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MDM2 Promoter Polymorphism Is Associated With Both an Increased Susceptibility to Gastric Carcinoma and Poor Prognosis

Naoki Ohmiya, Ayumu Taguchi, Nobuyuki Mabuchi, Akihiro Itoh, Yoshiki Hirooka, Yasumasa Niwa, Hidemi Goto

From the Department of Gastroenterology, Nagoya University Graduate School of Medicine; and the Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan

Address reprint requests to Naoki Ohmiya, MD, PhD, Department of Gastroenterology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Japan 466-8550; e-mail: nohmiya{at}med.nagoya-u.ac.jp

PURPOSE: Recently, a single-nucleotide polymorphism in the MDM2 promoter (SNP309) has been found to lower the age of onset of tumors and increase the occurrence of multiple primary tumors in Li-Fraumeni syndrome, and accelerate the development of sporadic adult soft tissue sarcoma. The aim of this study was to determine whether SNP309 is associated with susceptibility to gastric carcinoma and its prognosis.

PATIENTS AND METHODS: In a case-control study including 438 controls and 410 patients with sporadic gastric carcinoma, MDM2 SNP309 was genotyped. Serum pepsinogens (PGs) I and II were measured in 438 control subjects and 253 cases selected from 410 patients. Tumor tissue was immunostained with p53 and examined for mutations in exons 5 to 8 of p53 using polymerase chain reaction–based single strand conformational polymorphism analysis and direct sequencing.

RESULTS: The risk of overall gastric carcinoma for SNP309 (G/G) was significantly increased when compared with T carriers (P = .039), especially carcinomas with extragastric tumors (P = .005), carcinoma with severe atrophic gastritis positive for PG assay (PG I level < 70 ng/mL and PG I/II < 3.0; P = .005), antral carcinoma (P = .020), intestinal-type carcinoma (P = .023), p53-immunopositive carcinoma (P = .007), and carcinoma with p53 mutations (P = .007). No significant difference in age at diagnosis was observed among genotypes. SNP309 (G/G) was an independent marker of poor overall survival in advanced carcinoma (hazard ratio, 3.16; 95% CI, 1.22 to 8.20; P = .018).

CONCLUSION: This study provides evidence supporting the association of SNP309 with gastric carcinogenesis via p53 tumor suppressor pathway, extragastric tumorigenesis, and poor prognosis.

Presented in poster format at the American Gastroenterological Association (DDW 2006), Los Angeles, CA, May 24, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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