Demethylation of the MCJ gene in stage III/IV epithelial ovarian cancer and response to chemotherapy.
OBJECTIVE
Methylation of a CpG island within the Methylation controlled DNAJ (MCJ) gene results in loss of expression in normal and neoplastic cells. Normal ovarian surface epithelial cells are methylated at the MCJ CpG island and do not express the MCJ gene. Furthermore, re-expression of the MCJ gene, in ovarian cancer cell lines, has been correlated with increased sensitivity to several important chemotherapeutic drugs. The objective of this study was to determine the extent of MCJ promoter methylation in epithelial ovarian cancer patients and address the possible role of MCJ methylation levels in response to chemotherapy in ovarian cancer patients.


METHODS
The methylation status of 35 CpG sites within the MCJ CpG island was determined by sequencing of sodium bisulfite modified tumor DNA in 41 patients with stage III/IV epithelial ovarian tumors. Levels of methylation of the MCJ CpG island were then compared with response to therapy and overall survival in the patients.


RESULTS
The analysis identified frequent loss of MCJ methylation in ovarian tumors, with only a subset retaining high methylation levels. While 93% (38/41) of tumors examined showed some level of MCJ methylation, only 17% (7/41) retained very high levels (>90% methylation). The presence of such high levels of CpG island methylation correlated significantly with poor response of patients' tumors to therapy (P = 0.027) and poor overall survival (P = 0.023, hazard ratio = 2.9).


CONCLUSIONS
These results suggest that MCJ methylation may be useful as a marker of response to chemotherapy in ovarian cancer and are consistent with previous in vitro data linking loss of MCJ expression with drug resistance.
Strathdee
Gordon
G
Centre for Oncology and Applied Pharmacology, Cancer Research UK Beatson Laboratories, Glasgow University, Glasgow G61 1BD, UK. g.strathdee@beatson.gla.ac.uk
Vass
J Keith
JK
Oien
Karin A
KA
Siddiqui
Nadeem
N
Curto-Garcia
Jorge
J
Brown
Robert
R
D001483:Base Sequence; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D015996:Survival Rate
D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins