Robert Cormier
A long-term objective of our laboratory is to understand the full constellation of genetic events underlying susceptibility to colorectal cancer (CRC). Genetic factors that influence CRC may exist as natural polymorphic variants in the host or may arise as genetic or epigenetic somatic alterations in cancers. One strategy to identify these genetic factors employs forward and reverse genetic approaches in mouse models of CRC. For example, work by Dr. Cormier and other researchers identified the secretory phospholipase gene Pla2g2a as a component of the Mom1 tumor resistance locus (Cormier et al., Nature Genetics 1997; Oncogene, 2000). Expression of Pla2g2a confers resistance to tumorigenesis in several different mouse models of CRC and gene expression analysis has identified a large number of Pla2g2a target genes including the transcription factor Runx1, which has also been identified as a tumor suppressor gene in the gastrointestinal tract. Another strategy employs forward genetic screens using Sleeping Beauty transposon mutagenesis. Work with collaborators at the University of Minnesota has identified more than 100 novel candidate driver genes for CRC (Starr et al., Science, 2009; Starr et al., PNAS, 2011). Most recently, we have analyzed the role of these susceptibility genes identified in mice in human colorectal cancers. Two ion channel genes, KCNQ1 and CFTR, which were initially identified as tumor suppressors in mouse models, have been shown to be potent tumor suppressors in human CRC (Than et al, 2013). Current work is also focused on colorectal cancer genomics, employing next generation sequencing of human colorectal cancers to identify somatic mutations that can serve as prognostic predictors of disease progression and identify novel therapeutic targets. An interesting category of driver somatic mutations identified in our preliminary studies are fusion oncogenes.
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