Melanoma genetics

Our plain-English summary of Melanoma genetics, by J. Read, K.A. Wadt, N.K. Hayward (Journal of Medical Genetics, 2016).

The study

• Authors: J. Read, K.A. Wadt, N.K. Hayward
• Journal: Journal of Medical Genetics
• Published: 2016;53(1):1-14
• Type of article: Review
• Cited by: 179 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

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In plain English

This was a review, not a new study. The authors summarized published research on inherited genes that raise the risk of melanoma and on links between those genes and other cancers. The article did not discuss asbestos. The review stated that inherited CDKN2A mutations had been implicated in approximately 20–40% of familial melanoma. It said that mutations in seven known high penetrance genes (CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP and TERT) together were implicated in approximately 50% of familial melanoma cases. On BAP1, the review reported that a cancer syndrome including cutaneous melanoma, uveal melanoma and mesothelioma had been proposed for inherited BAP1 mutations. Of 21 families with BAP1 mutations reported so far, 16 had at least one person with cutaneous melanoma. It also described reported links between CDKN2A and pancreatic cancer, between MITF and BAP1 and renal cell carcinoma, and between POT1 and glioma. The authors concluded that routine genetic testing is currently not recommended. They added that many melanoma risk genes likely remain to be found.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published research on melanoma genetics (no new data collected)
• Who was studied: No study population of its own. The review covered published studies of melanoma families and melanoma patients and the genes linked to melanoma risk.
• Exposure: Inherited (germ line) gene variants linked to melanoma risk, grouped as high, medium and low penetrance genes. The high penetrance genes named are CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP and TERT. Ultraviolet radiation is discussed as an environmental modifier. Asbestos is not discussed.
• Main results:
  • The review reported, from earlier studies, that inherited CDKN2A mutations had been implicated in approximately 20–40% of familial melanoma.
  • The review stated that mutations in the known high penetrance genes together were implicated in approximately 50% of familial melanoma cases.
  • The review reported that a cancer syndrome including cutaneous melanoma, uveal melanoma and mesothelioma had been proposed for inherited BAP1 mutations.
  • Among 21 previously reported families with BAP1 mutations, 16 families had at least one member with cutaneous melanoma.
  • The review cited a report of a recurrent BAP1 mutation in three families. Those families showed clustering of uveal and cutaneous melanoma and only one mesothelioma case.
  • The review described the association between inherited CDKN2A mutations and pancreatic cancer as the most extensively documented link to another cancer.
  • The review reported that MITF and BAP1 had been associated with renal cell carcinoma, and POT1 with glioma.
• The authors' conclusion: The authors concluded that routine genetic testing for melanoma is currently not recommended, because of the complex combined effect of many genes on melanoma risk.
• Limitations the authors state:
  • The authors noted that the genetic basis remains unexplained for the remaining high-density melanoma families.
  • The authors stated that many more melanoma risk genes likely remain to be identified.
  • For the extra cancers seen in families with ACD and TERF2IP mutations, the authors noted that the numbers were too few to be statistically significant.

Topics

Medical terms in this study, explained in our Lexicon: CDKN2A, BAP1, Mesothelioma, Carcinoma, Oncogenesis, Genetic Counseling.

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