@article{1ab98a22775e4534b1d317b3fca34311,
title = "ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and the Cancer Genome Atlas",
abstract = "Objective. 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 associationwith clinical outcome in epithelial ovarian cancer (EOC). Methods. 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. Result. Fine-mapping revealed that rs1128503, rs2032582, and rs1045642were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survivaloroverall survival inanalysis ofdata from14 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. Conclusion. 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.",
keywords = "ABCB1, Chemotherapy, Genetics, Outcome, Ovarian cancer, Polymorphisms",
author = "Johnatty, {Sharon E.} and Jonathan Beesley and Bo Gao and Xiaoqing Chen and Yi Lu and Law, {Matthew H.} and Henderson, {Michelle J.} and Russell, {Amanda J.} and Hedditch, {Ellen L.} and Catherine Emmanuel and Sian Fereday and Webb, {Penelope M.} and Goode, {Ellen L.} and Vierkant, {Robert A.} and Fridley, {Brooke L.} and Cunningham, {Julie M.} and Fasching, {Peter A.} and Beckmann, {Matthias W.} and Ekici, {Arif B.} and Estrid Hogdall and Kjaer, {Susanne K.} and Allan Jensen and Claus Hogdall and Robert Brown and Jim Paul and Sandrina Lambrechts and Evelyn Despierre and Ignace Vergote and Jenny Lester and Karlan, {Beth Y.} and Florian Heitz and {Du Bois}, Andreas and Philipp Harter and Ira Schwaab and Yukie Bean and Tanja Pejovic and Levine, {Douglas A.} and Goodman, {Marc T.} and Camey, {Michael E.} and Thompson, {Pamela J.} and Galina Lurie and Joellen Shildkraut and Andrew Berchuck and Terry, {Kathryn L.} and Cramer, {Daniel W.} and Norris, {Murray D.} and Michelle Haber and Stuart MacGregor and Anna DeFazio and Georgia Chenevix-Trench",
note = "Funding Information: The Mayo Clinic study (MAY) was supported by R01 CA122443, P50 CA136393. Funding Information: SCOTROC biological studies were supported by Cancer Research UK (grant C536/A6689 ). Funding Information: The Danish Malignant Ovarian Tumor Study (MAL) was supported by a Danish Cancer Society research grant ( 94 222 52 ) and by the Mermaid I project Funding Information: The NEC study was supported by grant R01-CA54419 from the US National Institutes of Health and W81XWH-10-0280 from the Department of Defense . Funding Information: Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK ( C1287/A10118 , C1287/A 10710 , C12292/A11174 , C5047/A8384 , C5047/A15007 , C5047/A10692 ), the National Institutes of Health ( CA128978 ) and Post-Cancer GWAS initiative (No. 1 U19 CA 148537 — the GAME-ON initiative), the Department of Defence ( W81XWH-10-1-0341 ), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure , the Breast Cancer Research Foundation , and the Ovarian Cancer Research Fund . Funding Information: The AOCS was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729 , the National Health and Medical Research Council (NHMRC) of Australia ( 400413 , 400281 ), Cancer Council Victoria , Cancer Council Queensland , Cancer Council New South Wales , Cancer Council South Australia , The Cancer Foundation of Western Australia , and Cancer Council Tasmania . G. Chenevix-Trench is a Senior Principal Research fellow of the NHMRC, and this work was supported by NHMRC and Cancer Australia funding. Y. Li is funded by NHMRC grant 496675 , and S. MacGregor is supported by an NHMRC career development award, B Gao was supported by an NHMRC Scholarship and a Cancer Institute NSW Research Scholar Award. Funding Information: The LAX study (Women's Cancer Program) was supported by the American Cancer Society Early Detection Professorship ( 120950-SIOP-06-258-06-COUN ) and Entertainment Industry Foundation . ",
year = "2013",
month = oct,
doi = "10.1016/j.ygyno.2013.07.107",
language = "English (US)",
volume = "131",
pages = "8--14",
journal = "Gynecologic Oncology",
issn = "0090-8258",
publisher = "Academic Press Inc.",
number = "1",
}