JOURNAL OF PATHOLOGY, VOL. 178: 475 (1996) LETTER TO THE EDITOR THE SEQUENTIAL ACCUMULATION OF GENETIC ALTERATIONS CHARACTERISTIC OF THE COLORECTAL ADENOMA-CARCINOMA SEQUENCE DOES NOT OCCUR BETWEEN GASTRIC ADENOMA AND ADENOCARCINOMA In a recent issue of the Journal of Pathology (Vol. 176, No. 3, 249-258), Maesawa et al. reported that APC mutations were found in 20 per cent of gastric adenomas and 1.4 per cent of cases of gastric cancer, while the p53 gene was mutated in 35 per cent of cases of gastric carcinoma but not in gastric adenoma. Judging from these observations and loss of heterozygosity (LOH) at the DCC locus, they concluded that the adenomacarcinoma sequence does not exist for gastric carcinogenesis, as indicated by the title of their paper. In contrast to their study, we have recently reported that by using PCR-SSCP and direct sequencing analysis, APC mutations are detected in 25 per cent (2/8) of gastric cancer cell lines, 42 per cent (5/12) of gastric adenomas and 6 per cent (146) of intestinal metaplasia.' Moreover, we found APC mutations in 41 per cent (7/14) of very well differentiated adenocarcinomas by means of RNase protection analyses.2 Interestingly, both MKN-7 and MKN-28 cancer cell lines sharing APC mutations are derived from well differentiated adenocarcinomas of the stomach.' We previously reported that the p53 gene was mutated in 30 per cent (3/10) of gastric adenomas and in 56 per cent (9/16) of primary gastric carcinomas including early gastric cancer.334 Moreover, we sometimes experience the development of adenocarcinoma from the long-term follow-up of adenomatous lesions in daily surgical pathology diagnostic practice. Thus, we believe that at least some cases of gastric cancer can develop through an adenomaxarcinoma sequence. Indeed, a case of tubular adenoma with severe atypia containing p53 mutation and microsatellite instability developed a well differentiated adenocarcinoma from the adenoma 3 years after the initial diagno~is.~ There are two possible explanations for the differences between our results on the incidence of APC and p53 mutations in gastric adenoma and cancer and those of $2 1996 by John Wiley & Sons, Ltd. Maesawa et al., and in particular, their failure to detect mutation of the p53 gene in gastric adenoma and their recognition of only one case of APC mutation in gastric cancer. The first explanation concerns the use of different criteria for the histological diagnosis of gastric adenoma. Figure 1 in their paper, a gastric adenoma with severe dysplasia, would be viewed in our study as a well differentiated adenocarcinoma. Moreover, a gastric adenoma with moderate dysplasia has a possibility of adenocarcinoma. The second explanation may lie in differences in the molecular techniques used for detecting genetic mutations. The use of SSCP analysis alone frequently brings about false-negative results even if in vitro, although this point was addressed in their Discussion. In our opinion , the data on APC and p53 mutation reported by Maesawa et al. are underestimated and their claim in the title of their manuscript is not fully substantiated. EIICHITAHARA AND HIROSHI YOKOZAKI First Department of Pathology Hiroshima University School of Medicine 1-2-3 Kasumi, Minami-ku Hiroshima 734, Japan REFERENCES 1. 2. 3. 4. 5. Nishimura K, Yokozaki H, Haruma K, Kajiyama G, Tahara E. Alterations of the APC gene in carcinoma cell lines and ;Irecancerous lesions of the stomach. Int J Oncol 1995; 7: 587-592. Nakatsuru S, Yanagisawa A, Ichii S, et a/. Somatic mutation of the APC gene in gastric cancer: frequent mutations in very well differentiated adenocarcinoma and signet-ring cell carcinoma. Hum Mol Genet 1992; 1: 559--563. Todo H, Yokozaki H, Haruma K, Kajiyama G, Tahara E. pS3 mutations in gastric adenomas. Virchows Arch B [Cell Pothol] 1993; 63: 191-195. Yokozaki H, Kuniyasu H, Kitadai Y, ef al. p53 point mutations in primary human gastric carcinomas. J Cancer Res CIin Oncol 1992; 119 67-70. Semba S, Yokozaki H, Yasui W, Tahara E. Microsatellite instability in precancerous lesions and adenocarcinoma of the stomach. Cancer Suppl (in press).