1. ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas
- Author
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Marc T. Goodman, Catherine Emmanuel, Michelle J. Henderson, Kathryn L. Terry, Ira Schwaab, Julie M. Cunningham, Murray D. Norris, Anna deFazio, Philipp Harter, Yi Lu, Penelope M. Webb, Robert S. Brown, Allan Jensen, Pamela J. Thompson, Xiaoqing Chen, Sian Fereday, Peter A. Fasching, Yukie Bean, Brooke L. Fridley, Claus Høgdall, Amanda J. Russell, Tanja Pejovic, Matthias W. Beckmann, Douglas A. Levine, Florian Heitz, Stuart MacGregor, Jonathan Beesley, Beth Y. Karlan, Jenny Lester, Estrid Høgdall, Sandrina Lambrechts, Georgia Chenevix-Trench, Andrew Berchuck, Arif B. Ekici, Michael E. Camey, Ellen L. Hedditch, Andreas du Bois, Daniel W. Cramer, James Paul, Robert A. Vierkant, Susanne K. Kjaer, Ellen L. Goode, Bo Gao, Matthew Law, Sharon E. Johnatty, Ignace Vergote, Michelle Haber, Joellen Shildkraut, Galina Lurie, and Evelyn Despierre
- Subjects
Oncology ,endocrine system diseases ,Drug Resistance ,Kaplan-Meier Estimate ,Carcinoma, Ovarian Epithelial ,Bioinformatics ,Carboplatin ,chemistry.chemical_compound ,0302 clinical medicine ,Neoplasms ,Ovarian Epithelial ,Antineoplastic Combined Chemotherapy Protocols ,Obstetrics and Gynaecology ,Genotype ,2.1 Biological and endogenous factors ,Neoplasms, Glandular and Epithelial ,Aetiology ,Cancer ,P-glycoprotein ,Outcome ,Ovarian Neoplasms ,0303 health sciences ,biology ,Glandular and Epithelial ,Obstetrics and Gynecology ,ABCB1 ,Single Nucleotide ,Drug Resistance, Multiple ,female genital diseases and pregnancy complications ,3. Good health ,Subfamily B ,Paclitaxel ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,Multiple ,Australian Ovarian Cancer Study Group ,Member 1 ,medicine.medical_specialty ,ATP Binding Cassette Transporter, Subfamily B ,ATP Binding Cassette Transporter ,Oncology and Carcinogenesis ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Article ,Disease-Free Survival ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,Rare Diseases ,Ovarian cancer ,Internal medicine ,medicine ,Genetics ,Humans ,Chemotherapy ,Oncology & Carcinogenesis ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Polymorphism ,Gene ,Proportional Hazards Models ,030304 developmental biology ,business.industry ,Carcinoma ,Human Genome ,medicine.disease ,chemistry ,Drug Resistance, Neoplasm ,Pharmacogenetics ,biology.protein ,Neoplasm ,business ,Polymorphisms - Abstract
Objective\ud ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC).\ud Methods\ud The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either ‘standard’ first-line paclitaxel–carboplatin chemotherapy (n = 1158) or any first-line chemotherapy regimen (n = 2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients.\ud Result\ud Fine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77–1.01; p = 0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours.\ud Conclusion\ud Our study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.
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- 2013