Department of Medical Oncology, Christian Medical College (CMC), Vellore, India.
Molecular Endocrinology Laboratory, Department of Endocrinology, Diabetes and Metabolism, CMC, Vellore, India.
Eur J Hum Genet. 2024 Oct;32(10):1319-1326. doi: 10.1038/s41431-024-01596-w. Epub 2024 Mar 28.
Mutations in BRCA1 and BRCA2 significantly elevate the risk of developing breast and ovarian cancer. Limited data exists regarding the prevalence of BRCA mutations, and optimal, cost-effective testing strategies in developing countries like India. This study aimed to evaluate the utility of a Next Generation Sequencing (NGS) panel for BRCA1/2 mutation testing among women diagnosed with, or at risk of developing hereditary breast and ovarian cancers. We also aimed to identify population specific BRCA1/2 mutation hotspots, to enable the development of more affordable testing strategies. We identified 921 patients with breast and ovarian cancer who underwent mutation testing. The target enrichment was followed by targeted NGS in 772 patients and an allele-specific PCR (ASPCR) based genotyping for BRCA1:c.68_69delAG (or 185delAG), was carried out in 149 patients. We identified 188 (20.4%) patients with BRCA1/2 variants: 118 (62.8%) with pathogenic/likely pathogenic and 70 (37.2%) with VUS. The 185delAG was identified as a recurrent mutation in the Southern Indian population, accounting for 24.6% of the pathogenic variants. In addition, a family history of breast, ovary, pancreas, or prostate (BOPP) cancer was found to be associated with an increased risk of identifying a deleterious BRCA1/2 variant [OR = 2.11 (95% CI 1.45-3.07) p ≤ 0.001]. These results suggest that Targeted NGS is a sensitive and specific strategy for BRCA testing. For Southern Indian patients, a two-tiered approach can be considered: Initial screening with ASPCR for BRCA1 185delAG followed by NGS for those testing negative. Expanding the gene panel and identifying other population-specific mutation hot spots is a promising area with potential for improvements in testing and treatment strategies.
BRCA1 和 BRCA2 基因突变显著增加了罹患乳腺癌和卵巢癌的风险。关于 BRCA 基因突变的流行率，以及在印度等发展中国家的最佳、具有成本效益的检测策略，数据有限。本研究旨在评估下一代测序（NGS）在诊断为遗传性乳腺癌和卵巢癌或有患病风险的女性中进行 BRCA1/2 基因突变检测的效用。我们还旨在确定特定人群的 BRCA1/2 突变热点，以制定更经济实惠的检测策略。我们确定了 921 名患有乳腺癌和卵巢癌的患者进行了突变检测。在 772 名患者中进行了靶向富集，随后进行了靶向 NGS，在 149 名患者中进行了基于等位基因特异性 PCR（ASPCR）的 BRCA1:c.68_69delAG（或 185delAG）基因分型。我们发现 188 名（20.4%）患者存在 BRCA1/2 变异：118 名（62.8%）为致病性/可能致病性，70 名（37.2%）为意义未明变异。185delAG 被鉴定为印度南部人群中的一种复发性突变，占致病性变异的 24.6%。此外，家族中有乳腺癌、卵巢癌、胰腺癌或前列腺癌（BOPP）病史的患者，其发现有害 BRCA1/2 变异的风险增加[比值比（OR）=2.11（95%置信区间 1.45-3.07），p≤0.001]。这些结果表明，靶向 NGS 是一种敏感和特异的 BRCA 检测策略。对于印度南部患者，可以考虑采用两阶段方法：先用 ASPCR 对 BRCA1 185delAG 进行初始筛查，然后对检测结果为阴性的患者进行 NGS。扩大基因面板并确定其他特定人群的突变热点是一个很有前途的领域，有望改善检测和治疗策略。
