GENETIC-EVIDENCE FOR THE MULTICENTRIC ORIGIN OF SYNCHRONOUS MULTIPLE GASTRIC-CARCINOMA

Multiple gastric cancers, which constitute 4% to 10% of all gastric ca ncers, occur in older people and are associated with more extensive in testinal metaplasia. With regard to the genesis of multiple gastric ca ncers, multicentricity (independent origin) rather than multifocality (local or lateral spread of one cancer) has been the favored theory. C onventional morphologic study, however, has not been able to provide c onvincing evidence in support of multicentricity. The purpose of this study was to verify the multicentric origin of multiple gastric cancer s at a genetic level. For this purpose, immunohistochemical and molecu lar techniques were used to define the mutation pattern of APC, MCC an d p53 in multiple lesions of synchronous multiple gastric cancers. The study was based on a total of 30 gastric tumors from 13 patients, inc luding 10 double tumors, 2 triple tumors, and 1 quadruple tumor. Singl e-strand conformation polymorphism and polymerase chain reaction direc t sequencing were carried out for exons 5 to 8 of p53, and loss of het erozygosity was detected on the basis of polymerase chain reaction amp lification of polymorphism in exon 10 of MCC and in exon 11 of APC. Tw elve of 13 cases showed alteration in one or more genetic markers. Of these, three demonstrated a discordant mutation pattern of p53 in indi vidual lesions, and another two revealed allelic loss of MCC in one le sion and p53 mutation in the other. In six other cases, only one lesio n showed alteration of APC, MCC, or p53, and in the remaining case, on e lesion carried p53 and MCC mutations and the other carried MCC loss of heterozygosity only. The results of this study showed discordance o f the mutation pattern of APC, MCC, and p53 in individual lesions of m ultiple gastric cancers, providing genetic evidence for a multicentric origin of synchronous multiple gastric carcinomas. Collectively, thes e findings supported the theory of field cancerization in gastric carc inogenesis.