Improvement of Genetic Testing for Cutaneous Melanoma in Countries With Low to Moderate Incidence

Abstract

IMPORTANCE Genetic testing for melanoma-prone mutation in France, a country with low to moderate incidence of melanoma, is proposed in cases with 2 invasive cutaneous melanomas and/or related cancers in the same patient, or in first-or second-degree relatives (rule of 2). In preclinical studies, these rules led to disclosure of mutation(s) in more than 10% of these families, the threshold widely accepted to justify genetic testing for cancers.OBJECTIVE To reconsider these criteria in a general population testing of patients. DESIGN, SETTING, AND PARTICIPANTSThis was a retrospective study, performed from 2004 to 2015 at Angers and Lyons University Hospitals, of a cohort of 1032 patients who underwent genetic testing. MAIN OUTCOMES AND MEASURESFrequency of mutation in high (CDKN2A, CDK4, and BAP1) and intermediate (MITF) susceptibility genes; statistical effect of histologic subtype, age, dysplastic nevi syndrome, and associated cancers on mutation rate; and evaluation of cases with anamnestic uncertainty. RESULTSThe mutation rate was 67 of 1032 patients (6.5%). Their mean (SD) age was 54.5 (14.2) years [range, 18-89 years], and 543 (52.6%) were men. It increased to 38 of 408 patients (9.3%) when applying a rule of 3 (those with Ն3 primary melanomas or genetically related cancers) (P = .68) and to 27 of 150 patients (18.0%) with a rule of 4 (4 primary melanomas or related cancer) (P < .001). The impact of age at first melanoma was observed only in those younger than 40 years, with a rate of 32 of 263 (12.1%) (P = .12) for the rule of 2 and 22 of 121 (18.2%) (P = .001) for the rule of 3. Use of the rule of 2 in patients younger than 40 years reduced the number of missed CDKN2A-mutated-families when applying the rule of 3 from 14 of 43 to 7 of 43. Anamnestic uncertainty, found in 88 families (8.5%), if excluded, would have led us to withdraw of only 21 cases (23.8%), and only 1 mutation would have been missed. CONCLUSIONS AND RELEVANCEWe propose using the rule of 3 to recommend genetic testing in France and countries with low to moderate incidence of melanoma, except in families and patients with a first melanoma occurrence before age 40 years in whom the rule of 2 could be maintained.

The interplay of sun damage and genetic risk in Australian multiple and single primary melanoma cases and controls

“…2019 . Patients with MPM were classified as either ‘first diagnosis at age ≤ 40 years’ or ‘first diagnosis at age > 40 years’, based on literature suggesting that younger patients with melanoma are more likely to harbour genetic mutations …”

New Insights into Melanoma Tumor Syndromes

“…Current guidelines for genetic testing in melanoma are restricted to CDK2NA screening and employ the rule of twos, threes, and fours ( Delaunay et al., 2017 ). According to this rule, genetic testing is indicated for subjects with ≥2, ≥3, or ≥4 primary melanomas or genetically related cancers depending on the general population incidence.…”

Relationship of Chromosome Arm 10q Variants to Occurrence of Multiple Primary Melanoma in the Population-Based Genes, Environment, and Melanoma (GEM) Study

“…Notably, rs17119461 and rs17119490 were found to be nominally associated with pancreatic cancer, which shares genetic risk with familial melanoma (Wu et al, 2014). Some melanoma genetic testing panels for patients meeting specific criteria include intermediate risk variants, such as MITF c.952 G>A that have a low minor allele frequency (w0.0015) (Delaunay et al, 2017). Thus, if validated in additional studies, rs17119461 may be a potential candidate for genetic testing in populations at high risk for melanoma.…”