Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Koch Institute for Integrative Cancer Research, Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Sci Adv. 2020 Jan 29;6(5):eaay2611. doi: 10.1126/sciadv.aay2611. eCollection 2020 Jan.
Women harboring heterozygous germline mutations of have a 50 to 80% risk of developing breast cancer, yet the pathogenesis of these cancers is poorly understood. To reveal early steps in -associated carcinogenesis, we analyzed sorted cell populations from freshly-isolated, non-cancerous breast tissues of mutation carriers and matched controls. Single-cell whole-genome sequencing demonstrates that >25% of carrier ( ) luminal progenitor (LP) cells exhibit sub-chromosomal copy number variations, which are rarely observed in non-carriers. Correspondingly, primary breast epithelia exhibit DNA damage together with attenuated replication checkpoint and apoptotic responses, and an age-associated expansion of the LP compartment. We provide evidence that these phenotypes do not require loss of the wild-type allele. Collectively, our findings suggest that haploinsufficiency and associated DNA damage precede histologic abnormalities in vivo. Using these hallmarks of cancer predisposition will yield unanticipated opportunities for improved risk assessment and prevention strategies in high-risk patients.
携带有胚系突变的女性罹患乳腺癌的风险为 50%至 80%，但这些癌症的发病机制仍不清楚。为了揭示与相关的致癌作用的早期步骤，我们分析了来自携带有突变的女性和匹配对照者的新鲜非癌性乳腺组织中分离的细胞群体。单细胞全基因组测序表明，超过 25%的携带者（）腔前体细胞（LP）细胞表现出亚染色体拷贝数变异，而在非携带者中很少观察到这种变异。相应地，原发性乳腺上皮细胞表现出 DNA 损伤，同时减弱了复制检查点和凋亡反应，以及 LP 隔室的年龄相关扩张。我们提供的证据表明，这些表型不需要野生型等位基因的丢失。总之，我们的研究结果表明，杂合不足和相关的 DNA 损伤先于体内组织学异常。利用这些癌症易感性的特征将为高危患者提供改进风险评估和预防策略的机会。
