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Replication error 陽性消化器癌の分子生物学的検討：山本博幸^1,2,伊東文生¹,日野田裕治¹,Manuel Perucho²,今井浩三¹（¹札幌医大・医・１内,²The Burnham Inst.)

Molecular biological analysis of Replication error-positive gastrointestinal cancer：Hiroyuki YAMAMOTO^1,2, Fumio ITOH¹,Yuji HINODA¹,Manuel PERUCHO²,Kohzoh IMAI¹ (¹First Dept. of Int. Med.,Sapporo Medical Univ., ²The Burnham Inst.)

Replication error phenotype (RER) is the characteristic feature underlying most of hereditary nonpolyposis colorectal cancer and other sporadic cancers. Cancers with RER represent a distinct neoplastic pathway because the target genes mutated in these cancers are generally different from those found in cancers without RER. We have reported that the DNA mismatch repair genes (hMSH3 and hMSH6) and proapoptoic gene Bax are inactivated by frameshift mutations in sporadic RER-positive (RER+) colorectal cancer (Nature '96, Science '97). We have also found these frameshift mutations in HNPCC as well as sporadic gastric cancer with RER (Cancer Res. '97, '98). For the better understanding of molecular characteristics of RER+ gastrointestinal cancer, we analyzed alterations of hMLH1, hMSH2, b2-microglobulin, and p53 genes in 70 RER+ gastrointestinal cancers. The results were contrasted with mutations in hMSH3, hMSH6, and Bax genes. A negative association between Bax and p53 mutations was observed. Relatively frequent somatic mutations of b2-microglobulin were detected. A significant association between genetic and epigenetic alterations of hMLH1 and hMSH2 and frameshift mutations in hMSH3 and/or hMSH6 was observed. These results further support our "the mutator mutates another mutator" model describing the stepwise nature of the unfolding of the RER phenotype (Nature Med. '96). Using single cell clones of colon cancer cell line with Bax frameshift mutations in nude mice model, we also report the positive selection of these mutations in colon carcinogenesis.