title: Genetic variability in drug transport, metabolism or DNA repair affecting toxicity of chemotherapy in ovarian cancer.
abstract: BACKGROUND
  This study aimed to determine whether single nucleotide polymorphisms (SNPs) in genes involved in DNA repair or metabolism of taxanes or platinum could predict toxicity or response to first-line chemotherapy in ovarian cancer.
  
  
  METHODS
  Twenty-six selected SNPs in 18 genes were genotyped in 322 patients treated with first-line paclitaxel-carboplatin or carboplatin mono-therapy. Genotypes were correlated with toxicity events (anemia, neutropenia, thrombocytopenia, febrile neutropenia, neurotoxicity), use of growth factors and survival.
  
  
  RESULTS
  The risk of anemia was increased for variant alleles of rs1128503 (ABCB1, C > T; p = 0.023, OR = 1.71, 95% CI = 1.07-2.71), rs363717 (ABCA1, A > G; p = 0.002, OR = 2.08, 95% CI = 1.32-3.27) and rs11615 (ERCC1, T > C; p = 0.031, OR = 1.61, 95% CI = 1.04-2.50), while it was decreased for variant alleles of rs12762549 (ABCC2, C > G; p = 0.004, OR = 0.51, 95% CI = 0.33-0.81). Likewise, increased risk of thrombocytopenia was associated with rs4986910 (CYP3A4, T > C; p = 0.025, OR = 4.99, 95% CI = 1.22-20.31). No significant correlations were found for neurotoxicity. Variant alleles of rs2073337 (ABCC2, A > G; p = 0.039, OR = 0.60, 95% CI = 0.37-0.98), rs1695 (ABCC1, A > G; p = 0.017, OR = 0.55, 95% CI 0.33-0.90) and rs1799793 (ERCC2, G > A; p = 0.042, OR = 0.63, 95% CI 0.41-0.98) associated with the use of colony stimulating factors (CSF), while rs2074087 (ABCC1, G > C; p = 0.011, OR = 2.09, 95% CI 1.18-3.68) correlated with use of erythropoiesis stimulating agents (ESAs). Homozygous carriers of the rs1799793 (ERCC2, G > A) G-allele had a prolonged platinum-free interval (p = 0.016).
  
  
  CONCLUSIONS
  Our data reveal significant correlations between genetic variants of transport, hepatic metabolism, platinum related detoxification or DNA damage repair and toxicity or outcome in ovarian cancer.
authors.affiliation: Division of Gynaecologic Oncology and Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. sandrina.lambrechts@uzleuven.be.
authors.forename: Sandrina
authors.initials: S
authors.lastname: Lambrechts
authors.affiliation: Vesalius Research Center, VIB, Leuven, Herestraat 49, Box 912, 3000, Leuven, Belgium. diether.lambrechts@vib-kuleuven.be.|Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. diether.lambrechts@vib-kuleuven.be.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Division of Gynaecologic Oncology and Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. evelyn.despierre@gmail.com.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Despierre
authors.affiliation: Division of Gynaecologic Oncology and Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. els.vannieuwenhuysen@uzleuven.be.
authors.forename: Els
authors.initials: E
authors.lastname: Van Nieuwenhuysen
authors.affiliation: Vesalius Research Center, VIB, Leuven, Herestraat 49, Box 912, 3000, Leuven, Belgium. dominiek.smeets@vib-kuleuven.be.|Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. dominiek.smeets@vib-kuleuven.be.
authors.forename: Dominiek
authors.initials: D
authors.lastname: Smeets
authors.affiliation: Oncologisch Centrum, Algemeen Ziekenhuis Groeninge, Loofstraat 43, 8500, Kortrijk, Belgium. philip.debruyne@azgroeninge.be.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Debruyne
authors.affiliation: Dienst Oncologie, Algemeen Ziekenhuis Sint Lucas, Groenebriel 1, 9000, Gent, Belgium. vincent.renard@azstlucas.be.
authors.forename: Vincent
authors.initials: V
authors.lastname: Renard
authors.affiliation: Dienst Medische Oncologie, Onze-Lieve-Vrouwziekenhuis, Moorselbaan 164, 9300, Aalst, Belgium. philippe.vroman@olvz-aalst.be.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vroman
authors.affiliation: Dienst Medische Oncologie, Jessa Ziekenhuis, Stadsomvaart 11, 3500, Hasselt, Belgium. daisy.luyten@jessazh.be.
authors.forename: Daisy
authors.initials: D
authors.lastname: Luyten
authors.affiliation: Division of Gynaecologic Oncology and Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. patrick.neven@uzleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.affiliation: Division of Gynaecologic Oncology and Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. frederic.amant@uzleuven.be.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Amant
authors.affiliation: Division of Gynaecologic Oncology and Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. karin.leunen@uzleuven.be.
authors.forename: Karin
authors.initials: K
authors.lastname: Leunen
authors.affiliation: Division of Gynaecologic Oncology and Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. ignace.vergote@uzleuven.be.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced / Q000235:genetics; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects*; D002352:Carrier Proteins / Q000235:genetics*; D003115:Colony-Stimulating Factors / Q000009:adverse effects; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D005838:Genotype; D006397:Hematinics / Q000009:adverse effects; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D020258:Neurotoxicity Syndromes / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013921:Thrombocytopenia / Q000139:chemically induced / Q000235:genetics; D055815:Young Adult
chemical_list: C000715087:ABCC2 protein, human; D002352:Carrier Proteins; D003115:Colony-Stimulating Factors; D006397:Hematinics; D000089762:Multidrug Resistance-Associated Protein 2; D016190:Carboplatin; D017239:Paclitaxel