Clinically actionable genetic findings by exome sequencing performed for therapeutic purposes in children with very-high risk cancer included the MAPPYACTS study.
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Adamde Beaumais Tiphaine, Adnani Yahia, Guerrini-Rousseau Léa, Abbou Samuel, Acquaviva-Bourdain Cécile, Berlanga Pablo, Bonnard Adeline, Bougeard Gaelle, Bourdeaut Franck, Burnichon Nelly, Caputo Sandrine, Carrié Alain, Caron Olivier, Cavé Hélène, Chansavang Albain, Corradini Nadège, Cotteret Sophie, Denizeau Philippe, Fievet Alice, Filser Mathilde, Frébourg Thierry, Gauthier-Villars Marion, Geoerger Birgit, Hamzaoui Nadim, Kasper Edwige, Kyndt Florence, Lacroix Ludovic, Le Gall Jessica, Masliah-Planchon Julien, Pacot Laurence, Pagan Cécile, Pages Mélanie, Parfait Béatrice, Pasmant Eric, Pierron Gaelle, Richard Pascale, Roux-Buisson Nathalie, Saint-Martin Cécile, Sassi Hela, Schleiermacher Gudrun, Touraine Renaud, Uhrhammer Nancy, Vidaud Dominique, Brugières Laurence, Vassal Gilles, Rouleau Etienne, Vial Yoann, Golmard Lisa, Cabaret Odile
Аннотация
METHODS: Germline whole-exome sequencing (WES) was performed within the MAPPYACTS (MoleculAr Profiling for Pediatric and Young Adult Cancer Treatment Stratification) trial. Germline data were available for 674 patients with diverse relapsed or refractory malignancies. Families provided informed consent regarding disclosure of actionable germline findings. A multidisciplinary committee established a panel of 184 cancer predisposition genes with established surveillance recommendations and 49 medically actionable noncancer genes from the ACMG SF v3.1 list. Variants were analyzed using bioinformatic pipelines including quality filtering, ClinVar annotation, and computational pathogenicity assessment.
RESULTS: Overall, 98.6% of families consented to the disclosure of actionable genetic findings. Among 674 patients, a total of 148 likely pathogenic or pathogenic variants (LPV/PV) were identified in 130 patients (19.3%) across 53 cancer predisposition genes. Based on inheritance patterns and clinical relevance, genetic counseling was recommended for 58 patients (8.6%). The most frequently altered genes with clinical application were TP53 (n = 17), DICER1 (n = 5), and BRCA1 (n = 4). Predisposition findings corresponded to the expected tumor spectrum in 48% of cases with 35% of them had not been previously recognized. Additionally, 10 patients (1.5%) carried actionable LPV/PV in noncancer genes associated with cardiomyopathies, familial hypercholesterolemia, or transthyretin amyloidosis.
DISCUSSION: Systematic germline WES integrated into theranostic profiling may provide additional clinical value through the identification of actionable cancer predispositions and other inherited conditions. We propose recommendations for a structured, multidisciplinary framework to support clinical decision-making.