gBRCA1/2 mutations increase the incidence of breast cancer by interrupting the homologous recombination repair (HRR) pathway. Although gBRCA1 and gBRCA2 breast cancer have similar clinical profiles, different molecular characteristics have been observed. In this study, we conducted comprehensive genomic analyses and compared gBRCA1/2 breast cancer. Sanger sequencing to identify gBRCA1/2 mutations was conducted in 2,720 patients, and gBRCA1 (n = 128) and gBRCA2 (n = 126) mutations were analyzed. Within this population, deep target sequencing and matched whole-transcriptome sequencing (WTS) results were available for 46 and 34 patients, respectively. An internal database of patients with breast cancer with wild-type gBRCA was used to compile a target sequencing (n = 195) and WTS (n = 137) reference dataset. Three specific mutation sites, p.Y130X (n = 14) and p.1210Afs (n = 13) in gBRCA1 and p.R294X (n = 22) in gBRCA2, were comparably frequent. IHC subtyping determined that the incidence of triple-negative breast cancer was higher among those with a gBRCA1 mutation (71.9%), and estrogen receptor–positive breast cancer was dominant in those with a gBRCA2 mutation (76.2%). gBRCA1/2 mutations were mutually exclusive with PIK3CA somatic mutations (P < 0.05), and gBRCA1 frequently cooccurred with TP53 somatic mutations (P < 0.05). The median tumor mutation burden was 6.53 per megabase (MB) in gBRCA1 and 6.44 per MB in gBRCA2. The expression of AR, ESR1, and PGR was significantly upregulated with gBRCA2 mutation compared with gBRCA1 mutation. gBRCA1 and gBRCA2 breast cancer have similar clinical characteristics, but they have different molecular subtypes, coaltered somatic mutations, and gene expression patterns. Implications: Even though gBRCA1 and gBRCA2 mutations both alter HRR pathways, our results suggest that they generate different molecular characteristics and different mechanisms of carcinogenesis.

中文翻译：

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乳腺癌种系 BRCA1 或 BRCA2 突变的临床特征和探索性基因组分析

gBRCA1/2 突变通过中断同源重组修复 (HRR) 途径来增加乳腺癌的发病率。尽管 gBRCA1 和 gBRCA2 乳腺癌具有相似的临床特征，但已观察到不同的分子特征。在这项研究中，我们进行了全面的基因组分析并比较了 gBRCA1/2 乳腺癌。对 2,720 名患者进行了 Sanger 测序以识别 gBRCA1/2 突变，并分析了 gBRCA1（n = 128）和 gBRCA2（n = 126）突变。在该人群中，分别有 46 名和 34 名患者获得了深度目标测序和匹配的全转录组测序 (WTS) 结果。使用具有野生型 gBRCA 的乳腺癌患者的内部数据库来编译目标测序 (n = 195) 和 WTS (n = 137) 参考数据集。三个特定的突变位点，p。gBRCA1 中的 Y130X（n = 14）和 p.1210Afs（n = 13）以及 gBRCA2 中的 p.R294X（n = 22）相对频繁。IHC 亚型确定，gBRCA1 突变患者的三阴性乳腺癌发病率较高（71.9%），gBRCA2 突变患者的雌激素受体阳性乳腺癌占优势（76.2%）。gBRCA1/2 突变与 PIK3CA 体细胞突变相互排斥（P < 0.05），gBRCA1 经常与 TP53 体细胞突变同时发生（P < 0.05）。gBRCA1 中的中位肿瘤突变负荷为每兆碱基 (MB) 6.53，gBRCA2 中每 MB 为 6.44。与 gBRCA1 突变相比，AR、ESR1 和 PGR 的表达随着 gBRCA2 突变而显着上调。gBRCA1 和 gBRCA2 乳腺癌具有相似的临床特征，但它们具有不同的分子亚型、联合体细胞突变、和基因表达模式。启示：尽管 gBRCA1 和 gBRCA2 突变都改变了 HRR 通路，但我们的结果表明它们产生不同的分子特征和不同的致癌机制。