What are the genetic determinants of high risk for new primary melanoma?

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Clinical practice guidelines for the diagnosis and management of melanoma > What are the genetic determinants of high risk for new primary melanoma?


The current chapter updates the evidence regarding the genetic factors underlying individual risk of cutaneous melanoma.

Evidence reviewed

A non-systematic, expert review was undertaken to identify relevant published systematic reviews and meta-analyses on genetic determinants of high risk for new primary melanoma. This review of the literature since the 2008 Guidelines had two aims: to update the evidence of rare mutations that confer high risk of melanoma, and to highlight the new evidence that common variations in the genome collectively influence personal risk of melanoma.

Rare mutations associated with familial melanoma

These are carried by fewer than 0.1% of the population, cause large increases in personal melanoma risk, and are commonly signalled by a strong family history of melanoma.

The first germline (heritable) mutations found to confer high personal risk of cutaneous melanoma disrupt the two genes encoded by the CDKN2A locus (p16INK4A and p14ARF), or the CDK4 gene. These mutations are strongly associated with familial melanoma, albeit in a minority of cases, and are rare in melanoma cases that have not been selected for a strong positive family history of melanoma.[1] Since the 2008 Guidelines were prepared, several additional genes have been reported to be mutated in rare instances of familial cutaneous melanoma: BAP1, POT1, ACD, TERF2IP and TERT. A recent review[2] estimated that a combined total of 50% of dense melanoma kindreds internationally might include carriers of mutations in one of these seven genes, the vast majority in CDKN2A. However, this may be an overestimate for Australia, based on previous data showing that fewer than 20% of Australian kindreds with at least three cases of cutaneous melanoma carried CDKN2A mutations.[1]

The chance that a melanoma cluster is due to a family CDKN2A mutation increases with the number of relatives affected, the number who have had more than one primary melanoma, the earlier their age at diagnosis, and the number of relatives with pancreatic cancer. However these relationships are poorly quantified as yet. In the only population-based study to date, cases with first primary melanoma under the age of 40yr had an average CDKN2A mutation prevalence of 2.3%: 1.4% (7/500) of those with no family history and 7.3% (7/96) of those with at least one affected relative.[3] Better knowledge of the prevalence and predictors of family CDKN2A mutations in Australia would improve selection of families for genetic testing. Current recommendations regarding genetic testing in familial melanoma are still valid, but will need modification as the specific predictors of CDKN2A mutation in Australia become better defined.[1] Appropriately selected genetic testing has potential benefits, including facilitating prevention and early detection in mutation carriers. (see What interventions have been shown to reduce the risk of death from melanoma in those assessed to be at high risk of new primary melanoma?). The additional risk of melanoma that is conferred by a CDKN2A mutation is well known, averaging 20% by age 50 and 52% by age 80 in Australia.[4] This risk information should be used to guide genetic counselling of carriers of these mutations.

Because of their rarity, there is no case for routine testing for mutations in genes other than CDKN2A in Australian familial melanoma, however panel and whole-genome sequencing analysis may in time make this cost-effective outside research settings. A germline BAP1 mutation should be considered if the family includes BAP1 associated cancers such as renal cancer, mesothelioma and meningioma, or if the melanomas have BAP1-associated clinical and histologic features[5]; however, these features are only weakly predictive of the presence of germline BAP1 mutation. Paradoxically, such families have not been found to include cases of uveal (ocular) melanoma, whereas familial uveal melanoma alone is strongly associated with BAP1 mutations.

Non systematic review evidence summary and recommendations

Evidence summary Level References
A proportion of familial cutaneous melanoma (defined as clusters of several cases all related to each other), is accounted for by germline mutations in the CDKN2A gene and, rarely, the BAP1, POT1, ACD, TERF2IP and TERT genes III-3 [4], [2]

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Clinical genetic testing for CDKN2A mutations and genetic counselling should be considered in individuals with a strong family history of melanoma (3 or more cases related in the first- or second-degree) where predictive features are present, such as multiple primary melanoma, early age of onset, or pancreatic cancer.

Common genomic variants

Here we refer to genetic variations carried by at least 1% of the population, and which for most people are the main drivers of melanoma risk, together with sun exposure.

In the last edition, evidence was presented to show that a significant proportion of melanoma risk in the population is due to common variations in the MC1R gene, which contribute to skin pigmentation and sun sensitivity.[1]

Since the last edition, extensive evidence has accumulated from genome-wide association studies (GWAS) of case-control cohorts that common variations in many other genes contribute to risk of cutaneous melanoma and other skin cancers. These data will deepen and extend in years to come, expanding the number of genes known to influence melanoma risk, and better estimating the degree of risk that each confers. These gene variations are typically single-nucleotide polymorphisms (SNP), and they may or may not have readily-identifiable functional consequences. However, many of them are responsible for the common, clinically detectable risk factors for melanoma, namely skin pigmentation, sun sensitivity and increased naevus count.

