Allele-specific directionality and evolutionary timing of BRCA1/2 loss of heterozygosity in gastric cancer

Abstract

Abstract Germline pathogenic variants in BRCA1 and BRCA2 are established cancer predisposition factors, but their biological role in gastric cancer remains poorly defined. We investigated whether BRCA1/2 -associated gastric cancers acquire loss of heterozygosity, which allele is lost, when this event occurs during tumour evolution, and how it relates to homologous recombination deficiency. Four gastric cancers arising in BRCA1/2 germline pathogenic variant carriers were analysed using tumour–normal paired whole-exome sequencing and allele-specific copy number profiling. Loss-of-heterozygosity directionality was inferred from variant allele fractions, tumour purity, and locus-specific copy numbers; evolutionary timing was estimated by modelling, and homologous recombination deficiency was evaluated using genome instability scores and mutational signatures. All tumours were HER2-negative, CLDN18.2-negative, and microsatellite stable. One BRCA1 -associated tumour showed early loss of the wild-type allele with copy-number gain, resulting in biallelic BRCA1 inactivation, high genomic instability, SBS3 enrichment, and biallelic TP53 inactivation. By contrast, one BRCA2 -associated tumour showed loss consistent with mutant allele loss, lacked homologous recombination deficiency features, and had biallelic RB1 inactivation. The remaining tumours lacked BRCA1/2 loss of heterozygosity. These findings suggest that germline BRCA1/2 status alone may not be sufficient to predict a homologous recombination deficiency phenotype in gastric cancer and warrant validation in larger cohorts.