Mismatch repair deficiency: a temozolomide resistance factor in medulloblastoma cell lines that is uncommon in primary medulloblastoma tumours.

Published

Journal Article

Tumours are responsive to temozolomide (TMZ) if they are deficient in O(6)-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient.The effect of TMZ on medulloblastoma (MB) cell killing was analysed with clonogenic survival assays. Expression of DNA repair genes and enzymes was investigated using microarrays, western blot, and immunohistochemistry. DNA sequencing and promoter methylation analysis were employed to investigate the cause of loss of the expression of MMR gene MLH1.Temozolomide exhibited potent cytotoxic activity in D425Med (MGMT deficient, MLH1 proficient; IC(50)=1.7 μM), moderate activity against D341Med (MGMT proficient, MLH1 deficient), and DAOY MB cells (MGMT proficient, MLH1 proficient). MGMT inhibitor O(6)-benzylguanine sensitised DAOY, but not D341Med cells to TMZ. Of 12 MB cell lines, D341Med, D283Med, and 1580WÜ cells exhibited MMR deficiency due to MLH1 promoter hypermethylation. DNA sequencing of these cells provided no evidence for somatic genetic alterations in MLH1. Expression analyses of MMR and MGMT in MB revealed that all patient specimens (n=74; expression array, n=61; immunostaining, n=13) are most likely MMR proficient, whereas some tumours had low MGMT expression levels (according to expression array) or were totally MGMT deficient (3 out of 13 according to immunohistochemistry).A subset of MB may respond to TMZ as some patient specimens are MGMT deficient, and tumours appear to be MMR proficient.

Full Text

Duke Authors

Cited Authors

  • von Bueren, AO; Bacolod, MD; Hagel, C; Heinimann, K; Fedier, A; Kordes, U; Pietsch, T; Koster, J; Grotzer, MA; Friedman, HS; Marra, G; Kool, M; Rutkowski, S

Published Date

  • October 2012

Published In

Volume / Issue

  • 107 / 8

Start / End Page

  • 1399 - 1408

PubMed ID

  • 22976800

Pubmed Central ID

  • 22976800

Electronic International Standard Serial Number (EISSN)

  • 1532-1827

International Standard Serial Number (ISSN)

  • 0007-0920

Digital Object Identifier (DOI)

  • 10.1038/bjc.2012.403

Language

  • eng