Yj. Chung et al., Relationship between intratumor histological heterogeneity and genetic abnormalities in gastric carcinoma with microsatellite instability, INT J CANC, 82(6), 1999, pp. 782-788
Microsatellite instability (MSI)-mutator phenotype variably targets microsa
tellite-like sequences in coding regions of cancer-related genes. Intratumo
r histological heterogeneity of gastric carcinoma with MSI was evaluated an
d found to be linked with the topographical distribution of MSI-associated
mutations. One hundred fifty tumor sites derived from 51 gastric cancer pat
ients were microdissected with respect to histological and topographical cl
onality. We found 11 gastric carcinomas with a high frequency of MSI, which
were characterized by marked intratumor genetic heterogeneity arising from
the progressive MSI-phenotype that was associated with frameshift mutation
s on multiple cancer-related genes. The II MSI-tumor cases manifested the M
SI-phenotype in 34 of 36 tumor sites tested, but not in the remaining 2 sit
es. Most (88.2%, 30 of 34) MSI-positive sites and most (96.2%, 25 of 26) tu
mor sites harboring the frameshift mutations in transforming growth factor-
beta receptor type II gene exhibited intestinal-type histology, whereas the
2 MSI-negative sites were found to be of diffuse-type histology without ac
companying frameshift mutations. In 2 of 5 cases harboring E2F-4 frameshift
mutations, glandular structures of intestinal-type tumor were likely to be
variably differentiated in relation to the extent of the mutation, i.e., t
he number of mutated alleles and the size of deleted or inserted base pairs
. Overall, the intratumor histological heterogeneity of gastric carcinoma w
ith MSI was associated with the progressive frameshift mutations in transfo
rming growth factor-beta receptor type II and E2F-4 genes. (C) 1999 Wiley-L
iss, Inc.