Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas.
BACKGROUND
DNA repair genes critically regulate the cellular response to chemotherapy and epigenetic regulation of these genes may be influenced by chemotherapy exposure. Restoration of BRCA1 and BRCA2 mediates resistance to platinum chemotherapy in recurrent BRCA1 and BRCA2 mutated hereditary ovarian carcinomas. We evaluated BRCA1, BRCA2, and MLH1 protein expression in 115 sporadic primary ovarian carcinomas, of which 31 had paired recurrent neoplasms collected after chemotherapy. Additionally, we assessed whether promoter methylation of BRCA1, MLH1 or FANCF influenced response to chemotherapy or explained alterations in protein expression after chemotherapy exposure.


RESULTS
Of 115 primary sporadic ovarian carcinomas, 39 (34%) had low BRCA1 protein and 49 (42%) had low BRCA2 expression. BRCA1 and BRCA2 protein expression were highly concordant (p < 0.0001). MLH1 protein loss occurred in 28/115 (24%) primary neoplasms. BRCA1 protein loss in primary neoplasms was associated with better survival (p = 0.02 Log Rank test) and remained significant after accounting for either stage or age in a multivariate model (p = 0.04, Cox proportional hazards). In paired specimens, BRCA1 protein expression increased in 13/21 (62%) and BRCA2 protein expression increased in 15/21 (71%) of recurrent carcinomas with low or intermediate protein in the paired primary. In contrast MLH1 expression was rarely decreased in recurrent carcinomas (1/33, 3%). Similar frequencies of MLH1, BRCA1, and FANCF promoter methylation occurred in primary carcinomas without previous chemotherapy, after neoadjuvant chemotherapy, or in recurrent neoplasms.


CONCLUSIONS
Low BRCA1 expression in primary sporadic ovarian carcinoma is associated with prolonged survival. Recurrent ovarian carcinomas commonly have increased BRCA1 and/or BRCA2 protein expression post chemotherapy exposure which could mediate resistance to platinum based therapies. However, alterations in expression of these proteins after chemotherapy are not commonly mediated by promoter methylation, and other regulatory mechanisms are likely to contribute to these alterations.
Swisher
Elizabeth M
EM
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA. swishere@u.washington.edu
Gonzalez
Rachel M
RM
Taniguchi
Toshiyasu
T
Garcia
Rochelle L
RL
Walsh
Tom
T
Goff
Barbara A
BA
Welcsh
Piri
P
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics; D024682:BRCA2 Protein / Q000096:biosynthesis* / Q000235:genetics; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics*; D052219:Fanconi Anemia Complementation Group F Protein / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D043823:Taxoids / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D001952:Bridged-Ring Compounds; C499901:FANCF protein, human; D052219:Fanconi Anemia Complementation Group F Protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; C080625:taxane; D000070957:MutL Protein Homolog 1