Relationship of Gene Expression and Chromosomal Abnormalities in Colorectal Cancer

Abstract

Several studies have verified the existence of multiple chromosomal abnormalities in colon cancer. However, the relationships between DNA copy number and gene expression have not been adequately explored nor globally monitored during the progression of the disease. In this work, three types of array-generated data (expression, single nucleotide polymorphism, and comparative genomic hybridization) were collected from a large set of colon cancer patients at various stages of the disease. Probes were annotated to specific chromosomal locations and coordinated alterations in DNA copy number and transcription levels were revealed at specific positions. We show that across many large regions of the genome, changes in expression level are correlated with alterations in DNA content. Often, large chromosomal segments, containing multiple genes, are transcriptionally affected in a coordinated way, and we show that the underlying mechanism is a corresponding change in DNA content. This implies that whereas specific chromosomal abnormalities may arise stochastically, the associated changes in expression of some or all of the affected genes are responsible for selecting cells bearing these abnormalities for clonal expansion. Indeed, particular chromosomal regions are frequently gained and overexpressed (e.g., 7p, 8q, 13q, and 20q) or lost and underexpressed (e.g., 1p, 4, 5q, 8p, 14q, 15q, and 18) in primary colon tumors, making it likely that these changes favor tumorigenicity. Furthermore, we show that these aberrations are absent in normal colon mucosa, appear in benign adenomas (albeit only in a small fraction of the samples), become more frequent as disease advances, and are found in the majority of metastatic samples. (Cancer Res 2006; 66(4): 2129-37)

Aneuploidy: Cells Losing Their Balance

“…Similar results were obtained in mice with a partial trisomy for chromosome 16 or 17 (Kahlem et al 2004;Lyle et al 2004;Vacik et al 2005). In addition, changes in gene expression appear to correlate with changes in gene copy number in aneuploid cancer cells (Pollack et al 2002;Tsafrir et al 2006). If we assume that translation also occurs according to gene copy number-there is some evidence that this is the case at least for some proteins in yeast and trisomic mouse embryos (Klose and Putz 1983;Torres et al 2007)-aneuploidy would result in deviations from the normal stoichiometry of protein complex subunits.…”

Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

“…Notably, the same amplifi cation was also found in lung, colorectal, bone, and breast cancers (44)(45)(46)(47)(48); thus, it is plausible that similar considerations could be applied to other tumors harboring VEGFA gains.…”

Are microRNAs located in genomic regions associated with cancer?

“…Benetkiewicz et al, 2005;Tsafrir et al, 2006). It is natural to hypothesise that miRNA expression also correlates with copy number.…”