Abstract A006: Genetic predisposition discoveries of clinical utility by exome sequencing performed for therapeutic purposes in children with relapsing or refractory cancer in the MAPPYACTS study

Abstract Background: The access to next-generation sequencing, primarily performed for therapeutic purposes, has considerably increased in the real-time clinical practice in pediatric malignancies. Using germline DNA as a matched reference, this approach is also a unique opportunity to detect alterations in medically actionable genes (named "additional data"). The main objective of this project was to estimate the frequency of such genetic predisposition discoveries among children and adolescents with relapsing or refractory cancer. Methods: Among 791 children included in MAPPYACTS “MoleculAr Profiling for Pediatric and Young Adult Cancer Treatment Stratification” study, germline DNA exome sequencing was available for 674 patients with many distinct cancer types. Informed consent was obtained to disclose genetic findings if an actionable predisposition was detected. A multidisciplinary germline molecular board established the list of genes to be looked at, including 184 cancer predisposition genes with consensual surveillance guidelines, and 49 non cancer genes belonging to the ACMG Secondary Findings v3.1 list. Bioinformatic analysis included two different indel variant calling (Varscan and Haplotypecaller), quality controls and filters to ensure high-confidence variant calls, ClinVar annotations for pathological classification and in-silico function assessment by computational prediction (with several tools including CADD, SpliceAI and SPiP). Expert biologists have evaluated the pathogenicity of genetic variations with the use of genetic databases, computational predictions and medical literature. Results: Among 184 cancer genes, 16 607 genetic variants have emerged. Twenty-five per cent of them were classified as unknown significance corresponding to a median of 7 (0;47) variants/patient and 8% of variants were retained as likely pathogenic or pathogenic variant (LPV/PV). Thus, 132 patients (19.6%) carried one LPV/PV variant among 53 cancer genes. According to inheritance patterns (we retained heterozygous variant for dominant disease and only biallelic events for recessive disease), genetic counselling was recommended for 58 patients (8.6%). Only two patients had two different cancer predisposition. The most frequently involved genes were TP53 (n=16), DICER1 (n=5), NF1 (n=4) and BRCA1 (n=4). Those identified genetic predispositions to cancer corresponded to the expected tumor spectrum in 50% of cases and were previously known in 38% of families. Furthermore, 10 patients (1.5%) were germline carriers of LPV/PV in genes involved in other genetic conditions (n=6 for cardiopathy; n=2 familial hypercholesterolemia; n=2 transthyretin amyloidosis). Conclusion: A specific evaluation of exome sequenced for therapeutic purposes provides germline information that could be actionable for 10.1% of families to improve cancer prevention or manage some other genetic condition. The psychological impact induced by the return of secondary findings to families will be investigated. Citation Format: Tiphaine Adam de Beaumais, Yahia Adnani, Léa Guerrini-Rousseau, Samuel Abbou, Cécile Acquaviva-Bourdain, Pablo Berlanga, Adeline Bonnard, Gaelle Bougeard, Franck Bourdeaut, Nelly Burnichon, Sandrine Caputo, Alain Carrié, Olivier Caron, Hélène Cavé, Albain Chansavang, Nadège Corradini, Sophie Cotteret, Philippe Denizeau, Alice Fievet, Mathilde Filser, Marion Gauthier-Villars, Birgit Geoerger, Nadim Hamzaoui, Edwige Kasper, Florence Kyndt, Ludovic Lacroix, Jessica Le Gall, Julien Masliah-Planchon, Laurence Pacot, Cécile Pagan, Mélanie Pagès, Béatrice Parfait, Eric Pasmant, Gaelle Pierron, Pascale Richard, Nathalie Roux-Buisson, Cécile Saint-Martin, Hela Sassi, Gudrun Schleiermacher, Renaud Touraine, Nancy Uhrhammer, Dominique Vidaud, Laurence Brugières, Gilles Vassal, Etienne Rouleau, Yoann Vial, Lisa Golmard, Odile Cabaret. Genetic predisposition discoveries of clinical utility by exome sequencing performed for therapeutic purposes in children with relapsing or refractory cancer in the MAPPYACTS study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A006.