不同胃癌突變表現型的基因變化特徵(1/3)
Date Issued
2000
Date
2000
Author(s)
吳明賢
DOI
892314B002256
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.
Recently, CpG island methylator phenotype with concordant methylation at a
number of loci has been reported in a certain portion of colon cancer. To extend our
study, we will analyzed methylation status at multiple important genes (p16, E-cadherin,
p73, DAPK, GST, MGMT, TIMP-3, THBS1) and compared the global
changes using comparative genomic hybridization among different subtypes to
further characterize genomic alterations in GC with different mutator phenotypes.
Subjects
Gastric cancer
mutator phenotype
methylator phenotype
comparative
genomic hybridization
genomic hybridization
SDGs
Publisher
臺北市：國立臺灣大學醫學院內科
Type
report
File(s)![Thumbnail Image]()
Loading...
Name
892314B002256.pdf
Size
23.73 KB
Format
Adobe PDF
Checksum
(MD5):1273b8bfda48a457a14cd985bcfac8ea