The key evidence identified by the expert panel comprised the systematic review by Gerstenblith (2010)[6], and meta-analyses by Antonopoulou (2015)[7] and Law (2015)[8]. The meta-analysis by Law and colleagues focuses exclusively on genome-wide analyses, including data from 11 reported GWAS studies and additional datasets comprising a total 15,990 cutaneous melanoma cases and 26,409 controls, some from Australia.[8] Its findings include all but one positive finding from Antonopolou, are consistent with the earlier systematic review by Gerstenblith, and as the highest-powered such study to date, its results will be summarised here to represent the state of the field.

Twenty loci are now unequivocally associated with susceptibility to cutaneous melanoma (reaching P < 5x10-8, genome-wide) and are listed here by chromosome (Ch): (Ch 1) ARNT, PARP1; (Ch 2) CYP1B1, CASP8; (Ch 5) TERT, SLC45A2; (Ch 6) CDKAL1; (Ch 7) AGR3; (Ch 9) CDKN2A, RAD23B; (Ch 10) OBFC1; (Ch 11) CCND1, TYR, ATM; (Ch15) OCA2; (Ch 16) FTO, MC1R; (Ch 20) ASIP; (Ch 21) MX2; (Ch 22) PLA2G6. Five of these genes are in regions known to be related to pigmentation, three are in nevus-related regions and four are in regions related to telomere maintenance. For the other eight it is unclear what mechanisms may mediate their effect on melanoma susceptibility. These 20 genetic loci are estimated to account for 19.2% of the increased risk exhibited by relatives of melanoma cases. Of this total, about a quarter is due to MC1R variants alone, due to their high prevalence (10-15%) and moderate effect on risk (1.7-fold). A rare variant in the MITF gene, present in about 0.7% of the population, was also found to increase risk by a comparable amount to MC1R.[9]

Further melanoma risk loci will be confirmed as larger GWAS cohorts are assembled, and the proportion of melanoma in the population that is attributable to genetic background will continue to increase. There is preliminary evidence that testing of these SNP may have a future role in clinical practice, however few studies have assessed their contribution to risk in multivariate analysis with clinical variables (see What validated models integrate genetic and clinical risk factors into an overall measurement of high risk from new primary melanoma?).

Non systematic review evidence summary and recommendations

Evidence summary Level References
Common variations (SNPs) in at least twenty genes influence melanoma risk in the population, accounting for about 20% of the excess risk to relatives of melanoma cases IV [7], [8]

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Detection (genotyping) of melanoma susceptibility SNPs may have a future role in assessing and managing individual risk of melanoma.

Issues requiring more clinical research study

If gaps in the evidence are identified during the evidence review, please note areas for further research including a brief description. Genetic testing of familial melanoma kindreds in Australia needs to be informed by better estimates of the prevalence and predictors of CDKN2A mutation.


  1. 1.0 1.1 1.2 1.3 Australian Cancer Network Melanoma Guidelines Revision Working Party. Clinical Practice Guidelines for the Management of Melanoma in Australia and New Zealand. Wellington: Cancer Council Australia and Australian Cancer Network, Sydney and New Zealand Guidelines Group; 2008 Available from:
  2. 2.0 2.1 Read J, Wadt KA, Hayward NK. Melanoma genetics. J Med Genet 2016 Jan;53(1):1-14 Available from:
  3. Harland M, Cust AE, Badenas C, Chang YM, Holland EA, Aguilera P, et al. Prevalence and predictors of germline CDKN2A mutations for melanoma cases from Australia, Spain and the United Kingdom. Hered Cancer Clin Pract 2014;12(1):20 Available from:
  4. 4.0 4.1 Cust AE, Harland M, Makalic E, Schmidt D, Dowty JG, Aitken JF, et al. Melanoma risk for CDKN2A mutation carriers who are relatives of population-based case carriers in Australia and the UK. J Med Genet 2011 Apr;48(4):266-72 Available from:
  5. O'Shea SJ, Robles-Espinoza CD, McLellan L, Harrigan J, Jacq X, Hewinson J, et al. A population-based analysis of germline BAP1 mutations in melanoma. Hum Mol Genet 2017 Jan 5 Available from:
  6. Gerstenblith MR, Shi J, Landi MT. Genome-wide association studies of pigmentation and skin cancer: a review and meta-analysis. Pigment Cell Melanoma Res 2010 Oct;23(5):587-606 Available from:
  7. 7.0 7.1 Antonopoulou K, Stefanaki I, Lill CM, Chatzinasiou F, Kypreou KP, Karagianni F, et al. Updated field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma: the MelGene database. J Invest Dermatol 2015 Apr;135(4):1074-9 Available from:
  8. 8.0 8.1 8.2 Law MH, Bishop DT, Lee JE, Brossard M, Martin NG, Moses EK, et al. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma. Nat Genet 2015 Sep;47(9):987-95 Available from:
  9. Yokoyama S, Woods SL, Boyle GM, Aoude LG, MacGregor S, Zismann V, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 2011 Nov 13;480(7375):99-103 Available from: