Barber Thomas D, McManus Kirk, Yuen Karen W Y, Reis Marcelo, Parmigiani Giovanni, Shen Dong, Barrett Irene, Nouhi Yasaman, Spencer Forrest, Markowitz Sanford, Velculescu Victor E, Kinzler Kenneth W, Vogelstein Bert, Lengauer Christoph, Hieter Philip
The Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3443-8. doi: 10.1073/pnas.0712384105. Epub 2008 Feb 25.
Although the majority of colorectal cancers exhibit chromosome instability (CIN), only a few genes that might cause this phenotype have been identified and no general mechanism underlying their function has emerged. To systematically identify somatic mutations in potential CIN genes in colorectal cancers, we determined the sequence of 102 human homologues of 96 yeast CIN genes known to function in various aspects of chromosome transmission fidelity. We identified 11 somatic mutations distributed among five genes in a panel that included 132 colorectal cancers. Remarkably, all but one of these 11 mutations were in the homologs of yeast genes that regulate sister chromatid cohesion. We then demonstrated that down-regulation of such homologs resulted in chromosomal instability and chromatid cohesion defects in human cells. Finally, we showed that down-regulation or genetic disruption of the two major candidate CIN genes identified in previous studies (MRE11A and CDC4) also resulted in abnormal sister chromatid cohesion in human cells. These results suggest that defective sister chromatid cohesion as a result of somatic mutations may represent a major cause of chromosome instability in human cancers.
尽管大多数结直肠癌表现出染色体不稳定（CIN），但仅有少数可能导致这种表型的基因被识别出来，且尚未出现关于其功能的通用机制。为了系统地识别结直肠癌中潜在CIN基因的体细胞突变，我们测定了96个已知在染色体传递保真度的各个方面发挥作用的酵母CIN基因的102个人类同源基因的序列。在一个包含132例结直肠癌的样本中，我们在5个基因中鉴定出了11个体细胞突变。值得注意的是，这11个突变中除了1个之外，其余均位于调节姐妹染色单体黏连的酵母基因的同源基因中。然后我们证明，此类同源基因的下调会导致人类细胞中的染色体不稳定和染色单体黏连缺陷。最后，我们表明，先前研究中鉴定出的两个主要候选CIN基因（MRE11A和CDC4）的下调或基因破坏也会导致人类细胞中姐妹染色单体黏连异常。这些结果表明，体细胞突变导致的姐妹染色单体黏连缺陷可能是人类癌症中染色体不稳定的主要原因。
