Carcinogenesis Advance Access published online on August 8, 2007
Carcinogenesis, doi:10.1093/carcin/bgm175
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Identification and characterization of a novel germline p53 mutation in familial gastric cancer in the Japanese population
1 First Department of Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
2 Department of Materials and Life Science, Shizuoka Institute of Science and Technology, 2200-2 Toyosawa, Fukuroi, Shizuoka 437-8555, Japan
3 Department of Pathology, Yaizu Municipal Hospital, 1000 Dobara, Yaizu 425-8505, Japan
5 To whom requests for reprints should be addressed, at First Department of Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan Phone: 53-435-2220; Fax: 53-435-2225; E-mail: hsugimur{at}hama-med.ac.jp
Germline mutations of the p53 gene are known to cause Li-Fraumeni syndrome, and a germline p53 mutation has recently been reported in a small subset of familial gastric cancer (FGC) in Europe and Korea. Although the incidence of gastric cancer is very high in Japan and familial clustering is not uncommon, there has been little information on the genetic factors of FGC. Therefore, to determine the role of germline p53 mutations in FGC in the Japanese population in this study we used sequencing analysis to examine 80 individuals from 35 Japanese FGC families without germline CDH1 mutations for germline p53 mutations. One missense (c.91G>A: p.Val31Ile) and two intronic germline mutations were found, and transcriptional activity of the Ile31 mutant on p53 responsive genes was examined to determine the functional effect of the novel p.Val31Ile germline mutation. A luciferase reporter assay showed that the transcriptional activity of p21 (CDKN1A) and MDM2 promoters but not of the BAX promoter was significantly lower in the Ile31-type p53 than in the wild-type p53. Next, doxycycline-regulated p53-inducible H1299 cell lines were established by applying a retrovirus-mediated gene transfer system to a p53-null human H1299 cell line. Under similar p53 expression conditions shown by Western blot and immunofluorescence analyses, a cell proliferation assay showed that the Ile31-type p53 had significantly lower cell proliferation suppressing activity than wild-type p53. These results suggest that Ile31-type p53 may be partly involved in FGC because of its low transcriptional activity and low cell proliferation suppressing activity.
Received May 31, 2007; revised July 23, 2007; accepted July 23, 2007.
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