Brief Article
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World J Gastroenterol. Jan 7, 2012; 18(1): 70-78
Published online Jan 7, 2012. doi: 10.3748/wjg.v18.i1.70
Germline promoter hypermethylation of tumor suppressor genes in gastric cancer
Pu-Yuan Wu, Zheng Zhang, Jing-Mei Wang, Wen-Wen Guo, Nong Xiao, Qiong He, Ya-Ping Wang, Yi-Mei Fan
Pu-Yuan Wu, Zheng Zhang, Wen-Wen Guo, Ya-Ping Wang, Yi-Mei Fan, Department of Medical Genetics, Medical School, Nanjing University, Nanjing 210093, Jiangsu Province, China
Pu-Yuan Wu, Zheng Zhang, Wen-Wen Guo, Ya-Ping Wang, Yi-Mei Fan, Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, Jiangsu Province, China
Jing-Mei Wang, Department of Pathology, Drum Tower Hospital Affiliated to Medical School, Nanjing University, Nanjing 210093, Jiangsu Province, China
Nong Xiao, Qiong He, Department of Pathology, Lujiang Hospital, Lujiang, Chaohu 231500, Anhui Province, China
Author contributions: Wu PY and Zhang Z contributed equally to this work; Fan YM conceived and designed the study, and drafted the manuscript; Wu PY, Zhang Z, and Guo WW performed the experiments; Wang JM, Xiao N and He Q contributed to the collection of samples and clinical data; Wang YP reviewed and modified the paper; All of the authors have read and approved the final manuscript.
Supported by The National Natural Science Foundation of China, No. 30972535; the Natural Science Foundation of Jiangsu, China, No. BK2008269; the Fundamental Research Funds for the Central Universities of China, No. 1112021402
Correspondence to: Dr. Yi-Mei Fan, Associate Professor, Department of Medical Genetics, Medical School, Nanjing University, Hankou Road 22, Nanjing 210093, Jiangsu Province, China.
Telephone: +86-25-83593374 Fax: +86-25-83686559
Received: April 15, 2011
Revised: July 11, 2011
Accepted: July 18, 2011
Published online: January 7, 2012

AIM: To explore germline hypermethylation of the tumor suppressor genes MLH1, CDH1 and P16INK4a in suspected cases of hereditary gastric cancer (GC).

METHODS: A group of 140 Chinese GC patients in whom the primary cancer had developed before the age of 60 or who had a familial history of cancer were screened for germline hypermethylation of the MLH1, CDH1 and P16INK4a tumor suppressor genes. Genomic DNA was extracted from peripheral blood leukocytes and modified by sodium bisulfite. The treated DNA was then subjected to bisulfite DNA sequencing for a specific region of the MLH1 promoter. The methylation status of CDH1 or P16INK4a was assayed using methylation-specific PCR. Clonal bisulfite allelic sequencing in positive samples was performed to obtain a comprehensive analysis of the CpG island methylation status of these promoter regions.

RESULTS: Methylation of the MLH1 gene promoter was detected in the peripheral blood DNA of only 1/140 (0.7%) of the GC patient group. However, this methylation pattern was mosaic rather than the allelic pattern which has previously been reported for MLH1 in hereditary non-polyposis colorectal cancer (HNPCC) patients. We found that 10% of the MLH1 alleles in the peripheral blood DNA of this patient were methylated, consistent with 20% of cells having one methylated allele. No germline promoter methylation of the CDH1 or P16INK4a genes was detected.

CONCLUSION: Mosaic germline epimutation of the MLH1 gene is present in suspected hereditary GC patients in China but at a very low level. Germline epimutation of the CDH1 or P16INK4a gene is not a frequent event.

Keywords: Gastric cancer, Germline promoter methylation, MLH1, CDH1, P16INK4a