Spectrum of double heterozygosity in individuals diagnosed with hereditary breast and ovarian cancer.

BACKGROUND

(Likely) pathogenic variants (pVs) in hereditary breast and/or ovarian cancer (HBOC) genes increase cancer risk, but the clinical implications of multiple pVs remain insufficiently understood.

METHODS

Using data from the prospective nationwide German Consortium for HBOC registry, we conducted a case-control study of genotype-phenotype associations, matching female carriers to compare cancer risk and disease severity between multiple and single heterozygous (SH) pV carriers.

RESULTS

Among 26,983 carriers of single or multiple HBOC-associated pVs, 409 individuals had multiple heterozygosities, including 400 double heterozygous (DH) carriers. In a subcohort tested for 13 core genes, 98/3407 (2.9%) individuals had multiple HBOC-associated pVs. Breast cancers (BCs) in DH women with pVs in BRCA1 and another gene were predominantly triple-negative, even when the second, non-BRCA1 pV was typically associated with hormone receptor (HR)-positive BC. By contrast, BRCA1/CHEK2 DH carriers showed more HR-positive BCs than BRCA1 SH women. The median age at first BC was similar in female ATM/CHEK2 DH carriers and BRCA1 SH carriers (41.5 [IQR 14.0] vs. 41.3 [14.1] years). Matched BRCA1 and BRCA2 SH carriers were less likely to present with higher disease severity than BRCA1/BRCA2 DH carriers (BRCA1: OR 0.396 [0.180-0.87]; BRCA2: OR 0.224 [0.100-0.50]).

CONCLUSIONS

Multiple heterozygosity in HBOC core genes is more frequent than previously assumed. Our data indicate that gene-gene constellations can reshape tumour phenotype and clinical severity rather than following single-gene expectations. Integrating multiple pVs into risk assessment and counselling may enhance personalised surveillance and risk-reducing strategies for DH individuals and their families in the era of widespread multigene testing.