Identification, genetic testing, and management of hereditary melanoma

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.

Family communication and patient distress after germline genetic testing in individuals with pancreatic ductal adenocarcinoma

“…Pedigree information was reviewed to determine whether subjects met then‐current criteria for genetic evaluation for any of the known genetic syndromes that predispose to PDAC. Specific criteria were tracked for familial pancreatic cancer, hereditary breast and ovarian cancer, and Lynch syndrome; familial adenomatous polyposis, Li‐Fraumeni syndrome, Peutz‐Jeghers syndrome, and familial atypical multiple mole melanoma syndrome also were assessed …”

“…Specific criteria were tracked for familial pancreatic cancer, hereditary breast and ovarian cancer, and Lynch syndrome; familial adenomatous polyposis, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, and familial atypical multiple mole melanoma syndrome also were assessed. 10,22,[25][26][27][28][29] The MICRA and family communication surveys both were administered by telephone in a single, Cancer July 15, 2019 20-minute interview. This interview was completed at least 12 weeks after the disclosure of genetic testing results to allow time for family communication of results.…”

CM-Score: a validated scoring system to predict CDKN2A germline mutations in melanoma families from Northern Europe

“…The guidelines for CDKN2A mutation testing proposed by Leachman et al in 200925 were recently updated 38. In view of the recent reports of non- CDKN2A melanoma syndromes, such as those related to germline mutations in BAP1 39 (MIM 603089), POT1 40 (MIM 606478) and MITF 41 (MIM 156845), the authors propose tailored multigene panel testing in melanoma families instead of CDKN2A mutation testing alone.…”

Genes e Melanoma

“…4,5 Assim, o fenótipo típico do doente com melanoma, de fototipo baixo, com olhos e cabelo claros, sugere que estes genes de elevada prevalência e baixa penetrância como o MC1R interajam com factores ambientais, nomeadamente a exposição solar, sendo responsáveis pela maioria dos casos esporádicos de melanoma. Por outro lado, os genes de elevada penetrância e baixa prevalência, explicam que cerca de um terço dos melanomas familiares tenham uma mutação germinal no gene CDKN2A.…”

“…1,3 No que respeita à transmissão familiar da doença, cerca de 10% dos melanomas cutâneos têm história familiar, com pelo menos um ou dois familiares afectados. [3][4][5] Atualmente, com os progressos notórios em termos de reconhecimento de mutações e compreensão do perfil molecular das células tumorais do melanoma, há uma necessidade crescente de subdivisão genómica dos diversos tipos de melanoma. Desta forma, em 2015, a Cancer Genome Atlas Network propôs a classificação deste tumor de acordo com a mutação genética predominante, existindo assim quatro subtipos: BRAF mutado, RAS mutado, NF1 mutado e triplos selvagens ou wild type.…”