Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer.
Microsatellite instability (MSI) is an indicator of DNA instability and is caused by abnormalities in DNA mismatch repair (MMR) genes such as hMLH1, hMSH2 and hMSH6. MSI occurs frequently in endometrial cancer (in approximately 30% of cases), and accumulation of gene mutations due to MSI may therefore have a major role in the mechanism of malignant transformation. However, a responsible target gene has not been identified in endometrial cancer. In this study, we analyzed mutations in 11 cancer-related genes with mononucleotide repeats susceptible to MSI in a coding region [hMSH3 (A8), hMSH6 (C8), TGF-beta RII (A10), MBD4 (A10), BAX (G8), PTEN (A6 in exon 7), HDAC2 (A9), EPHB2 (A9), Caspase-5 (A10), TCF-4 (A9) and Axin2 (G7)] in 22 patients with MSI-H sporadic endometrial cancer. Mutations in hMSH6 (C8) and TGF-beta RII (A10) were found most frequently, at rates of 36.3% (8/22) each. Mutations of BAX (G8) and TCF-4 (A9), which are common in MSI-positive colorectal cancer, occurred at rates of 22.7 and 0%, respectively, which suggests that the MSI target gene may differ between endometrial and colorectal cancers. Mutations in hMSH6 (C8) were correlated with reduced protein expression (p=0.042) and patients with these mutations had significantly more mutations in mononucleotide repeats in other cancer-related genes compared to patients without hMSH6 (C8) mutations (p=0.042). This suggests the possibility of a novel cascade in carcinogenesis of endometrial cancer in which MSI mutates hMSH6 (C8), increases gene instability, and leads to accumulation of mutations in other cancer-related genes. To our knowledge, this is the first report to show that hMSH6 (C8) has an important role as an MSI target gene in sporadic endometrial cancer.
Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Makiko
M
Kawaguchi
Kouji
K
Banno
Megumi
M
Yanokura
Yusuke
Y
Kobayashi
Arisa
A
Kishimi
Seiji
S
Ogawa
Iori
I
Kisu
Hiroyuki
H
Nomura
Akira
A
Hirasawa
Nobuyuki
N
Susumu
Daisuke
D
Aoki
D001483:Base Sequence; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein