A Cluster of Cooperating Tumor-Suppressor Gene Candidates in Chromosomal Deletions
A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions Wen Xuea,1,2, Thomas Kitzinga,1,3, Stephanie Roesslerb, Johannes Zubera, Alexander Krasnitza, Nikolaus Schultzc, Kate Revilla, Susann Weissmuellerd,3, Amy R. Rappaporta, Janelle Simona,e,3, Jack Zhanga, Weijun Luoa, James Hicksa, Lars Zendera,4, Xin Wei Wangb, Scott Powersa, Michael Wiglera,5, and Scott W. Lowea,e,3,5 aCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; bLaboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; cComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; dWatson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; and eHoward Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Contributed by Michael Wigler, April 12, 2012 (sent for review January 13, 2012) The large chromosomal deletions frequently observed in cancer the extent of chromosome 8p deletions from cancer genome genomes are often thought to arise as a “two-hit” mechanism in the datasets derived from array-based comparative genomic hybrid- process of tumor-suppressor gene (TSG) inactivation. Using a murine ization (aCGH) performed at Cold Spring Harbor Laboratory and model system of hepatocellular carcinoma (HCC) and in vivo RNAi, the Cancer Genome Atlas (TCGA) project, totaling 1411 primary we test an alternative hypothesis, that such deletions can arise from tumor samples and cell lines of HCC and breast, colon, and lung selective pressure to attenuate the activity of multiple genes. By cancers (Fig. 1A and Materials and Methods). According to these targeting the mouse orthologs of genes frequently deleted on hu- data, approximately half of these tumors harbor heterozygous man 8p22 and adjacent regions, which are lost in approximately deletions of human chromosome 8p, often encompassing a large half of several other major epithelial cancers, we provide evidence portion of or even the entire chromosome arm (Fig.
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