANCE: Several kindreds having germline BAP1 mutations with a propensity for uveal and cutaneous melanomas and other internal malignancies have been described in an autosomal dominant tumor predisposition syndrome. However, clinically atypical moles have not been previously recognized as a component of this syndrome, to our knowledge. We describe the first kindred to date with a germline mutation in BAP1 associated with multiple cutaneous melanomas and classic dysplastic nevus syndrome.
OBSERVATIONS: We describe a 53-year-old man who was initially seen in 2003 with dysplastic nevus syndrome, multiple atypical melanocytic proliferations showing loss of immunostaining for BAP1, and 7 cutaneous melanomas. Germline testing was performed in the proband, his 16-year-old son, and his 13-year-old daughter, revealing a germline mutation in the BAP1 gene (c.592G>T, p.Glu198X) in the proband and in his 16-year-old son. CDKN2A and CDK4 genes were wild type. No members of this kindred reported a history of uveal melanoma.
CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first report of a patient with multiple melanomas, dysplastic nevus syndrome, and an inactivating germline BAP1 mutation. The coexistence of dysplastic nevus syndrome and a BAP1 germline mutation extends the spectrum of the BAP1 tumor predisposition syndrome and may confer a greater risk for cutaneous melanomas.

Potjer TP, van der Stoep N, Houwing-Duistermaat JJ, et al.
Pancreatic cancer-associated gene polymorphisms in a nation-wide cohort of p16-Leiden germline mutation carriers; a case-control study.
BMC Res Notes. 2015; 8:264 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: The p16-Leiden founder mutation in the CDKN2A gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands. Individuals with this mutation are at increased risk for developing melanoma of the skin, as well as pancreatic cancer. However, there is a notable interfamilial variability in the occurrence of pancreatic cancer among p16-Leiden families. We aimed to test whether previously identified genetic risk factors for pancreatic cancer modify the risk for pancreatic cancer in p16-Leiden germline mutation carriers.
METHODS: Seven pancreatic cancer-associated SNPs were selected from the literature and were genotyped in a cohort of 185 p16-Leiden germline mutation carriers from 88 families, including 50 cases (median age 55 years) with pancreatic cancer and 135 controls (median age 64 years) without pancreatic cancer. Allelic odds ratios per SNP were calculated.
RESULTS: No significant association with pancreatic cancer was found for any of the seven SNPs.
CONCLUSIONS: Since genetic modifiers for developing melanoma have already been identified in CDKN2A mutation carriers, this study does not exclude that genetic modifiers do not play a role in the individual pancreatic cancer risk in this cohort of p16-Leiden germline mutation carriers. The search for these modifiers should therefore continue, because they can potentially facilitate more targeted pancreatic surveillance programs.

Governa M, Caprarella E, Dalla Pozza E, et al.
Association of CDK4 germline and BRAF somatic mutations in a patient with multiple primary melanomas and BRAF inhibitor resistance.
Melanoma Res. 2015; 25(5):443-6 [PubMed] Related Publications
Many genetic alterations, including predisposing or somatic mutations, may contribute toward the development of melanoma. Although CDKN2A and CDK4 are high-penetrance genes for melanoma, MC1R is a low-penetrance gene that has been associated most consistently with the disease. Moreover, BRAF is the most frequently somatically altered oncogene and is a validated therapeutic target in melanoma. This paper reports a case of multiple primary melanoma with germline CDK4 mutation, MC1R variant, and somatic BRAF mutation in nine out of 10 melanomas, indicating that a common pathogenesis, because of a predisposing genetic background, may be shared among distinct subsequent melanomas of probable clonal origin. After 3 months of targeted therapy with BRAF inhibitor, our patient developed resistance with rapid progression of the disease leading to death. This is the first case in which early resistance to BRAF inhibitor has been reported in a patient with CDK4 germline mutation.

