title: Frequent p16 CpG island hypermethylation in primary remnant gastric cancer suggesting an independent carcinogenic pathway.
abstract: Cancer found in the post-operative remnant stomach includes both newly developed cancer after surgery for benign-disease (PRC) and metachronous multiple cancer (MRC). Differences in the carcinogenic pathway between PRC and MRC have been suspected from clinical studies. However, no study has demonstrated the difference in molecular alteration between these diseases. P16 is inactivated predominantly by epigenetic change, rather than genetic alteration. We analyzed the methylation status and protein expression of the p16 gene in cancers of the remnant stomach. Eleven lesions of PRC, 24 lesions of MRC and corresponding non-cancerous tissue, as well as 13 primary gastric cancer (PC) lesions were examined. DNA was extracted by the micro-dissection method from paraffin-embedded surgical specimens. The methylation status of the promoter CpG island of the p16 gene was examined by using a methylation-specific polymerase chain reaction technique. To detect protein expression, immunohistochemical staining was employed. p16 promoter hypermethylation was observed more often in remnant gastric cancer than in PC. A significantly more frequent hypermethylation in the p16 gene was found in PRC (64%) than in MRC (21%) or PC (23%). Moreover, a significant correlation was found between p16 promoter hypermethylation and diminishment of protein expression in cancers of the remnant stomach. Silencing of the p16 gene by methylation of its promoter CpG island was suggested as a unique molecular mechanism in the carcinogenesis of PRC compared with MRC or PC.
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Mino
authors.forename: Naoyoshi
authors.initials: N
authors.lastname: Onoda
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.forename: Makoto
authors.initials: M
authors.lastname: Aya
authors.forename: Ichiro
authors.initials: I
authors.lastname: Fujiwara
authors.forename: Naoshi
authors.initials: N
authors.lastname: Kubo
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Sawada
authors.forename: Masaichi
authors.initials: M
authors.lastname: Ohira
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kato
authors.forename: Kosei
authors.initials: K
authors.lastname: Hirakawa
mesh_terms: D000368:Aged; D018899:CpG Islands / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis* / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018365:Neoplasm, Residual; D016133:Polymerase Chain Reaction / Q000379:methods; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D025803:Tumor Suppressor Protein p14ARF / Q000032:analysis* / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D025803:Tumor Suppressor Protein p14ARF