Distinct High-Profile Methylated Genes in Colorectal Cancer

Abstract

BackgroundMutations and promoters' methylation of a set of candidate cancer genes (CAN genes) are associated with progression of colorectal cancer (CRC). We hypothesized that these genes' promoters are inactivated through epigenetic silencing and may show a different profile in high-risk populations. We investigated the status of CAN gene methylation and CHD5 protein expression in African American CRC tissue microarrays (TMA) using immunohistochemical staining.Methodology/Principal FindingsThe promoter methylation status of the CAN genes was studied by methylation-specific PCR (MSP) in 51 Iranians (a white population) and 51 African Americans (AA). Microsatellite instability (MSI) was analyzed as well. The differential frequency of methylation for each gene was tested by chi-square analysis between the two groups based on matched age and sex. CHD5 protein expression was evaluated in moderate to well differentiated and poorly differentiated carcinomas compared to matched normal tissue using TMA. In addition, the correlation between these epigenetic biomarkers and various clinicopathological factors, including, age, location, and stage of the disease were analyzed.Seventy-seven and 34% of tumors were distal in Iranian and African American patients, respectively. In both populations, the percentage of methylation was >65% for SYNE1, MMP2, APC2, GPNMB, EVL, PTPRD, and STARD8, whereas methylation was <50% for LGR6, RET, CD109, and RNF. The difference in methylation between the two populations was statistically significant for CHD5, ICAM5 and GPNMB. Thirty-one percent AA tumors showed MSI-H, compared to 28% in Iranians.Conclusions/SignificanceA significantly higher methylation rate was found for GPNMB, ICAM5, and CHD5 genes in AA patients compared to Iranians. These genes might play a role in the high incidence and aggressiveness of CRC in the AA population. The hypermethylation of the CAN genes can be considered as a marker of colon carcinogenesis.

MGMT-B Gene Promoter Hypermethylation in Patients with Inflammatory Bowel Disease - A Novel Finding

“…Genomic DNA was extracted from samples, as described previously (Mokarram et al, 2008).We used the standard phenol/chloroform method for DNA extraction from fresh tumor samples (Mokarram, et al, 2008).…”

“…We determined promoter methylation status of MGMT, SFRP2 and APC1A genes by chemical treatment with sodium bisulfite and subsequent MSP, as described (Mokarram, et al, 2008). In brief, this technique uses bisulfate modification to convert unmethylated, but not methylatedcytosine to uracil.…”

“…Several studies have reported age-dependent methylation (Mokarram, et al, 2008), therefore, we divided both IBD and control groups into ≥29 and <29-year old groups. The median age of IBD patients (29years) was chosen for this division.…”

Molecular Biomarkers of Colorectal Cancer: A Review of Published Articles From Iran

“…The basic tests identify five markers (NR-21, BAT-26, BA T -25, NR-27 and NR-24) to devise the simplest diagnostic assay (9). Previous reports have shown significant diversity regarding the most common marker for microsatellite testing; BAT 25, BAT26 and NR21 have been reported in HNPCC and sporadic CRCs (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Table 1 shows the reports from Iran that studied the frequency of MMR genes in both hereditary and sporadic colorectal cancers.…”

Decreased expression of the CHD5 gene and its clinicopathological significance in breast cancer: Correlation with aberrant DNA methylation

“…These changes in DNA methylation are not due to any alteration in the DNA sequence (14). CHD5, as an ATP-dependent chromatin-remodeling enzyme, has been observed to exhibit aberrant methylation of CpG islands in human cancer cell lines and primary tumors, particularly gliomas and colon and breast carcinomas (10,15). The present study focused on DNA methylation analysis of CHD5 protein, in order to elucidate an epigenetic mechanism of aberrant gene silencing.…”