乳腺癌易感基因BRCA1是重要的抑癌基因，参与人体正常细胞DNA损伤修复、有丝分裂周期检查点、染色质重塑、转录调控、蛋白质泛素化等必不可少的生物学过程，该基因缺陷（包括单核苷酸变异或拷贝数变异）可引起乳腺癌等恶性肿瘤发生，尤其三阴性乳腺癌，故迫切需要从癌前早期到肿瘤进展转移阶段在基因组水平深入了解BRCA1相关乳腺癌，以制定预防和治疗此类癌症的有效策略。对单个细胞全部基因外显子进行测序，是解密肿瘤内异质性和确定癌症驱动基因的有效方法。不过，目前为止，同时分析单个细胞的单核苷酸变异和拷贝数变异始终相当困难。
2020年9月25日，英国《自然》旗下《自然通讯》在线发表中国澳门大学健康科学学院的研究报告，探讨了BRCA1缺陷型三阴性乳腺癌的驱动基因和抑制基因。
该研究同时对小鼠三阴性乳腺癌（4T1）和人类三阴性乳腺癌（MDA-MB-231）BRCA1野生型和突变型肿瘤组织和癌前组织大量细胞和单个细胞的单核苷酸变异和拷贝数变异分析，发现肿瘤始于单核苷酸变异的细胞，癌变前和癌变期间可影响驱动基因，随后从具有癌症驱动基因的染色体区域获得拷贝数变异。这些事件随机发生，除了TP53以外，还可影响许多已知的癌症驱动基因，从而为各个肿瘤产生独特的基因和病理特征。最终，该研究确定蛋白激酶C底物编码基因PLEKHA5为肿瘤的转移抑制基因，该基因缺陷可促进乳腺癌肝肺转移，而不影响原发肿瘤。
因此，该研究结果表明，PLEKHA5可能为BRCA1缺陷型三阴性乳腺癌的转移抑制基因，可用于早期预测肝肺转移，有助于此类癌症的早期预防和早期治疗。
Nat Commun. 2020 Sep 25;11(1):4875.
Characterization of BRCA1-deficient premalignant tissues and cancers identifies Plekha5 as a tumor metastasis suppressor.
Liu J, Adhav R, Miao K, Su SM, Mo L, Chan UI, Zhang X, Xu J, Li J, Shu X, Zeng J, Zhang X, Lyu X, Pardeshi L, Tan K, Sun H, Wong KH, Deng C, Xu X.
University of Macau, Macau, China.
Single-cell whole-exome sequencing (scWES) is a powerful approach for deciphering intratumor heterogeneity and identifying cancer drivers. So far, however, simultaneous analysis of single nucleotide variants (SNVs) and copy number variations (CNVs) of a single cell has been challenging. By analyzing SNVs and CNVs simultaneously in bulk and single cells of premalignant tissues and tumors from mouse and human BRCA1-associated breast cancers, we discover an evolution process through which the tumors initiate from cells with SNVs affecting driver genes in the premalignant stage and malignantly progress later via CNVs acquired in chromosome regions with cancer driver genes. These events occur randomly and hit many putative cancer drivers besides p53 to generate unique genetic and pathological features for each tumor. Upon this, we finally identify a tumor metastasis suppressor Plekha5, whose deficiency promotes cancer metastasis to the liver and/or lung.
PMID: 32978388
DOI: 10.1038/s41467-020-18637-9
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