Germline variants observed in pediatric cancer patients related to hereditary breast and ovarian cancer in adults.

Abstract

Genetic predisposition is a major cause of cancer, yet little is known about the role of adult cancer predisposition syndromes (CPSs) in childhood cancers. Although extensively studied in adults, information about the impact of germline variants in genes associated with hereditary breast and ovarian cancer (HBOC) remains scarce in the pediatric context. To elucidate whether (likely) pathogenic variants (LP/PVs) in 25 selected HBOC-related genes may contribute to cancer risk in children, we analyzed the spectrum of occurring germline variants. We assessed 372 children (median age at diagnosis 5.1 [0-22.2] years; 160 girls [43%]), including 212 (57%) with hematologic neoplasms, 71 (19%) with brain tumors, and 89 (24%) with various solid entities. Twenty-seven of 372 patients (7%) carried LP/PVs in the candidate genes; for 12 of 27 (44%) no CPS was suspected prior to genotyping. LP/PV carriers were particularly at risk for second malignancies (SMN; 5/27 vs. 13/345; OR = 5.8; p = .0021); yet, LP/PVs in SMN-developing patients resided exclusively in TP53 (n = 3), NBN (n = 1), and ATM (n = 1). Burden testing of our single-center cohort revealed considerable associations between monoallelic LP/PVs in five HBOC-related genes (TP53, CHEK2, ATM, NF1, and NBN) and pediatric cancers compared to healthy adults (gnomAD v.3.1.1, non-cancer dataset). Joint analyses adding 1120 individuals from a previous study Zhang et al. (2015) confirmed significant associations for TP53, CHEK2, NF1, and MSH2. Monoallelic LP/PVs in constrained HBOC-related genes are significantly associated with pediatric cancers. However, particularly in clinically unexpected cases, detection of contributing LP/PVs by genotype-driven approaches may improve patient outcomes by enabling risk-adapted therapy and surveillance.