TY - JOUR
T1 - Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer
AU - Haugen, Astrid C.
AU - Goel, Ajay
AU - Yamada, Kanae
AU - Marra, Giancarlo
AU - Nguyen, Thuy Phuong
AU - Nagasaka, Takeshi
AU - Kanazawa, Shinsaku
AU - Koike, Junichi
AU - Kikuchi, Yoshinori
AU - Zhong, Xiaoling
AU - Arita, Michitsune
AU - Shibuya, Kazutoshi
AU - Oshimura, Mitsuo
AU - Hemmi, Hiromichi
AU - Boland, C. Richard
AU - Koi, Minoru
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2008/10/15
Y1 - 2008/10/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-08-0002
DO - 10.1158/0008-5472.CAN-08-0002
M3 - Article
C2 - 18922920
AN - SCOPUS:54249144723
VL - 68
SP - 8465
EP - 8472
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 20
ER -