Association of survival and disease progression with chromosomal instability: A genomic exploration of colorectal cancer

Michal Sheffer, Manny D. Bacolod, Or Zuk, Sarah F. Giardina, Hanna Pincas, Francis Barany, Philip B. Paty, William L. Gerald, Daniel A. Notterman, Eytan Domany

Research output: Contribution to journalArticle

224 Scopus citations

Abstract

During disease progression the cells that comprise solid malignancies undergo significant changes in gene copy number and chromosome structure. Colorectal cancer provides an excellent model to study this process. To indentify and characterize chromosomal abnormalities in colorectal cancer, we performed a statistical analysis of 299 expression and 130 SNP arrays profiled at different stages of the disease, including normal tissue, adenoma, stages 1-4 adenocarcinoma, and metastasis. We identified broad (> 1/2 chromosomal arm) and focal (< 1/2 chromosomal arm) events. Broad amplifications were noted on chromosomes 7, 8q, 13q, 20, and X and broad deletions on chromosomes 4, 8p, 14q, 15q, 17p, 18, 20p, and 22q. Focal events (gains or losses) were identified in regions containing known cancer pathway genes, such as VEGFA, MYC, MET, FGF6, FGF23, LYN. MMP9, MYBL2, AURKA, UBE2C. and PTEN. Other focal events encompassed potential new candidate tumor suppressors (losses) and oncogenes (gains), including CCDC68, CSMD1, POLR1D, and PMEPA1. From the expression data, we identified genes whose expression levels reflected their copy number changes and used this relationship to impute copy number changes to samples without accompanying SNP data. This analysis provided the statistical power to show that deletions of 8p, 4p, and 15q are associated with survival and disease progression, and that samples with simultaneous deletions in 18q, 8p, 4p, and 15q have a particularly poor prognosis. Annotation analysis reveals that the oxidative phosphorylation pathway shows a strong tendency for decreased expression in the samples characterized by poor prognosis.

Original languageEnglish (US)
Pages (from-to)7131-7136
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number17
DOIs
StatePublished - Apr 28 2009

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Colon cancer
  • DNA copy number
  • Gene expression
  • SNP arrays

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