Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer

Makiko Kawaguchi, Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Arisa Kishimi, Seiji Ogawa, Iori Kisu, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki

研究成果: Article査読

25 被引用数 (Scopus)

抄録

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-βRII (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-βRII (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.

本文言語English
ページ(範囲)977-982
ページ数6
ジャーナルInternational journal of oncology
35
5
DOI
出版ステータスPublished - 2009 11 1

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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