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Distinct clinicopathologic and genetic profiles in sporadic gastric cancer with different mutator phenotypes
Author(s) -
Wu MingShiang,
Lee ChungWei,
Shun ChiaTung,
Wang HsiuPo,
Lee WeiJei,
Chang MingChu,
Sheu JinChuan,
Lin JawTown
Publication year - 2000
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/(sici)1098-2264(200004)27:4<403::aid-gcc10>3.0.co;2-1
Subject(s) - microsatellite instability , mlh1 , msh6 , frameshift mutation , biology , dna mismatch repair , msh2 , cancer research , carcinogenesis , epigenetics , methylation , cancer , genetics , phenotype , microsatellite , gene , allele , colorectal cancer
A subset of sporadic gastric cancers (GC) exhibits microsatellite instability (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 10 microsatellite markers. Mutational analyses of TGFβRII , 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 TGFβRII , IGFIIR , BAX , MSH3 , and E2F4 genes but a lower incidence of TP53 mutations. Furthermore, hypermethylation of the 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 an entirely different pathway. Genes Chromosomes Cancer 27:403–411, 2000. © 2000 Wiley‐Liss, Inc.