Purpose: Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC). The high TNBC prevalence (>25%) in India remains a challenge in clinical management. Association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. These studies are however predominantly representative of western population. Therefore, we investigated germline profiles of multi-institutional cohort of TNBC patients in India Methods: Using a multi-gene NGS (next-generation sequencing) panel of 26 ACMG recommended genes associated with inherited cancers. Results: In our study cohort of 193 TNBC patients, we identified 57 pathogenic mutations of which BRCA1 (71.93%) and BRCA2 (14.03%) were most commonly mutated. Additionally, 8 pathogenic mutations were identified in non-BRCA genes associated with the HR pathway. 10 novel mutations were identified in 3 genes namely BRCA1, BRCA2 and PALB2. Comparison of allele-frequency with the global databases like TCGA (The Cancer Genome Atlas), gnomAD and Genome Asia 100K indicated that the novel mutations were unique. Furthermore, we identified 48 variants of uncertain significance (VUS) (24.9%). Conclusions: Our study confirms the major proportion of mutations in BRCA1/2 genes in TNBCs in India. Interestingly, a higher proportion of VUS were found in the non-BRCA genes compared to BRCA1/2 emphasizing the need for functional studies of the non-BRCA genes. Additionally, large scale studies are also warranted to elucidate the landscape of germline mutations relevant to the Indian population and their probable clinical implications.

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评估三阴性乳腺癌的种系突变谱及其临床病理学关联

目的：乳腺癌是印度女性最常见的癌症，其中三阴性乳腺癌（TNBC）的发病率很高。印度 TNBC 的高患病率（>25%）仍然是临床管理的一个挑战。 TNBC 中种系 BRCA1/2 突变的关联已被确定为遗传性乳腺癌风险的诱发因素。然而，这些研究主要代表西方人口。因此，我们研究了印度多机构 TNBC 患者队列的种系概况。方法：使用由 26 个与遗传性癌症相关的 ACMG 推荐基因组成的多基因 NGS（下一代测序）面板。结果：在由 193 名 TNBC 患者组成的研究队列中，我们确定了 57 种致病突变，其中 BRCA1 (71.93%) 和 BRCA2 (14.03%) 是最常见的突变。此外，在与 HR 通路相关的非 BRCA 基因中发现了 8 个致病性突变。在 BRCA1、BRCA2 和 PALB2 3 个基因中发现了 10 个新突变。等位基因频率与 TCGA（癌症基因组图谱）、gnomAD 和 Genome Asia 100K 等全球数据库的比较表明，新突变是独特的。此外，我们还发现了 48 个意义不确定的变异 (VUS) (24.9%)。结论：我们的研究证实了印度 TNBC 中 BRCA1/2 基因突变的主要比例。有趣的是，与 BRCA1/2 相比，在非 BRCA 基因中发现了更高比例的 VUS，这强调了对非 BRCA 基因进行功能研究的必要性。此外，还需要进行大规模研究来阐明与印度人群相关的种系突变情况及其可能的临床意义。