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Abstract
An understanding of early genetic/epigenetic changes in colorectal cancer would aid in diagnosis and prognosis. To identify these changes in human preneoplastic tissue, we first studied our mouse model in which Mthfr⁺/⁻ BALB/c mice fed folate-deficient diets develop intestinal tumors in contrast to Mthfr⁺/⁺ BALB/c mice fed control diets. Transcriptome profiling was performed in normal intestine from mice with low or high tumor susceptibility. We identified 12 upregulated and 51 downregulated genes in tumor-prone mice. Affected pathways included retinoid acid synthesis, lipid and glucose metabolism, apoptosis and inflammation. We compared murine candidates from this microarray analysis, and murine candidates from an earlier strain-based comparison, with a set of human genes that we had identified in previous methylome profiling of normal human colonic mucosa, from colorectal cancer patients and controls. From the extensive list of human methylome candidates, our approach uncovered five orthologous genes that had shown changes in murine expression profiles (PDK4, SPRR1A, SPRR2A, NR1H4, and PYCARD). The human orthologs were assayed by bisulfite-pyrosequencing for methylation at 14 CpGs. All CpGs exhibited significant methylation differences in normal mucosa between colorectal cancer patients and controls; expression differences for these genes were also observed. PYCARD and NR1H4 methylation differences showed promise as markers for presence of polyps in controls. We conclude that common pathways are disturbed in preneoplastic intestine in our animal model and morphologically normal mucosa of patients with colorectal cancer, and present an initial version of a DNA methylation-based signature for human preneoplastic colon.
Highlights
One million people worldwide develop colorectal cancer every year [1]
We considered BALB/c Mthfrþ/þ mice fed control diets (CD) as the group with higher tumor resistance and BALB/c Mthfrþ/À FD group as the tumor-susceptible group
There were 63 genes with significant expression changes (51 increased and 12 decreased; Supplementary Fig. S3A) in FD Mthfrþ/À BALB/c mice compared with CD Mthfrþ/þ BALB/c mice (Supplementary Table S6)
Summary
One million people worldwide develop colorectal cancer every year [1]. Colorectal cancer results from a combination of environmental and genetic factors that convert normal epithelium into a malignant tumor through multiple stages. An understanding of early events in tumorigenesis will lead to timely diagnoses and improved outcomes. Epigenetic changes are early events in colorectal cancer and other neoplasias. Authors' Affiliations: 1Departments of Human Genetics and Pediatrics, McGill University, Montreal Children's Hospital site of the McGill University Health Centre Research Institute, Montreal, Canada; and 2Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania. Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).
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