Nielsen M, Dogrusöz M, Bleeker JC, et al.
The genetic basis of uveal melanoma.
J Fr Ophtalmol. 2015; 38(6):516-21 [PubMed] Related Publications
Uveal melanoma (UM) is the most common intraocular malignancy in adults with an incidence of about 1/100,000 new cases per year in the Western world. Risk factors are having a light skin, blond hair and blue eyes. As some UM patients have a young age at diagnosis or an affected family history for UM or other malignancies, there may be an underlying genetic basis. This review discusses known or suspected risk factors for UM, the cancer risk in UM patients and their family members, and the genes that have been reported to predispose to UM (germline mutations) and tumor development (somatic mutations).

Ozola A, Pjanova D
The lack of E318K MITF germline mutation in Latvian melanoma patients.
Cancer Genet. 2015; 208(6):355-6 [PubMed] Related Publications

Gupta MP, Lane AM, DeAngelis MM, et al.
Clinical Characteristics of Uveal Melanoma in Patients With Germline BAP1 Mutations.
JAMA Ophthalmol. 2015; 133(8):881-7 [PubMed] Related Publications
IMPORTANCE: Somatic mutations in BAP1 (BRCA1-associated protein 1 gene) are frequently identified in uveal melanoma. To date, the role of germline BAP1 mutations in uveal melanoma has not been characterized.
OBJECTIVE: To characterize the clinical phenotype of uveal melanoma in patients with germline BAP1 mutations.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study at an academic ophthalmology referral center among 507 patients with uveal melanoma who consented for collection of blood samples. The study dates were June 22, 1992, to December 14, 2010.
MAIN OUTCOMES AND MEASURES: Clinical characteristics of uveal melanoma and the development of metastases. BAP1 gene sequencing from blood samples of patients with uveal melanoma was correlated with clinical characteristics.
RESULTS: Of 507 blood samples analyzed, 25 patients (4.9%) exhibited 18 BAP1 polymorphisms, of which 9 were novel. Computational analyses predicted that 8 BAP1 mutations in 8 patients (1.6%) were likely to result in damaged BAP1 protein. Five of these 8 mutations were novel. These 8 patients were compared with 482 patients in whom no BAP1 polymorphisms were identified. In univariate analyses, patients with germline BAP1 mutations exhibited larger tumor diameters (mean, 15.9 vs 12.3 mm; P = .004) and higher rates of ciliary body involvement (75.0% vs 21.6%, P = .002) and metastases (71.4% vs 18.0%, P = .003) compared with control subjects. Patients with germline BAP1 mutations exhibited increased frequency of family history of cancer (100% vs 65.9%, P = .06), particularly cutaneous melanoma (62.5% vs 9.9%, P < .001) and ocular melanoma (25.0% vs 1.9%, P = .01). No differences were identified in age at diagnosis, sex, history of other malignant neoplasm, presenting visual acuity, distance of the tumor from the optic nerve or fovea, iris involvement, extrascleral extension, or tumor pigmentation. Germline BAP1 mutations increased risk of metastasis independent of ciliary body involvement (P = .02). Germline BAP1 mutation approached significance as an independent risk factor for metastasis (P = .09).
CONCLUSIONS AND RELEVANCE: These data suggest that germline BAP1 mutations occur infrequently in uveal melanoma and are associated with larger tumors and higher rates of ciliary body involvement, 2 known risk factors for metastasis.

