Evaluation of the genetic basis of familial-associated early-onset hematologic cancers in an ancestral/ethnically diverse population

Genetic predisposition to hematologic malignancies has historically been addressed utilizing patients recruited from clinical trials and pedigrees constructed at major treatment centers. Such efforts leave unexplored the genetic basis of variations in risk by race/ethnic group shown in population-based surveillance data where cancer registration, compulsory by law, delivers universal enrollment. To address this, we performed exome sequencing on DNA isolated from newborn bloodspots derived from sibling pairs with early-onset cancers across California in which at least one of the siblings developed a hematologic cancer, using unbiased recruitment from the full state population. We identified pathogenic/likely pathogenic (P/LP) variants among 1172 selected cancer genes that were private or present at low allele frequencies in reference populations. Within 64 subjects from 32 families, we found 9 LP variants shared between siblings, and an additional 7 such variants in singleton children (not shared with their sibling). In eight of the shared cases, the ancestral origin of the local haplotype that carries P/LP variants matched the dominant global ancestry of study participant families. This was the case for Latino sibling pairs on FLG and CBLB, non-Latino White sibling pairs in TP53 and NOD2, and a shared GATA2 variant for a non-Latino Black sibling pair. A new inherited mutation in HABP2 was identified in a sibling pair, one with diffuse large B-cell lymphoma and the other with neuroblastoma. Overall, the profile of P/LP germline variants across ancestral/ethnic groups suggests that rare alleles contributing to hematologic diseases originate within their race/ethnic origin parental populations, demonstrating the value of this discovery process in diverse, population-based registries.