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

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)977-982
Number of pages6
JournalInternational Journal of Oncology
Volume35
Issue number5
DOIs
Publication statusPublished - Nov 1 2009
Externally publishedYes

Fingerprint

Microsatellite Instability
Genetic Association Studies
Endometrial Neoplasms
Mutation
antineoplaston A10
Neoplasm Genes
Genes
Colorectal Neoplasms
DNA Mismatch Repair
Caspases
Exons
Carcinogenesis
DNA

Keywords

  • Endometrial cancer
  • hMSH6
  • Microsatellite instability
  • Mononucleotide repeat
  • Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer. / Kawaguchi, Makiko; Banno, Kouji; Yanokura, Megumi; Kobayashi, Yusuke; Kishimi, Arisa; Ogawa, Seiji; Kisu, Iori; Nomura, Hiroyuki; Hirasawa, Akira; Susumu, Nobuyuki; Aoki, Daisuke.

In: International Journal of Oncology, Vol. 35, No. 5, 01.11.2009, p. 977-982.

Research output: Contribution to journalArticle

Kawaguchi, M, Banno, K, Yanokura, M, Kobayashi, Y, Kishimi, A, Ogawa, S, Kisu, I, Nomura, H, Hirasawa, A, Susumu, N & Aoki, D 2009, 'Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer', International Journal of Oncology, vol. 35, no. 5, pp. 977-982. https://doi.org/10.3892/ijo-00000411
Kawaguchi, Makiko ; Banno, Kouji ; Yanokura, Megumi ; Kobayashi, Yusuke ; Kishimi, Arisa ; Ogawa, Seiji ; Kisu, Iori ; Nomura, Hiroyuki ; Hirasawa, Akira ; Susumu, Nobuyuki ; Aoki, Daisuke. / Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer. In: International Journal of Oncology. 2009 ; Vol. 35, No. 5. pp. 977-982.
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abstract = "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.",
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AU - Kobayashi, Yusuke

AU - Kishimi, Arisa

AU - Ogawa, Seiji

AU - Kisu, Iori

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AU - Susumu, Nobuyuki

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AB - 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.

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