BRCA1/2 germline sequencing in children and adolescents with cancer: it is the context that matters

Extract

In this issue of the Journal, Li et al.¹ employed a methodologically robust probabilistic approach that used segregation analysis from family pedigrees to provide further compelling evidence arguing against an elevated non–breast cancer risk in the first 3 decades of life in individuals with heterozygous BRCA1/2 germline pathogenic variants. Li et al. collated general cancer information and germline BRCA1/2 status (confirmed positive or negative or untested) from 47 117 individuals (3086 families) with at least 1 ascertained individual with a BRCA1/2 germline pathogenic variant. Primary cancers were reported in 274 individuals younger than 30 years of age, most of which were breast cancers specifically diagnosed in the third decade of life (relative risk of 11.4 and 5.2 for developing breast cancer in BRCA1 carriers and BRCA2 carriers aged 20-29 years, respectively).

Results from the study by Li et al.¹ showing no evidence of an elevated cancer risk in children and adolescents are aligned with previous epidemiological research and do not contradict the observation that adult-onset cancer-predisposing genes (especially genes involved in DNA repair) are among the most prevalent germline findings in children with cancer who undergo extensive DNA sequencing.^2,3 Research incorporating molecular tumor analyses on children with cancer and germline pathogenic variants in BRCA1/2 have invariably demonstrated a lack of a classic “second hit” in BRCA1/2 (eg, loss of heterozygosity), which further argues against a primary cancer driver effect of the germline pathogenic variant.^4,5 Even after 30 years, the question of haploinsufficiency and the resulting cellular phenotype in BRCA1/2 heterozygotes remains unclear, although recent data suggest that in certain tissue types, it is associated with excess accumulation of mutational events.^6-8 In agreement with this finding, Villani et al.⁵ showed functional evidence for homologous recombination deficiency in a proportion of tumors in children with heterozygous BRCA1/2 germline pathogenic variants without classic second somatic hits in BRCA1/2, leading the researchers to consider other mechanisms driving genomic instability. In addition, epidemiological studies highlighting increased frequencies of BRCA1/2 germline pathogenic variants in pediatric cancer survivors who develop subsequent malignancies have led to generalized concern about the possibility of incremental toxicity from chemotherapy and radiation in individuals with germline pathogenic variants in DNA repair genes.^9,10