Gh. Kang et al., GENETIC-EVIDENCE FOR THE MULTICENTRIC ORIGIN OF SYNCHRONOUS MULTIPLE GASTRIC-CARCINOMA, Laboratory investigation, 76(3), 1997, pp. 407-417
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.