不同胃癌突變表現型的基因變化特徵(3/3)
Date Issued
2002
Date
2002
Author(s)
吳明賢
DOI
902314B002146
Abstract
Mutator phenotype judged by microsatellite instability(MSI) and its
associated mutations plays an important role in gastric carcinogenesis. A
subset of sporadic gastric cancers (GC) exhibits MSI. To define the precise
role of MSI in GC, a total of 100 patients with sporadic GC were classified
into three groups, i.e., high-frequency MSI (MSI-H), low-frequency MSI
(MSI-L) and microsatellite stable (MSS) based on ten microsatellite markers.
Mutational analyses of TGFâRII, IGFIIR, BAX, MSH3, MSH6, E2F4, MSH2,
MLH1 and TP53 genes, and methylation and protein expression of MLH1 and
MSH2 were performed and correlated. Twenty-seven percent of GC showed
MSI at least in one locus and could be further graded as MSI-H (14%) and
MSI-L (13%). No clinicopathologic difference was noted between GC with
MSI-L and MSS. Compared with GC with MSI-L or MSS, GC with MSI-H had
a significantly higher frequency of antral location, intestinal subtype, H. pylori
seropositivity, but a lower incidence of lymph node metastasis, and displayed
a higher frequency of frameshift mutations of TGFâRII, IGFIIR, BAX, MSH3,
and E2F4 genes but a lower incidence of TP53 mutations. Furthermore,
hypermethylation of MLH1 promoter was responsible for the loss of protein
function in 13 of 14 MSI-H tumors. It was concluded that a specific phenotype
and a distinct profile of genetic alterations exist in MSI-H GC. We speculate
that epigenetic inactivation of MLH1 by methylation plays a crucial role in
initiating such a pathway of carcinogenesis. In contrast, GCs with MSS and
MSI-L exhibit clinicopathologic features that are distinct from MSI-H tumors
and have a higher frequency of TP53 mutations, suggesting that they may
evolve through entirely different pathway.
DNA copy number abnormalities(CNAs) were assessed in 53 GC using
comparative genomic hybridization (CGH) and correlated with
clinicopathogical characteristics and status of TP53 and microsatellite
instability (MSI). The number of CNAs per tumor was 6.8 (gain 5.3 loss 1.5)
and the number of changes was higher in tumors with advanced stage, Tp53
mutations and without MSI than in those with early stage (7.7 vs. 3.0), no
TP53 mutations (12.4 vs. 4.8) or MSI phenotype (8.2 vs. 2.6). Frequent
abnormalities included gasins on chromosomal arms 8q (43%), 6q (26%), 11q (26%), 13q (24%), 7p (23%), 17q (23%), and 20q (23%) and losees on
chromosomal arms 16q (26%), 19p (23%), 5q (19%), 3p (15%), 4q (15%),
and 1p (15%). Advanced GC demonstrated a higher prevalence of gains of
8q (51% vs. 10%, p< 0.05) and loss of 16q (33% vs. 0%, p<0.05) than early
GC. Gains n 8q (64% vs. 20%, p<0.05), 17q (39% vs. 4%, p<0.05) and
losses oon 3p (25% vs. 4%, p=0.05) and 5q *32% vs. 4%, p<0.05) were
higher in intestinal GC than in diffuse GC. On theother hand, gains on 13q
were more common in the diffuse type (40% vs. 11%, p<0.05). As compared
with noncardia cancer, cardia cancer showed more gains on 7p (58% vs.
12%, p<0.05) and 20q (58% vs. 12%, p<0.05) and more losses on 4q (50%
vs. 5%, p<0.05). The finding of histology-related aberrations and the
combination of CGH and molecular data thus provide aditional evidence
suggesting genetic heterogeneity of GC.
Recently, CpG island methylator phenotype and mutator phenotype in
colorectal cancer have been ascribed to alterations of methyltransferase and
demethylase. We analyzed expression of DNA methyltransferan (DNMT) and
demethylase (MBD) by real-time PCR in tumorous and nontumortumorous
portion of GC. Our results revealed overexpression of DNMT1 and MBD2,
rather than DNMT3A and DNMT3B, was associated with GC.
Subjects
Gastric cancer
mutator phenotype
methylator phenotype
comparative genomic hybridization
SDGs
Publisher
臺北市：國立臺灣大學醫學院內科
Type
report
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