ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and the Cancer Genome Atlas

Sharon E. Johnatty, Jonathan Beesley, Bo Gao, Xiaoqing Chen, Yi Lu, Matthew H. Law, Michelle J. Henderson, Amanda J. Russell, Ellen L. Hedditch, Catherine Emmanuel, Sian Fereday, Penelope M. Webb, Ellen L. Goode, Robert A. Vierkant, Brooke L. Fridley, Julie M. Cunningham, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Estrid HogdallSusanne K. Kjaer, Allan Jensen, Claus Hogdall, Robert Brown, Jim Paul, Sandrina Lambrechts, Evelyn Despierre, Ignace Vergote, Jenny Lester, Beth Y. Karlan, Florian Heitz, Andreas Du Bois, Philipp Harter, Ira Schwaab, Yukie Bean, Tanja Pejovic, Douglas A. Levine, Marc T. Goodman, Michael E. Camey, Pamela J. Thompson, Galina Lurie, Joellen Shildkraut, Andrew Berchuck, Kathryn L. Terry, Daniel W. Cramer, Murray D. Norris, Michelle Haber, Stuart MacGregor, Anna DeFazio, Georgia Chenevix-Trench

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38 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8-14
Number of pages7
JournalGynecologic Oncology
Volume131
Issue number1
DOIs
StatePublished - Oct 2013

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Keywords

  • ABCB1
  • Chemotherapy
  • Genetics
  • Outcome
  • Ovarian cancer
  • Polymorphisms

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Oncology

Cite this

Johnatty, S. E., Beesley, J., Gao, B., Chen, X., Lu, Y., Law, M. H., Henderson, M. J., Russell, A. J., Hedditch, E. L., Emmanuel, C., Fereday, S., Webb, P. M., Goode, E. L., Vierkant, R. A., Fridley, B. L., Cunningham, J. M., Fasching, P. A., Beckmann, M. W., Ekici, A. B., ... Chenevix-Trench, G. (2013). ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and the Cancer Genome Atlas. Gynecologic Oncology, 131(1), 8-14. https://doi.org/10.1016/j.ygyno.2013.07.107