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Expression of the mitotic checkpoint gene MAD2L2 has prognostic significance in colon cancer
Author(s) -
Rimkus Caroline,
Friederichs Jan,
Rosenberg Robert,
Holzmann Bernhard,
Siewert JörgRüdiger,
Janssen KlausPeter
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22155
Subject(s) - mad2 , aneuploidy , chromosome instability , colorectal cancer , mitosis , cancer research , biology , spindle checkpoint , anaphase , microsatellite instability , downregulation and upregulation , mitotic index , cancer , cell cycle , gene expression , gene expression profiling , gene , pathology , medicine , genetics , chromosome , kinetochore , allele , microsatellite
Aneuploidy and genetic instability are a hallmark of colorectal cancer and other solid tumors, and they are thought to enhance tumor progression. The gene MAD2L 2 (mitotic arrest deficient 2‐like 2) encodes the spindle checkpoint protein MAD2L2 (or MAD2B), a key component of a surveillance system that delays anaphase until all chromosomes are correctly oriented. Defects in this mitotic checkpoint are known to contribute to genetic instability, i.e. , numerical and structural aberrations of chromosomes. We have previously identified MAD2L 2 as significantly upregulated in locally restricted colorectal tumors by gene expression profiling. So far, MAD2L 2 has not been reported to play a major role in human cancer in contrast to its homologue MAD2 . To address this question, 118 histologically confirmed colorectal lesions were analyzed by quantitative real‐time PCR for expression of MAD2L 2 , and compared to normal colon tissue from 11 patients. Twenty‐five out of 118 tumor samples (21%) showed MAD2L 2 overexpression of 3‐fold or more compared to normal colon, and the fraction of overexpressing tumors increased with tumor stage. Correspondingly, protein levels of MAD2L2 were found to be significantly upregulated in tumors as compared to matched normal tissue. Tumors with upregulated MAD2L 2 expression had significantly higher numbers of aberrant mitotic figures (anaphase bridges), an indication of chromosomal instability. Elevated expression of MAD2L 2 was significantly correlated with reduced patient survival. By multivariate analysis, MAD2L 2 expression was retained as an independent prognostic parameter for patient survival. Thus, our results demonstrate that overexpression of MAD2L 2 correlates with bad prognosis in colorectal cancer. © 2006 Wiley‐Liss, Inc.