ERCC5 is a novel biomarker of ovarian cancer prognosis.
OBJECTIVE
To identify a biomarker of ovarian cancer response to chemotherapy. PATIENTS AND METHODS Study: participants had epithelial ovarian cancer treated with surgery followed by platinum-based chemotherapy. DNA and RNA were isolated from frozen tumors and normal DNA was isolated from matched peripheral blood. A whole-genome loss of heterozygosity (LOH) analysis was performed using a high-density oligonucleotide array. Candidate genomic areas that predicted enhanced response to chemotherapy were identified with Cox proportional hazards methods. Gene expression analyses were performed through microarray experiments. Candidate genes were tested for independent effects on survival using Cox proportional hazards models, Kaplan-Meier survival curves, and the log-rank test.


RESULTS
Using a whole-genome approach to study the molecular determinants of ovarian cancer response to platinum-based chemotherapy, we identified LOH of a 13q region to predict prolonged progression-free survival (PFS; hazard ratio, 0.23; P = .006). ERCC5 was identified as a candidate gene in this region because of its known function in the nucleotide excision repair pathway, the unique DNA repair pathway that removes platinum-DNA adducts. We found LOH of the ERCC5 gene locus and downregulation of ERCC5 gene expression to predict prolonged PFS. Integration of genomic and gene expression data shows a correlation between 13q LOH and ERCC5 gene downregulation.


CONCLUSIONS
ERCC5 is a novel biomarker of ovarian cancer prognosis and a potential therapeutic target of ovarian cancer response to platinum chemotherapy.
Walsh
Christine S
CS
Department of Obstetrics and Gynecology, Cedars-Sinai Women's Cancer Research Institute, Samuel Oschin Comprehensive Cancer Institute, David Geffen School of Medicine, University of California at Los Angeles, CA 90048, USA. walshc@cshs.org
Ogawa
Seishi
S
Karahashi
Hisae
H
Scoles
Daniel R
DR
Pavelka
James C
JC
Tran
Hang
H
Miller
Carl W
CW
Kawamata
Norihiko
N
Ginther
Charles
C
Dering
Judy
J
Sanada
Masashi
M
Nannya
Yasuhito
Y
Slamon
Dennis J
DJ
Koeffler
H Phillip
HP
Karlan
Beth Y
BY
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D004273:DNA, Neoplasm / Q000032:analysis; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D018572:Disease-Free Survival; D004720:Endonucleases / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D015996:Survival Rate; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D000099250:DNA Excision Repair Protein ERCC-5
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5