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(American Journal of Pathology. 2007;171:1509-1519.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070331

The Cables Gene on Chromosome 18q Is Silenced by Promoter Hypermethylation and Allelic Loss in Human Colorectal Cancer

Do Youn Park*{dagger}, Hideo Sakamoto{ddagger}, Sandra D. Kirley*, Shuji Ogino§, Takako Kawasaki, Eunjeong Kwon*, Mari Mino-Kenudson*, Gregory Y. Lauwers*, Daniel C. Chung||, Bo R. Rueda{ddagger} and Lawrence R. Zukerberg*{ddagger}

From the Department of Pathology,* and Gastroenterology,|| and the Vincent Center for Reproductive Biology,{ddagger} Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; the Department of Pathology,§ Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; and the Department of Pathology,{dagger} Pusan National University Hospital and Medical Research Institute, Pusan National University, Busan, Korea

Cables is a cyclin-dependent kinase-binding nuclear protein that maps to chromosome 18q11-12. Here, we assessed Cables expression in 160 colorectal cancers (CRCs), its role in colon cancer cell growth, and the potential mechanisms of Cables inactivation. Expression levels, promoter methylation, and mutational status of Cables were investigated in colon cancer cell lines and primary colon tumors. Chromosome 18q loss of heterozygosity (LOH) was evaluated with multiple polymorphic markers. Cables inhibited cellular proliferation and colony formation in colon cancer cell lines. Cables expression was reduced in 65% of primary CRCs. No mutations were detected in 10 exons of Cables in 20 primary colon tumors. Cables promoter was methylated in cell lines with decreased Cables expression and vice versa. 5-Aza-2'-deoxycytidine resulted in increased Cables expression in methylated cell lines. There was a significant correlation between promoter methylation and Cables gene expression in primary colon tumors. Sixty-five percent of primary colon tumors demonstrated chromosome 18q LOH. LOH involving the Cables region was observed in 35% of cases, including those in which more distal portions of chromosome 18q were retained, and Cables expression was decreased in all such cases. Loss of Cables expression in 65% of CRCs suggests that it is a common event in colonic carcinogenesis, with promoter methylation and LOH appearing to be important mechanisms of Cables gene inactivation.






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Copyright © 2007 by the American Society for Investigative Pathology.