Helgadottir H, Höiom V, Tuominen R, et al.
CDKN2a mutation-negative melanoma families have increased risk exclusively for skin cancers but not for other malignancies.
Int J Cancer. 2015; 137(9):2220-6 [PubMed] Related Publications
Germline CDKN2A mutations are found in 5-20% of melanoma families. Numerous studies have shown that carriers of CDKN2A mutations have increased risks of non-melanoma cancers, but so far there have been no studies investigating cancer risks in CDKN2A wild type (wt) melanoma families. In this prospective cohort study, index melanoma cases (n = 224) and their first-degree relatives (n = 944) were identified from 154 confirmed CDKN2A wt melanoma families. Cancer diagnoses in family members and matched controls were obtained from the Swedish Cancer Registry. Relative risks (RR), odds ratios (OR) and two-sided 95% confidence intervals (95% CI) were calculated. In index cases and first-degree relatives, the prospective RR for melanoma was 56.9 (95% CI 31.4-102.1) and 7.0 (95% CI 4.2-11.4), respectively, and for squamous cell skin cancers 9.1 (95% CI 6.0-13.7) and 3.4 (95% CI 2.2-5.2), respectively. In neither group, elevated risks were seen for non-skin cancers. In a subgroup analysis, CDKN2A wt melanoma families with young (<40 years) melanoma cases were found to have increased risk of non-skin cancers (RR 1.5, 95% CI 1.0-1.5). Further, MC1R gene variants were increased in familial melanoma cases compared to controls (OR 2.4, 95% CI 1.6-3.4). Our findings suggest that in the majority of CDKN2A wt melanoma families, a segregation of variants in low-risk melanoma genes such as MC1R causes increased skin cancer susceptibility, rather than mutations in high-risk cancer predisposing genes, such mutations are more probable to be found in melanoma families with young melanoma cases. This study further supports an implication of CDKN2A mutation screening as a clinical test that determines counseling and follows up routines of melanoma families.

Marušić Z, Buljan M, Busam KJ
Histomorphologic spectrum of BAP1 negative melanocytic neoplasms in a family with BAP1-associated cancer susceptibility syndrome.
J Cutan Pathol. 2015; 42(6):406-12 [PubMed] Related Publications
BACKGROUND: Multiple BAP1 negative melanocytic neoplasms are a hallmark of familial cancer susceptibility syndrome caused by BAP1 germline mutation. The syndrome is characterized by increased incidence of renal cell carcinoma, mesothelioma, cholangiocarcinoma, cutaneous and uveal melanoma and some other neoplasms.
METHODS: We report histomorphologic characteristics of six cutaneous melanocytic neoplasms with loss of BAP1 expression in two members of a family with BAP1-associated cancer susceptibility syndrome.
RESULTS: The neoplasms were dermal melanocytic nevi characterized by a proliferation of large epithelioid (spitzoid) melanocytes, and adipocytic metaplasia. Nuclear pseudoinclusions and multinucleated melanocytes were present in most neoplasms. In two of the cases, a nodular melanoma was found associated with a dermal nevus. None of the melanomas recurred or metastasized after 6 and 3 years of follow up.
CONCLUSIONS: We report two new cases of melanoma arising in a BAP1-deficient melanocytic nevus in the setting of familial tumor predisposition syndrome. Adipocytic metaplasia and nuclear pseudoinclusions may be additional morphologic clues to a BAP1-deficient nevus. It remains to be seen whether these features are more common in familial than sporadic lesions.

Aspinwall LG, Stump TK, Taber JM, et al.
Impact of melanoma genetic test reporting on perceived control over melanoma prevention.
J Behav Med. 2015; 38(5):754-65 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
To determine whether receiving melanoma genetic test results undermines perceived control over melanoma prevention, control-related beliefs were examined among 60 adults from melanoma-prone families receiving CDKN2A/p16 test results (27 unaffected noncarriers, 15 unaffected carriers, 18 affected carriers; response rate at 2 years = 64.9 % of eligible respondents). Multilevel modeling of perceived control ratings over a 2-year period revealed significant variation in individual trajectories: most participants showed increases (45 %) or no change (38.3 %), while 16.7 % showed decreases. At the group level, noncarriers reported sustained increases through the 2-year follow-up (ps < .05); unaffected carriers reported significant short-term increases (ps < .05); and affected carriers reported no change. Participants in all groups continued to rate photoprotection as highly effective in reducing melanoma risk and reported decreased beliefs that carrying the p16 mutation would inevitably lead to the development of melanoma. Qualitative responses immediately following counseling and test reporting corroborated these findings, as 93 % indicated it was possible to either prevent (64.9 %) or decrease the likelihood (28.1 %) of future melanomas. Thus, genetic test reporting does not generally undermine perceived control over melanoma prevention, though variability in response to positive results warrants future study.

Wadt KA, Aoude LG, Krogh L, et al.
Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition.
PLoS One. 2015; 10(3):e0122662 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Both environmental and host factors influence risk of cutaneous melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma.

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