Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer

Astrid C. Haugen, Ajay Goel, Kanae Yamada, Giancarlo Marra, Thuy Phuong Nguyen, Takeshi Nagasaka, Shinsaku Kanazawa, Junichi Koike, Yoshinori Kikuchi, Xiaoling Zhong, Michitsune Arita, Kazutoshi Shibuya, Mitsuo Oshimura, Hiromichi Hemmi, C. Richard Boland, Minoru Koi

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101 Citations (Scopus)

Abstract

Microsatellite instability (MSI) is a hallmark of mismatch repair (MMR) deficiency. High levels of MSI at mononucleotide and dinucleotide repeats in colorectal cancer (CRC) are attributed to inactivation of the MMR genes, hMLH1 and hMSH2. CRC with low levels of MSI (MSI-L) exists; however, its molecular basis is unclear. There is another type of MSI - elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) - where loci containing [AAAG]n or [ATAG]n repeats are unstable. EMAST is frequent in non-CRCs; however, the incidence of EMAST and its cause in CRC is not known. Here, we report that MutS homologue 3 (MSH3) knockdown or MSH3-deficient cells exhibit the EMAST phenotype and low levels of mutations at dinucleotide repeats. About 60% of 117 sporadic CRC cases exhibit EMAST. All of the cases defined as MSI-H (16 cases) exhibited high levels of EMAST. Among 101 non-MSI-H cases, all 19 cases of MSI-L and 35 of 82 cases of MSS exhibited EMAST. Although non-MSI-H CRC tissues contained MSH3-negative tumor cells ranging from 2% to 50% of the total tumor cell population, the tissues exhibiting EMAST contained more MSH3-negative cells (average, 31.5%) than did the tissues not exhibiting EMAST (8.4%). Taken together, our results support the concept that MSH3 deficiency causes EMAST or EMAST with low levels of MSI at loci with dinucleotide repeats in CRC.

Original languageEnglish
Pages (from-to)8465-8472
Number of pages8
JournalCancer Research
Volume68
Issue number20
DOIs
Publication statusPublished - Oct 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Haugen, A. C., Goel, A., Yamada, K., Marra, G., Nguyen, T. P., Nagasaka, T., Kanazawa, S., Koike, J., Kikuchi, Y., Zhong, X., Arita, M., Shibuya, K., Oshimura, M., Hemmi, H., Boland, C. R., & Koi, M. (2008). Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer. Cancer Research, 68(20), 8465-8472. https://doi.org/10.1158/0008-5472.CAN-08-0002