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Cell, Tumor, and Stem Cell Biology |
1 Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel; 2 Department of Microbiology, Weill Medical College of Cornell University; Departments of 3 Pathology and 4 Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; 5 Departments of Pediatrics and Molecular Genetics, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, Piscataway, New Jersey; and 6 School of Engineering and Applied Science, Princeton University, Princeton, New Jersey
Requests for reprints: Eytan Domany, Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, 76100 Israel. Phone: 972-8-934-3964; Fax: 972-8-934-4109; E-mail: eytan.domany{at}weizmann.ac.il.
Several studies have verified the existence of multiple chromosomal abnormalities in colon cancer. However, the relationships between DNA copy number and gene expression have not been adequately explored nor globally monitored during the progression of the disease. In this work, three types of array-generated data (expression, single nucleotide polymorphism, and comparative genomic hybridization) were collected from a large set of colon cancer patients at various stages of the disease. Probes were annotated to specific chromosomal locations and coordinated alterations in DNA copy number and transcription levels were revealed at specific positions. We show that across many large regions of the genome, changes in expression level are correlated with alterations in DNA content. Often, large chromosomal segments, containing multiple genes, are transcriptionally affected in a coordinated way, and we show that the underlying mechanism is a corresponding change in DNA content. This implies that whereas specific chromosomal abnormalities may arise stochastically, the associated changes in expression of some or all of the affected genes are responsible for selecting cells bearing these abnormalities for clonal expansion. Indeed, particular chromosomal regions are frequently gained and overexpressed (e.g., 7p, 8q, 13q, and 20q) or lost and underexpressed (e.g., 1p, 4, 5q, 8p, 14q, 15q, and 18) in primary colon tumors, making it likely that these changes favor tumorigenicity. Furthermore, we show that these aberrations are absent in normal colon mucosa, appear in benign adenomas (albeit only in a small fraction of the samples), become more frequent as disease advances, and are found in the majority of metastatic samples. (Cancer Res 2006; 66(4): 2129-37)
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