title: Genes with aberrant expression in murine preneoplastic intestine show epigenetic and expression changes in normal mucosa of colon cancer patients.
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.
authors.affiliation: Montreal Children's Hospital Research Institute, 4060 Ste-Catherine West, Room 200, Montreal, Canada H3Z 2Z3. rima.rozen@mcgill.ca.
authors.forename: Daniel
authors.initials: D
authors.lastname: Leclerc
authors.forename: Nancy
authors.initials: N
authors.lastname: Lévesque
authors.forename: Yuanhang
authors.initials: Y
authors.lastname: Cao
authors.forename: Liyuan
authors.initials: L
authors.lastname: Deng
authors.forename: Qing
authors.initials: Q
authors.lastname: Wu
authors.forename: Jasmine
authors.initials: J
authors.lastname: Powell
authors.forename: Carmen
authors.initials: C
authors.lastname: Sapienza
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D042965:Methylenetetrahydrofolate Reductase (NADPH2)