Comparison of ERCC1/XPF genetic variation, mRNA and protein levels in women with advanced stage ovarian cancer treated with intraperitoneal platinum

Abstract Objective Approximately 20% of patients receiving platinum-based chemotherapy for epithelial ovarian cancer (EOC) are refractory or develop early recurrence. Identifying these patients early could reduce treatment-associated morbidity and allow quicker transfer to more effective therapies....

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Published in:	Gynecologic oncology Vol. 126; no. 3; pp. 448 - 454
Main Authors:	DeLoia, Julie A, Bhagwat, Nikhil R, Darcy, Kathleen M, Strange, Mary, Tian, Chunquio, Nuttall, Kevin, Krivak, Thomas C, Niedernhofer, Laura J
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-09-2012
Subjects:	Adult Aged Antineoplastic Agents - therapeutic use Biomarker Carcinoma, Ovarian Epithelial Chemoresistance Cisplatin - therapeutic use Disease-Free Survival DNA repair DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Endonucleases - genetics Endonucleases - metabolism Female Genotype Hematology, Oncology and Palliative Medicine Humans Kaplan-Meier Estimate Middle Aged Neoplasms, Glandular and Epithelial - drug therapy Neoplasms, Glandular and Epithelial - genetics Neoplasms, Glandular and Epithelial - metabolism Obstetrics and Gynecology Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism Platinum therapy Polymorphism, Single Nucleotide Predictive Value of Tests Prognosis Proportional Hazards Models Retrospective Studies RNA, Messenger - metabolism Single nucleotide polymorphism Statistics, Nonparametric Biomarker Prognosis Single nucleotide polymorphism Platinum therapy DNA repair Chemoresistance
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Summary:	Abstract Objective Approximately 20% of patients receiving platinum-based chemotherapy for epithelial ovarian cancer (EOC) are refractory or develop early recurrence. Identifying these patients early could reduce treatment-associated morbidity and allow quicker transfer to more effective therapies. Much attention has focused on ERCC1 as a potential predictor of response to therapy because of its essential role in the repair of platinum-induced DNA damage. The purpose of this study was to accurately measure protein levels of ERCC1 and its essential binding partner XPF from patients with EOC treated with platinum-based therapy and determine if protein levels correlate with mRNA levels, patient genotypes or clinical outcomes. Methods ERCC1 and XPF mRNA and protein levels were measured in frozen EOC specimens from 41 patients receiving intraperitoneal platinum-based chemotherapy using reverse transcription polymerase chain reaction and western blots. Genotypes of common nucleotide polymorphisms were also analyzed. Patient outcomes included progression free (PFS) and overall survival (OS). Results Expression of ERCC1 and XPF were tightly correlated with one another at both the mRNA and protein level. However, the mRNA and protein levels of ERCC1 were not positively correlated. Likewise, none of the SNPs analyzed correlated with ERCC1 or XPF protein levels. There was an inverse correlation between mRNA levels and patient outcomes. Conclusion Neither genotype nor mRNA levels are predictive of protein expression. Despite this, low ERCC1 mRNA significantly correlated with improved PFS and OS.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0090-8258 1095-6859
DOI:	10.1016/j.ygyno.2012.05.006