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Gene expression comparison of colorectal cancer samples from patients diagnosed at a young and elderly age

ABSTRACT: Colorectal cancer (CRC) incidence increases with age and early onset of the disease is an indication of genetic predisposition, estimated to cause up to 30 % of all CRC cases. To identify genes associated with an increased risk for CRC, genome-wide gene expression levels of CRCs from patients diagnosed at an early age and CRCs from patients diagnosed at higher age were investigated. Patients with known hereditary predisposition syndromes were excluded from the study.

ORGANISM(S): Homo sapiens

PROVIDER: GSE25071 | GEO | 2011/09/07

SECONDARY ACCESSION(S): PRJNA134735

REPOSITORIES: GEO

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Project description:Background an Aim: Epigenetics are thought to play a major role in the carcinogenesis of patients that develop multiple colorectal cancers (CRC) in the non-hereditary setting. Previous studies have suggested concordant DNA hypermethylation between tumor pairs. However, only a few methylation markers have been analyzed. This study was aimed at describing the underlying epigenetic signature that differentiates multiple from solitary colorectal cancer tumors using a genome-scale DNA methylation profiling. Patients and Methods: We used a population-based cohort (EPICOLON II) of 12 patients with synchronous CRC and 29 age- sex- and tumor location-paired solitary CRC patients. DNA methylation profiling was performed using the Illumina Infinium HM27 DNA methylation assay. The most significantly hypermethylated CpG sites results were validated by Methylight. Tumors samples were also analyzed for the CpG Island Methylator Phenotype (CIMP) using the Infinium DNA methylation data; KRAS and BRAF mutations; microsatellite instability; and immunohistochemistry for MLH1/MSH2/MSH6/PMS2. Functional annotation clustering of differentially methylated genes between multiple and solitary CRCs was performed. Results: We identified 102 CpG sites that showed significant DNA hypermethylation in multiple versus solitary tumors (difference in M-NM-2 value >0.1 and p<0.05). Methylight assays validated the array results for 4 selected significantly hypermethylated genes (MAP1B, HTRA1, ALOX15, TIMP3) identified in the profiling (p=0.0002). Based on the Infinium data, 8/12 (66.6%) of multiple tumors were classified as CIMP-high, as compared to 5/29 (17%) solitary tumors (p=0.004). CIMP-high tumors displayed significant hypermethylation in 301 CpG sites (difference in M-NM-2 value >0.1; p value <0.05). Interestingly, 76/102 (74.5%) of the hypermethylated CpG sites found in multiple vs. solitary tumors were also seen to be hypermethylated in CIMP-H tumors. Functional analysis of hypermethylated genes found in multiple vs. solitary tumors showed the presence and enrichment of genes involved in different tumorigenic functions. Conclusions: Multiple colorectal cancers are associated with a distinct methylation phenotype, with a close association between tumor multiplicity and CIMP-high. Our results may be important to unravel the underlying mechanism of tumor multiplicity in the non-hereditary scenario, and provide novel potential biomarkers for identifying high-risk patients and tailoring surveillance strategies. We used a population-based cohort (EPICOLON II) of 12 patients with synchronous CRC and 29 solitary CRC patients. DNA methylation profiling was performed using the Illumina Infinium HM27 DNA methylation assay.

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Gene expression comparison of colorectal cancer samples from patients diagnosed at a young and elderly age

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