Comparison of the somatic mutations in breast carcinomas in sporadic and BRCA1 carrier patients through targeted next generation sequencing.

Women who carry a germline mutation in BRCA1 have an increased lifetime risk of developing breast cancer (BC). Prior Next-Generation Sequencing (NGS) studies on BCs from patients with germline BRCA1 mutations (gBRCA1) were limited, mostly with small cohorts and had generally been conducted on unselected BC cases, which may bias the results. The goal of this study was to analyze the somatic mutational landscape of gBRCA1 BC and compare it to sporadic BC, controlling for tumor grade and hormone receptor (HR) status. Next-generation sequencing (NGS) was performed on 72 BCs using one of two panels, including 134 genes and 50 genes, respectively, with 44 genes shared between the two panels. Twenty-six BCs were from gBRCA1 patients, 45 from sporadic patients, and one case with BRCA1 mutation in tumor but without germline information. Missense or nonsense single-nucleotide variants (SNV) with a variant allele frequency >3% and coverage >150 reads were considered as altered. Pathogenicity was determined using ClinVar and Varsome systems. Fisher's Exact Test was used for statistical analysis. gBRCA1 BCs were diagnosed at younger age than sporadic BCs (median age 51 vs 63), with more high-grade (HG, 65% vs. 43%) and ER/PR/HER2 negative (TN) tumors (42% vs. 16%), compared with sporadic BCs in the TCGA dataset. Pathogenic/likely pathogenic mutations were identified in 12 genes in at least one BC. Seventy-six percent of sporadic BCs had at least one gene with pathogenic/likely pathogenic mutations, compared to 46% of gBRCA1 BCs (p = 0.020). TP53 was the most commonly mutated gene with pathogenic/likely pathogenic mutations in a total of 28 of 72 (39%) BCs, mostly in HG BCs compared with non-HG BCs, in both sporadic (57% vs 6.7%, p = 0.001) and gBRCA1 (53% vs 0%, p = 0.009) cohorts. However, we did not observe a significant difference in TP53 mutation frequency between sporadic and gBRCA1 when stratifying by tumor grade (p > 0.99 for both non-HG and HG) and HR status (p > 0.99 for HR+, p = 0.70 for TN). PIK3CA was the second most commonly mutated gene, with 27% in sporadic and 7.7% in gBRCA1 BCs (p = 0.067). Twenty-nine percent of TP53 mutated tumors (including both sporadic and gBRCA1) had additional somatic pathogenic/likely pathogenic mutations, while 25% of tumors with other than TP53 gene mutations had additional somatic pathogenic/likely pathogenic mutations (p > 0.99). Our study is one of the largest studies analyzing somatic mutations in gBRCA1 BCs. Although we used relatively small NGS panels, a similar gene mutation trend in BCs was observed as in other large NGS studies on BCs. Furthermore, while gBRCA1 had higher frequency of HG and triple negative BCs, we did not observe higher TP53 mutation frequency in this group of BCs, compared with grade- and HR status-matched sporadic BCs. Additionally, sporadic BCs appeared to have an overall higher frequency of pathogenic/likely pathogenic mutations than gBRCA1 BCs, a phenomenon shown by other studies as well. Having a TP53 somatic mutation did not increase the likelihood of other pathogenic/likely pathogenic somatic mutations in either gBRCA1 or sporadic BCs.