Juliette Delaunay1, Ludovic Martin2, Brigitte Bressac-de Paillerets3,4, Gerard Duru5, Olivier Ingster6, Luc Thomas1,7,8. 1. Service de Dermatologie Centre Hospitalier, Lyon Sud, France. 2. Service de Dermatologie, CHU d'Angers, Angers CEDEX, France. 3. Gustave Roussy, Université Paris-Saclay, Département de Biologie et Pathologie Médicales, Villejuif, France. 4. INSERM U1186, Université Paris-Saclay, Villejuif, France. 5. Equipe d'accueil 4129, Université Claude Bernard Lyon 1, Lyon, France. 6. Service de Génétique, CHU Angers, Angers CEDEX, France. 7. Université Claude Bernard Lyon 1-Santé, Lyon, France. 8. Centre de Recherche en Cancérologie de Lyon, INSERM U1052/CNRS UMR5286, Lyon France.
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 Participants: This 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 Measures: Frequency 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. Results: The 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 ≥3 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 Relevance: We 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.
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 Participants: This 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 Measures: Frequency 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. Results: The 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 ≥3 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 Relevance: We 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.
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