High resolution analysis of gene copy alterations on chromosome arm 18q and cancer genes reveals several distinct categories of colorectal carcinoma

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Genomic instability is a major feature of neoplastic development in colorectal carcinoma and other cancers. Specific genomic instability events such as allelic imbalances in chromosomes and alterations in gene copy number have potential utility as biologically relevant prognostic biomarkers. Loss of heterozygosity (LOH) on 18q is an indicator of colorectal carcinoma recurrence and potentially useful as a prognostic indicator. Adapting a novel genomic technology referred to as molecular inversion probes (MIP), we have analyzed colorectal carcinoma cell lines and primary tumor samples. The MIP genomic assay measures genomic instability via gene copy number changes and allelic imbalances at the genomic resolution of individual exons. For this initial study, a probe set was designed to interrogate the individual exons of a large number of cancer genes with an overall distribution covering all chromosome arms. Also represented in our set was a series of probes along chromosome arm 18q. To validate the application of molecular inversion probes for quantifying gene copy number and allelic imbalance analysis, a panel of colorectal cancer and other tumor cell lines containing known genomic instability events were analyzed for gene copy alterations. We were able to distinguish different categories of genomic instability among the colorectal cancer cell lines. We analyzed a cohort of colorectal carcinoma primary tumors for gene copy number alterations or allelic imbalance events as 18q loss of heterozygosity (LOH). Our analysis indicates that there are several distinct subtypes of colorectal carcinoma and significant 18q categories being important in the classification. This finding has potential clinical ramifications given the application of 18q LOH events as a potential indicator for adjuvant treatment in stage II colorectal carcinoma.