TY - JOUR
T1 - Frequent microsatellite instability in non-Hodgkin lymphomas irresponsive to chemotherapy
AU - Miyashita, Kaname
AU - Fujii, Kei
AU - Yamada, Yu
AU - Hattori, Hiroyoshi
AU - Taguchi, Kenichi
AU - Yamanaka, Takeharu
AU - Yoshida, Mitsuaki A.
AU - Okamura, Jun
AU - Oda, Shinya
AU - Muta, Koichiro
AU - Nawata, Hajime
AU - Takayanagi, Ryoichi
AU - Uike, Naokuni
N1 - Funding Information:
We are most grateful to P. Karran and M. Sekiguchi for their helpful advice. The expert assistance in DNA extraction, DNA sequencing and immunohistochemistry by Y. Ogata, M. Hanaki, S. Kato and Y. Kubota is also gratefully acknowledged. We also thank K. Nishiyama and H. Yamamoto for their histopathological expertise. This study was supported by a Grant-in-aid for Cancer Research from the Ministry of Health, Labour and Welfare and grants from the Ministry of Education, Science, Sports and Culture of Japan. K.M. was supported by a grant from the Foundation for Promotion of Cancer Research (Japan) for the 3rd Term Comprehensive 10-Year-Strategy for Cancer Control.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2008/8
Y1 - 2008/8
N2 - Microsatellite instability (MSI) in haematopoietic malignancies has been controversial. Particularly in non-Hodgkin lymphoma, the data published to date lack unity. Using a unique fluorescent technique, we found MSI in eight (14%) tumours in a panel of 59 carefully selected non-Hodgkin lymphoma patients. Our fluorescent technique also reveals two qualitatively distinct modes of MSI, i.e. Type A and Type B. Based on our previous studies using DNA mismatch repair (MMR) gene-knock out animals, we have concluded that Type A MSI is a direct consequence of defective MMR. MSI observed in non-Hodgkin lymphomas was uniformly Type A, which implies that MMR deficiency occurs in this malignancy. Intriguingly, in non-Hodgkin lymphoma patients treated by CHOP/VEPA-based therapies, response to chemotherapy was significantly worse in those with microsatellite-unstable tumours (p = 0.027). As a consequence, the patient outcomes at 1 year after treatment were significantly less favourable in this population (p = 0.046), although the survival difference was not statistically confirmed in a longer term. These findings suggest that in some non-Hodgkin lymphomas MMR deficiency may lead to drug resistance in tumour cells and, consequently, to poor patient outcomes. In non-Hodgkin lymphoma, MSI may be a potential biomarker that predicts the tumour response against chemotherapy.
AB - Microsatellite instability (MSI) in haematopoietic malignancies has been controversial. Particularly in non-Hodgkin lymphoma, the data published to date lack unity. Using a unique fluorescent technique, we found MSI in eight (14%) tumours in a panel of 59 carefully selected non-Hodgkin lymphoma patients. Our fluorescent technique also reveals two qualitatively distinct modes of MSI, i.e. Type A and Type B. Based on our previous studies using DNA mismatch repair (MMR) gene-knock out animals, we have concluded that Type A MSI is a direct consequence of defective MMR. MSI observed in non-Hodgkin lymphomas was uniformly Type A, which implies that MMR deficiency occurs in this malignancy. Intriguingly, in non-Hodgkin lymphoma patients treated by CHOP/VEPA-based therapies, response to chemotherapy was significantly worse in those with microsatellite-unstable tumours (p = 0.027). As a consequence, the patient outcomes at 1 year after treatment were significantly less favourable in this population (p = 0.046), although the survival difference was not statistically confirmed in a longer term. These findings suggest that in some non-Hodgkin lymphomas MMR deficiency may lead to drug resistance in tumour cells and, consequently, to poor patient outcomes. In non-Hodgkin lymphoma, MSI may be a potential biomarker that predicts the tumour response against chemotherapy.
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U2 - 10.1016/j.leukres.2007.11.024
DO - 10.1016/j.leukres.2007.11.024
M3 - Article
C2 - 18177936
AN - SCOPUS:42749091253
VL - 32
SP - 1183
EP - 1195
JO - Leukemia Research
JF - Leukemia Research
SN - 0145-2126
IS - 8
ER -