乳腺癌和结肠癌的DNA破坏

发布者：PNAS 发布时间：2008-10-13　

Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers

Rebecca J. Leary*, Jimmy C. Lin*, Jordan Cummins*, Simina Boca*,†, Laura D. Wood*, D. Williams Parsons*, Siân Jones*, Tobias Sjöblom*, Ben-Ho Park‡, Ramon Parsons§, Joseph Willis¶, Dawn Dawson¶, James K. V. Willson‖,Tatiana Nikolskaya**,††,Yuri Nikolsky††, Levy Kopelovich‡‡, Nick Papadopoulos*, Len A. Pennacchio§§, Tian-Li Wang*, Sanford D. Markowitz¶, Giovanni Parmigiani*,†,Kenneth W. Kinzler*, Bert Vogelstein*,¶¶, and Victor E. Velculescu*,¶¶

*The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231;
†Departments of Bioinformatics and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231;
‡The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231;
§Institute for Cancer Genetics, Columbia University, New York, NY 10032;
¶Department of Medicine and Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, and Howard Hughes Medical Institute, Cleveland, OH 44106;
‖Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
**Vavilov Institute of General Genetics, Moscow, B333, 117809, Russia;
††GeneGo, Inc., St. Joseph, MI 49085;
‡‡National Cancer Institute, Division of Cancer Prevention, Bethesda, MD 20892-7322; and
§§Department of Energy Joint Genome Institute, Department of Energy, Walnut Creek, CA 94598　

Contributed by Bert Vogelstein, August 21, 2008 (sent for review July 29, 2008)

Abstract
We have performed a genome-wide analysis of copy number changes in breast and colorectal tumors using approaches that can reliably detect homozygous deletions and amplifications. We found that the number of genes altered by major copy number changes, deletion of all copies or amplification to at least 12 copies per cell, averaged 17 per tumor. We have integrated these data with previous mutation analyses of the Reference Sequence genes in these same tumor types and have identified genes and cellular pathways affected by both copy number changes and point alterations. Pathways enriched for genetic alterations included those controlling cell adhesion, intracellular signaling, DNA topological change, and cell cycle control. These analyses provide an integrated view of copy number and sequencing alterations on a genome-wide scale and identify genes and pathways that could prove useful for cancer diagnosis and therapy.

amplification; copy number changes; Digital Karyotyping; high-density SNP arrays; homozygous deletion

PNAS published October 13, 2008, doi:10.1073/pnas.0808041105