TY - JOUR
T1 - The role of mismatch repair in small-cell lung cancer cells
AU - Hansen, L T
AU - Thykjaer, T
AU - Ørntoft, T F
AU - Rasmussen, L J
AU - Keller, P
AU - Spang-Thomsen, M
AU - Edmonston, T Bocker
AU - Schmutte, C
AU - Fishel, R
AU - Petersen, L Nørgård
N1 - Keywords: Adaptor Proteins, Signal Transducing; Base Pair Mismatch; Blotting, Northern; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Carrier Proteins; DNA Methylation; DNA-Binding Proteins; Humans; Lung Neoplasms; Microsatellite Repeats; MutS Homolog 2 Protein; Neoplasm Proteins; Nuclear Proteins; Proto-Oncogene Proteins; Tumor Cells, Cultured
PY - 2003
Y1 - 2003
N2 - The role of mismatch repair (MMR) in small-cell lung cancer (SCLC) is controversial, as the phenotype of a MMR-deficiency, microsatellite instability (MSI), has been reported to range from 0 to 76%. We studied the MMR pathway in a panel of 21 SCLC cell lines and observed a highly heterogeneous pattern of MMR gene expression. A significant correlation between the mRNA and protein levels was found. We demonstrate that low hMLH1 gene expression was not linked to promoter CpG methylation. One cell line (86MI) was found to be deficient in MMR and exhibited resistance to the alkylating agent MNNG. Surprisingly, MSI was not detected in 86MI and it appears to express all the major MMR components hMSH2, hMSH6, hMLH1, hPMS2, hMSH3, hMLH3, MBD4 (MED1) and hExo1. These data are consistent with at least two possibilities: (1) A missense mutation in one of the MMR genes, which dissociates MSI from drug resistance, or (2) inactivation of a second pathway that leads to MMR-deficiency and MNNG resistance, but induces negligible levels of MSI. We conclude that MMR deficiency is largely not associated with the pathogenesis of SCLC.
AB - The role of mismatch repair (MMR) in small-cell lung cancer (SCLC) is controversial, as the phenotype of a MMR-deficiency, microsatellite instability (MSI), has been reported to range from 0 to 76%. We studied the MMR pathway in a panel of 21 SCLC cell lines and observed a highly heterogeneous pattern of MMR gene expression. A significant correlation between the mRNA and protein levels was found. We demonstrate that low hMLH1 gene expression was not linked to promoter CpG methylation. One cell line (86MI) was found to be deficient in MMR and exhibited resistance to the alkylating agent MNNG. Surprisingly, MSI was not detected in 86MI and it appears to express all the major MMR components hMSH2, hMSH6, hMLH1, hPMS2, hMSH3, hMLH3, MBD4 (MED1) and hExo1. These data are consistent with at least two possibilities: (1) A missense mutation in one of the MMR genes, which dissociates MSI from drug resistance, or (2) inactivation of a second pathway that leads to MMR-deficiency and MNNG resistance, but induces negligible levels of MSI. We conclude that MMR deficiency is largely not associated with the pathogenesis of SCLC.
M3 - Journal article
C2 - 12826050
SN - 0959-8049
VL - 39
SP - 1456
EP - 1467
JO - European Journal of Cancer, Supplement
JF - European Journal of Cancer, Supplement
IS - 10
ER -
