乳腺癌易感基因BRCA1是重要的抑癌基因,，參與人體正常細(xì)胞DNA損傷修復(fù)、有絲分裂周期檢查點,、染色質(zhì)重塑,、轉(zhuǎn)錄調(diào)控、蛋白質(zhì)泛素化等必不可少的生物學(xué)過程,，該基因缺陷（包括單核苷酸變異或拷貝數(shù)變異）可引起乳腺癌等惡性腫瘤發(fā)生,，尤其三陰性乳腺癌，故迫切需要從癌前早期到腫瘤進展轉(zhuǎn)移階段在基因組水平深入了解BRCA1相關(guān)乳腺癌,，以制定預(yù)防和治療此類癌癥的有效策略,。對單個細(xì)胞全部基因外顯子進行測序，是解密腫瘤內(nèi)異質(zhì)性和確定癌癥驅(qū)動基因的有效方法,。不過,，目前為止，同時分析單個細(xì)胞的單核苷酸變異和拷貝數(shù)變異始終相當(dāng)困難,。

　　2020年9月25日,，英國《自然》旗下《自然通訊》在線發(fā)表中國澳門大學(xué)健康科學(xué)學(xué)院的研究報告，探討了BRCA1缺陷型三陰性乳腺癌的驅(qū)動基因和抑制基因,。

　　該研究同時對小鼠三陰性乳腺癌（4T1）和人類三陰性乳腺癌（MDA-MB-231）BRCA1野生型和突變型腫瘤組織和癌前組織大量細(xì)胞和單個細(xì)胞的單核苷酸變異和拷貝數(shù)變異分析,，發(fā)現(xiàn)腫瘤始于單核苷酸變異的細(xì)胞，癌變前和癌變期間可影響驅(qū)動基因,，隨后從具有癌癥驅(qū)動基因的染色體區(qū)域獲得拷貝數(shù)變異,。這些事件隨機發(fā)生，除了TP53以外,，還可影響許多已知的癌癥驅(qū)動基因,，從而為各個腫瘤產(chǎn)生獨特的基因和病理特征。最終,，該研究確定蛋白激酶C底物編碼基因PLEKHA5為腫瘤的轉(zhuǎn)移抑制基因,，該基因缺陷可促進乳腺癌肝肺轉(zhuǎn)移，而不影響原發(fā)腫瘤,。

　　因此,，該研究結(jié)果表明，PLEKHA5可能為BRCA1缺陷型三陰性乳腺癌的轉(zhuǎn)移抑制基因,，可用于早期預(yù)測肝肺轉(zhuǎn)移,，有助于此類癌癥的早期預(yù)防和早期治療。

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