title: Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations.
abstract: Identification of polymorphisms that influence pemetrexed tolerability could lead to individualised treatment regimens and improve quality of life. Twenty-eight polymorphisms within eleven candidate genes were genotyped using the Illumina Human Exome v1.1 BeadChip and tested for their association with the clinical outcomes of non-small cell lung cancer and mesothelioma patients receiving pemetrexed/platinum doublet chemotherapy (n=136). GGH rs11545078 was associated with a reduced incidence of grade ⩾3 toxicity within the first four cycles of therapy (odds ratio (OR) 0.25, P=0.018), as well as reduced grade ⩾3 haematological toxicity (OR 0.13, P=0.048). DHFR rs1650697 conferred an increased risk of grade ⩾3 toxicity (OR 2.14, P=0.034). Furthermore, FOLR3 rs61734430 was associated with an increased likelihood of disease progression at mid-treatment radiological evaluation (OR 4.05, P=0.023). Polymorphisms within SLC19A1 (rs3788189, rs1051298 and rs914232) were associated with overall survival. This study confirms previous pharmacogenetic associations and identifies novel markers of pemetrexed toxicity.
authors.affiliation: Purine Research Laboratory, GSTS Pathology, Guy's and St Thomas' Hospital NHS Foundation Trust, 4th Floor, North Wing, St Thomas Hospital, Lambeth Palace Road, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Corrigan
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, 8th Floor Tower Wing, Guy's Hospital, London, UK.
authors.forename: J L
authors.initials: JL
authors.lastname: Walker
authors.affiliation: Purine Research Laboratory, GSTS Pathology, Guy's and St Thomas' Hospital NHS Foundation Trust, 4th Floor, North Wing, St Thomas Hospital, Lambeth Palace Road, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Wickramasinghe
authors.affiliation: Purine Research Laboratory, GSTS Pathology, Guy's and St Thomas' Hospital NHS Foundation Trust, 4th Floor, North Wing, St Thomas Hospital, Lambeth Palace Road, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Hernandez
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and (Institute of Psychiatry) King's College London, London, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Newhouse
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and (Institute of Psychiatry) King's College London, London, UK.
authors.forename: A A
authors.initials: AA
authors.lastname: Folarin
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, 8th Floor Tower Wing, Guy's Hospital, London, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Lewis
authors.affiliation: Department of Gastroenterology, Guy's and St Thomas' Hospital NHS Foundation Trust, College House, St Thomas' Hospital, London, UK.
authors.forename: J D
authors.initials: JD
authors.lastname: Sanderson
authors.affiliation: Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Spicer
authors.affiliation: Purine Research Laboratory, GSTS Pathology, Guy's and St Thomas' Hospital NHS Foundation Trust, 4th Floor, North Wing, St Thomas Hospital, Lambeth Palace Road, London, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Marinaki
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D016190:