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

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.colon cancer ͉ DNA copy number ͉ gene expression ͉ SNP arrays

Gene Dysregulations Driven by Somatic Copy Number Aberrations-Biological and Clinical Implications in Colon Tumors

“…Along with losses in 14q, 17p, and 15q, these are the most commonly occurring chromosomal aberrations in CRCs. [22][23][24][25] In contrast, a typical MIN tumor (sample C0323A; Figure 1C is devoid of these chromosomal aberrations and remains diploid. Of all of the common somatic copy number changes in CRCs, it is the loss of 18q 24,26 -39 that is most clearly associated with poor prognosis (Table 1).…”

“…Both these genes are often up-regulated in CRCs. [45][46][47] The 13q and 20q chromosomal arms, both of which harbor a great percentage of genes with up-regulated expression, 24,25 are also often gained in CRCs. In our CRC genome-wide expression analysis, one of the 13q genes that turned out to be very highly up-regulated was CUL4A, which has also been found to be copy number-dysregulated (ie, amplified in both copy number and expression) in breast cancer.…”

Tumor-suppressive effects of CDK8 in endometrial cancer cells

“…In addition, we tested the effect of CDK8 reduction on cell cycle distribution by flow cytometry analyses, and we observed that knockdown of CDK8 evidence that links dysregulated CDK8 to a variety of human cancers in recent years. 17 For example, CDK8 gene is amplified or overexpressed in colorectal and gastric cancers, 6,[17][18][19][20][21][22][23] and overexpression of wild-type CDK8 in untransformed 3T3 cells led to anchorage-independent growth. 6 In addition, loss of the histone variant macroH2A increases the expression of CDK8 in melanoma.…”

An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth

“…The clinical relevance of these alterations is highlighted by their association to metastatic progression and poor prognosis in CRC patients (Sheffer et al 2009;Loo et al 2013). Structural and functional interrogations of these regions have described putative oncogenes at chromosomes Ó 2014 Adler et al This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml).…”