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

Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7131-6. doi: 10.1073/pnas.0902232106. Epub 2009 Apr 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosomal Instability / genetics*
  • Chromosome Deletion
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology*
  • Disease Progression
  • Fibroblast Growth Factor-23
  • Gene Dosage / genetics
  • Gene Expression Regulation, Neoplastic
  • Genome, Human / genetics*
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Oxidation-Reduction
  • Phosphorylation
  • Polymorphism, Single Nucleotide / genetics
  • RNA, Untranslated / genetics
  • Survival Rate

Substances

  • FGF23 protein, human
  • RNA, Untranslated
  • Fibroblast Growth Factor-23