Tolerance of human MSH2+/- lymphoblastoid cells to the methylating agent temozolomide.
Members of hereditary nonpolyposis colon cancer (HNPCC) families harboring heterozygous germline mutations in the DNA mismatch repair genes hMSH2 or hMLH1 present with tumors generally two to three decades earlier than individuals with nonfamilial sporadic colon cancer. We searched for phenotypic features that might predispose heterozygous cells from HNPCC kindreds to malignant transformation. hMSH2(+/-) lymphoblastoid cell lines were found to be on average about 4-fold more tolerant than wild-type cells to killing by the methylating agent temozolomide, a phenotype that is invariably linked with impairment of the mismatch repair system. This finding was associated with an average 2-fold decrease of the steady-state level of hMSH2 protein in hMSH2(+/-) cell lines. In contrast, hMLH1(+/-) heterozygous cells were indistinguishable from normal controls in these assays. Thus, despite the fact that HNPCC families harboring mutations in hMSH2 or hMLH1 cannot be distinguished clinically, the early stages of the carcinogenic process in hMSH2 and hMLH1 mutation carriers may be different. Should hMSH2(+/-) colonocytes and lymphoblasts harbor a similar phenotype, the increased tolerance of the former to DNA-damaging agents present in the human colon may play a key role in the initiation of the carcinogenic process.
Marra
G
G
Institute of Medical Radiobiology of the University of Zürich, August Forel-Strasse 7, CH-8008 Zürich, Switzerland.
D'Atri
S
S
Corti
C
C
Bonmassar
L
L
Cattaruzza
M S
MS
Schweizer
P
P
Heinimann
K
K
Bartosova
Z
Z
Nyström-Lahti
M
M
Jiricny
J
J
D048868:Adaptor Proteins, Signal Transducing; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D002352:Carrier Proteins; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D004260:DNA Repair; D004268:DNA-Binding Proteins; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000633:toxicity*; D006579:Heterozygote; D006801:Humans; D008214:Lymphocytes; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D000077204:Temozolomide; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D018906:Antineoplastic Agents, Alkylating; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D003606:Dacarbazine; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D000077204:Temozolomide