Identification, genetic testing, and management of hereditary melanoma

Our plain-English summary of Identification, genetic testing, and management of hereditary melanoma, by S.A. Leachman, O.M. Lucero, J.E. Sampson, et al (Cancer Metastasis Reviews, 2017).

The study

• Authors: S.A. Leachman, O.M. Lucero, J.E. Sampson, P. Cassidy, W. Bruno, P. Queirolo, P. Ghiorzo
• Journal: Cancer Metastasis Reviews
• Published: 2017;36(1):77-90
• Cited by: 105 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Several distinct melanoma syndromes have been defined, and genetic tests are available for the associated causative genes. Guidelines for melanoma genetic testing have been published as an informal "rule of twos and threes," but these guidelines apply to CDKN2A testing and are not intended for the more recently described non-CDKN2A melanoma syndromes. In order to develop an approach for the full spectrum of hereditary melanoma patients, we have separated melanoma syndromes into two types: "melanoma dominant" and "melanoma subordinate." Syndromes in which melanoma is a predominant cancer type are considered melanoma dominant, although other cancers, such as mesothelioma or pancreatic cancers, may also be observed. These syndromes are associated with defects in CDKN2A, CDK4, BAP1, MITF, and POT1. Melanoma-subordinate syndromes have an increased but lower risk of melanoma than that of other cancer(s) seen in the syndrome, such as breast and ovarian cancer or Cowden syndrome. Many of these melanoma-subordinate syndromes are associated with well-established predisposition genes (e.g., BRCA1/2, PTEN). It is likely that these predisposition genes are responsible for the increased susceptibility to melanoma as well but with lower penetrance than that observed for the dominant cancer(s) in those syndromes. In this review, we describe our extension of the "rule of twos and threes" for melanoma genetic testing. This algorithm incorporates an understanding of the spectrum of cancers and genes seen in association with melanoma to create a more comprehensive and tailored approach to genetic testing.

In plain English

This article was a review about inherited melanoma, not a study of asbestos-exposed people, and it reported no new patient data. The authors, from institutions in Portland, Oregon, and Genoa, Italy, described melanoma syndromes linked to genes such as CDKN2A, CDK4, BAP1, MITF and POT1. They extended an earlier testing guideline, the "rule of twos and threes", into a scoring tool: families reaching 3 points would be offered genetic testing. A melanoma counted 1 point in moderate- or high-incidence areas and 1.5 points in low-incidence areas. Each of uveal melanoma, paraganglioma, mesothelioma, atypical Spitz tumors or clear cell renal carcinoma in the patient or a first-degree relative scored 1.5 points as signs of a BAP1 syndrome. The authors wrote that BAP1 mutation carriers should be warned about asbestos exposures because of their predisposition toward mesothelioma. They stated that data on pre-test probabilities for many cancer combinations did not yet exist, and that larger gene panels increase the risk of uncertain results.

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 that proposed a scoring tool and a tailored genetic-testing approach for hereditary melanoma; no new patient data were reported
• Who was studied: No study population. The review addressed individuals and families with a suspected hereditary cancer pattern that includes melanoma, as handled at the authors' institutions (Oregon Health & Science University, USA; University of Genoa and IRCCS AOU San Martino-IST, Italy).
• Exposure: Inherited mutations in cancer predisposition genes (CDKN2A, CDK4, BAP1, MITF, POT1 and others). Asbestos exposure was not studied; it appeared only in a recommendation for BAP1 mutation carriers.
• Main results:
  • In the authors' scoring tool, a score of 3 is the threshold for genetic testing. A melanoma counts one point in moderate- or high-incidence areas and 1.5 points in low-incidence areas.
  • Signs of a BAP1 cancer syndrome score 1.5 points per cancer type when they occur in the patient or a first-degree relative: uveal melanoma, paraganglioma, mesothelioma, atypical Spitz tumors or clear cell renal carcinoma.
  • The authors' recommended melanoma panel includes BAP1, CDK4 and CDKN2A.
  • When a family has melanoma together with cancers such as mesothelioma, the authors stated a BAP1 test alone may be sufficient.
  • The authors recommended that BAP1 mutation carriers be explicitly warned about asbestos exposures, given their predisposition toward mesothelioma.
• The authors' conclusion: The authors concluded that their institutions had implemented panel testing for melanoma-dominant and melanoma-subordinate syndromes, both to care for high-risk individuals and to improve understanding of these syndromes.
• Limitations the authors state:
  • The data needed to set a 10% pre-test probability for every combination of melanoma and other cancers do not yet exist, so the point values for other cancers are not based on such data.
  • Testing larger numbers of genes increases the risk of finding irrelevant mutations or variants of uncertain significance.

Topics

Medical terms in this study, explained in our Lexicon: CDKN2A, Mesothelioma, BAP1, Ovarian Cancer.

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• Melanoma genetics — J. Read, K.A. Wadt, et al. (2016)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
• Clinical Implications of Real-time Integrative Sequencing in Management of Patients With Suspected Germline BAP1 Mutations — S. Sengupta, A.C. Weyand, et al. (2019)
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