Distinct High-Profile Methylated Genes in Colorectal Cancer |
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| Authors: | Pooneh Mokarram Krishan Kumar Hassan Brim Fakhraddin Naghibalhossaini Mehdi Saberi-firoozi Mehdi Nouraie Robert Green Ed Lee Duane T Smoot Hassan Ashktorab |
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| Institution: | 1. Department of Internal Medicine and Gastroenterology Research Center, Shiraz, Iran University of Medical Sciences, Tehran, Iran.; 2. Department of Medicine and Cancer Center, Howard University, College of Medicine, Washington, D. C., United States of America.; 3. Department of Pathology, Howard University, College of Medicine, Washington, D. C., United States of America.;Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Germany |
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| 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. |
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