加拿大英属哥伦比亚大学Samuel Aparicio等研究人员合作发现，携带BRCA1或BRCA2突变的乳腺上皮细胞和非携带者之间存在共同的乳腺癌拷贝数变异。该项研究成果于2024年11月20日在线发表在《自然—遗传学》杂志上。

通过对BRCA1和BRCA2携带者或野生型个体的乳腺上皮进行单细胞DNA测序（49238个细胞），研究人员鉴定出了反复出现的拷贝数变异（CNA）（例如，1q增益和7q、10q、16q及22q缺失），这些变异在几乎所有样本中都存在于一小部分细胞中（n=28）。

在BRCA1/BRCA2携带者中，这些CNA出现在野生型等位基因丧失杂合性（LOH）之前。这些在恶性肿瘤中常见的CNA在腔面细胞中富集，但在基底肌上皮细胞中缺失。

对常见CNA的等位基因特异性分析表明，它们是通过独立的突变事件产生的，符合趋同演化的模式。BRCA1/BRCA2携带者中存在一小部分细胞具有极端的非整倍体特征，表现为TP53丧失、BRCA1/BRCA2 LOH及多个与乳腺癌相关的CNA。我们的研究结果表明，正常腔面乳腺上皮中出现的CNA可能是克隆扩增肿瘤基因组的前体。

研究人员表示，乳腺上皮中的体细胞CNA的普遍性和性质，以及它们在肿瘤启动和演化中的作用仍不甚明了。

附：英文原文

Title: Luminal breast epithelial cells of BRCA1 or BRCA2 mutation carriers and noncarriers harbor common breast cancer copy number alterations

Author: Williams, Marc J., Oliphant, Michael U. J., Au, Vinci, Liu, Cathy, Baril, Caroline, OFlanagan, Ciara, Lai, Daniel, Beatty, Sean, Van Vliet, Michael, Yiu, Jacky CH, OConnor, Lauren, Goh, Walter L., Pollaci, Alicia, Weiner, Adam C., Grewal, Diljot, McPherson, Andrew, Norton, Klarisa, Moore, McKenna, Prabhakar, Vikas, Agarwal, Shailesh, Garber, Judy E., Dillon, Deborah A., Shah, Sohrab P., Brugge, Joan S., Aparicio, Samuel

Issue&Volume: 2024-11-20

Abstract: The prevalence and nature of somatic copy number alterations (CNAs) in breast epithelium and their role in tumor initiation and evolution remain poorly understood. Using single-cell DNA sequencing (49,238 cells) of epithelium from BRCA1 and BRCA2 carriers or wild-type individuals, we identified recurrent CNAs (for example, 1q-gain and 7q, 10q, 16q and 22q-loss) that are present in a rare population of cells across almost all samples (n = 28). In BRCA1/BRCA2 carriers, these occur before loss of heterozygosity (LOH) of wild-type alleles. These CNAs, common in malignant tumors, are enriched in luminal cells but absent in basal myoepithelial cells. Allele-specific analysis of prevalent CNAs reveals that they arose by independent mutational events, consistent with convergent evolution. BRCA1/BRCA2 carriers contained a small percentage of cells with extreme aneuploidy, featuring loss of TP53, BRCA1/BRCA2 LOH and multiple breast cancer-associated CNAs. Our findings suggest that CNAs arising in normal luminal breast epithelium are precursors to clonally expanded tumor genomes.

DOI: 10.1038/s41588-024-01988-0

Source: https://www.nature.com/articles/s41588-024-01988-0