Abstract 3256: Identification of germline variants associated with somatic mutational profiles in triple-negative breast cancer among African American women

Abstract African American (AA) women have a higher incidence of triple-negative breast cancer (TNBC) and are diagnosed at an earlier age than women of European ancestry, yet remain underrepresented in cancer genomic studies. We recently charted the mutational landscape of TNBC in 426 AA women. Here, we investigated the associations between germline variants and somatic mutational profiles in those patients. Whole-exome sequencing was performed on germline and tumor DNA from 426 patients; 402 also had germline whole-genome sequencing or array data. We analyzed somatic mutation status of 49 TNBC or other cancer genes (2% frequency) and mutational signatures present in20% samples (SBS1, SBS2, SBS3, SBS5, SBS13, ID6, ID8, and a new indel signature characterized by longer indels ≥5 bp). Germline factors included 1) pathogenic variants at TNBC genes, 2) cis-variants within 500kb of somatic mutated genes, 3) polygenic risk scores (PRS) for TNBC and overall breast cancer in AA women, and 4) credible causal variants (CCVs) with posterior inclusion probability 0.8 at breast cancer risk loci. Pathogenic variants included 34 germline mutations identified in BRCA1, BRCA2, PALB2, and CDH1, which were classified as pathogenic or likely pathogenic by ClinVar (n=25) or nonsense/frameshift variants (n=9). Firth logistic regression and zero-inflated negative binomial regression were used, adjusting for age at diagnosis, mutation rate, tumor purity, stage, grade, carrier of pathogenic variant (in analyses for other germline factors), and top five germline genotype principal components. There was no significant association of somatic mutations in the 49 genes with pathogenic variants, cis-variants, or CCVs at risk loci. Patients carrying pathogenic variants in BRCA1, BRCA2, PALB2, and CDH1 were substantially more likely to exhibit SBS3 and ID6, two homologous recombination deficiency (HRD)-related signatures, with 15% (incidence relative ratio, IRR 1.15, 95% CI 1.03-1.28) and 48% (IRR 1.48, 95% CI 1.18-1.87) higher counts, respectively. PRS for TNBC showed no significant associations with mutational signatures. The PRS for overall breast cancer showed a nominally significant inverse association with SBS2 and SBS5 (P=0.01 and 0.02), which may be attributable to potential collider bias inherent to the case-only design. Although no CCVs reached significance after Bonferroni correction, the risk allele of rs6482189, a variant included in the PRS for overall breast cancer but not for TNBC, was associated with the new ID signature (IRR 1.33, 1.17-1.50, P=7.93×10-6). In summary, this study this study examined germline-somatic relationships in TNBC among AA women, confirmed enrichment of HRD-related signatures in pathogenic variant carriers, and identified a breast cancer risk variant associated with a novel indel signature, offering insights into TNBC biology in AA women. Citation Format: Guochong Jia, Jie Ping, Christine B. Ambrosone, John D. Carpten, Julie R. Palmer, Song Yao, Wei Zheng. Identification of germline variants associated with somatic mutational profiles in triple-negative breast cancer among African American women abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3256.