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人类乳腺组织由复杂的导管和小叶组成，哺乳期间产生并运输乳汁喂养后代。乳腺的导管和小叶由双层上皮组成，内层是管腔细胞，外层是基底肌上皮细胞。乳腺组织上皮细胞发生变异，就可能导致乳腺癌等疾病。例如，正常人体细胞有23对染色体，共计46条染色体，非整倍体细胞可能有45或47条染色体，是遗传病的主要诱因之一，也常见于乳腺癌细胞。不过，此前尚未发现正常乳腺组织是否存在非整倍体上皮细胞。
2024年11月20日，全球自然科学三大旗舰期刊之首、英国《自然》正刊在线发表美国德克萨斯大学MD安德森癌症中心和贝勒医学院的研究报告，首次发现健康女性原本看似正常的乳腺组织可能存在非整倍体上皮细胞群，该研究结果质疑了对乳腺癌遗传起源的传统看法，这可能对将来的早期乳腺癌检测方法具有重要指导意义。
该研究之前已对超过71.4万个细胞进行分析，在细胞水平生成了正常乳腺组织的全部基因图谱。此次采用单细胞基因测序对来自49例接受乳房缩小手术而且未患已知疾病健康女性乳腺组织的8万3206个上皮细胞拷贝数变异进行分析，并对其中19例女性的乳腺标本采用单细胞基因和转座酶可及染色质测序联合测定，再与临床乳腺癌数据进行比较。
结果发现，全部49例健康女性乳腺组织0.27%至20.90%、中位3.19%的正常上皮细胞染色体增加或减少，并且该比例随着年龄增长而增加。这些正常乳腺组织中位82.67%、四分位69.43%至90.06%的非整倍体上皮细胞发生克隆扩增，并且存在拷贝数变异，最常见的变异是染色体1q拷贝数增加以及10q、16q和22q拷贝数减少，这些变异通常可见于乳腺浸润癌。联合分析表明，非整倍体细胞主要与两种管腔上皮基因特征相关，其中一些拷贝数变异类似雌激素受体阳性乳腺癌，另一些似乎与雌激素受体阴性乳腺癌一致，空间分布显示这些变异位于组织病理学正常的导管和小叶结构，突显了它们可能不同的起源。
随后，该研究继续利用分子诊断方法对乳腺导管原位癌（又称零期乳腺癌）活检标本进行早期检测，结果发现存在假阳性风险，因为这些细胞可能被错误地与乳腺浸润癌混淆。癌症研究者或肿瘤科医师看到这些正常乳腺组织细胞的基因组图谱，往往将其归类为乳腺浸润癌。众所周知，正常细胞有23对染色体，但这似乎是不准确的，因为该研究分析的每位健康女性都有异常，这就提出一个非常有启发性的问题：癌症究竟发生于何时？
因此，该研究结果表明，即使是健康女性，其乳腺组织也存在罕见的非整倍体上皮细胞克隆扩增，这对我们过去认为“正常”的乳腺组织提出了疑问。这是关于正常人群发现罕见非整倍体细胞的横向研究报告，需要进一步的纵向研究确定哪些潜在风险因素可能导致这些细胞癌变。此外，上皮细胞存在于人体多个系统，这凸显这些发现可能适用于其他器官的可能性。这也说明我们的身体在某些方面并不完美，可以在一生中产生这些类型的细胞，不仅对乳腺癌领域有相当大的影响，而且可能对多种癌症都有影响，这并不一定意味着每个人都有癌前病变，但是我们需要考虑如何开展更大规模的研究以了解其对癌症发展的影响。
有趣的是，英国《自然》旗下《自然遗传学》在同一天发表美国纽约纪念医院斯隆凯特林癌症中心、哈佛大学医学院、达纳法伯癌症研究院、布莱根和波士顿妇女医院、加拿大不列颠哥伦比亚癌症研究中心和不列颠哥伦比亚大学的研究报告，对28例健康女性乳腺组织4万9238个乳腺细胞进行基因组分析，结果也发现几乎全部女性大约3.25%的乳腺细胞存在癌症相关非整倍体基因变异，与上述研究结果不谋而合。
Nature. 2024 Nov 20. IF: 50.5Normal breast tissues harbour rare populations of aneuploid epithelial cells.Yiyun Lin, Junke Wang, Kaile Wang, Shanshan Bai, Aatish Thennavan, Runmin Wei, Yun Yan, Jianzhuo Li, Heba Elgamal, Emi Sei, Anna Casasent, Mitchell Rao, Chenling Tang, Asha S. Multani, Jin Ma, Jessica Montalvan, Chandandeep Nagi, Sebastian Winocour, Bora Lim, Alastair Thompson, Nicholas Navin.University of Texas MD Anderson Cancer Center, Houston, TX, USA; Baylor College of Medicine, Houston, TX, USA.Aneuploid epithelial cells are common in breast cancer; however, their presence in normal breast tissues is not well understood. To address this question, we applied single-cell DNA sequencing to profile copy number alterations in 83,206 epithelial cells from the breast tissues of 49 healthy women, and we applied single-cell DNA and assay for transposase-accessible chromatin sequencing co-assays to the samples of 19 women. Our data show that all women harboured rare aneuploid epithelial cells (median 3.19%) that increased with age. Many aneuploid epithelial cells (median 82.22%) in normal breast tissues underwent clonal expansions and harboured copy number alterations reminiscent of invasive breast cancers (gains of 1q; losses of 10q, 16q and 22q). Co-assay profiling showed that the aneuploid cells were mainly associated with the two luminal epithelial lineages, and spatial mapping showed that they localized in ductal and lobular structures with normal histopathology. Collectively, these data show that even healthy women have clonal expansions of rare aneuploid epithelial cells in their breast tissues.DOI: 10.1038/s41586-024-08129-xNat Genet. 2024 Nov 20. IF: 31.7Luminal breast epithelial cells of BRCA1 or BRCA2 mutation carriers and noncarriers harbor common breast cancer copy number alterations.Marc J. Williams, Michael U. J. Oliphant, Vinci Au, Cathy Liu, Caroline Baril, Ciara O'Flanagan, Daniel Lai, Sean Beatty, Michael Van Vliet, Jacky CH Yiu, Lauren O'Connor, Walter L. Goh, Alicia Pollaci, Adam C. Weiner, Diljot Grewal, Andrew McPherson, Klarisa Norton, McKenna Moore, Vikas Prabhakar, Shailesh Agarwal, Judy E. Garber, Deborah A. Dillon, Sohrab P. Shah, Joan S. Brugge, Samuel Aparicio.Memorial Sloan Kettering Cancer Center, New York City, NY, USA; Harvard Medical School (HMS), Boston, MA, USA; Dana-Farber Cancer Institute (DFCI), Boston, MA, USA; Brigham and Women's Hospital (BWH), Boston, MA, USA; British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada; University of British Columbia, Vancouver, British Columbia, Canada.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
