Clinically actionable genetic findings by exome sequencing performed for therapeutic purposes in children with very-high risk cancer included the MAPPYACTS study.

Germline pathogenic or likely pathogenic variants in 184 cancer predisposition genes and 49 actionable noncancer genes (ACMG SF v3.1 list), detected by germline WES performed for therapeutic purposes

Sequencing performed to guide treatment of pediatric cancers provides an opportunity to identify germline predisposition variants and other actionable inherited conditions. In the MAPPYACTS trial, germline WES data were available for 674 patients with relapsed or refractory malignancies, analysed across 184 cancer predisposition genes and 49 actionable noncancer genes from the ACMG SF v3.1 list; 98.6% of families consented to disclosure of these findings. Overall, 148 pathogenic or likely pathogenic variants were identified in 130 patients (19.3%) across 53 predisposition genes, and genetic counseling was recommended for 58 patients (8.6%), the most frequent genes being TP53 (n = 17), DICER1 (n = 5) and BRCA1 (n = 4). Predisposition findings matched the expected tumor spectrum in 48% of cases, 35% of which had not been previously recognized. In addition, 10 patients (1.5%) carried an actionable variant in a noncancer gene (cardiomyopathies, familial hypercholesterolemia, transthyretin amyloidosis).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Near-universal acceptance of disclosure (98.6%) shows that the challenge is not consent but organization: who interprets, who discloses, who follows up. The gap between 19.3% of patients carrying a pathogenic or likely pathogenic variant and 8.6% referred for genetic counseling reflects the weight of clinical triage (inheritance pattern, relevance), whose criteria should be read in the full article. Once the exome is performed for treatment, not reading its germline component means missing unrecognized predispositions.

Analysis by Dr Thibaut Benquey