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 association with 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Johnatty
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beesley
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Law
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Henderson
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Russell
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Hedditch
authors.forename: Catherine
authors.initials: C
authors.lastname: Emmanuel
authors.forename: Sian
authors.initials: S
authors.lastname: Fereday
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Webb
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.forename: Estrid
authors.initials: E
authors.lastname: Hogdall
authors.forename: Susanne K
authors.initials: SK
authors.lastname: Kjaer
authors.forename: Allan
authors.initials: A
authors.lastname: Jensen
authors.forename: Claus
authors.initials: C
authors.lastname: Hogdall
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
authors.forename: Jim
authors.initials: J
authors.lastname: Paul
authors.forename: Sandrina
authors.initials: S
authors.lastname: Lambrechts
authors.forename: Evelyn
authors.initials: E
authors.lastname: Despierre
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
authors.forename: Jenny
authors.initials: J
authors.lastname: Lester
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.forename: Florian
authors.initials: F
authors.lastname: Heitz
authors.forename: Andreas
authors.initials: A
authors.lastname: du Bois
authors.forename: Philipp
authors.initials: P
authors.lastname: Harter
authors.forename: Ira
authors.initials: I
authors.lastname: Schwaab
authors.forename: Yukie
authors.initials: Y
authors.lastname: Bean
authors.forename: Tanja
authors.initials: T
authors.lastname: Pejovic
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.forename: Marc T
authors.initials: MT
authors.lastname: Goodman
authors.forename: Michael E
authors.initials: ME
authors.lastname: Camey
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Thompson
authors.forename: Galina
authors.initials: G
authors.lastname: Lurie
authors.forename: Joellen
authors.initials: J
authors.lastname: Shildkraut
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Terry
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Cramer
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.forename: Anna
authors.initials: A
authors.lastname: deFazio
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D000077216:Carcinoma, Ovarian Epithelial; D018450:Disease Progression; D018572:Disease-Free Survival; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D017239:Paclitaxel / Q000008:administration & dosage; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016190:Carboplatin; D017239:Paclitaxel
keywords: ABCB1; Chemotherapy; Genetics; Outcome; Ovarian cancer; Polymorphisms
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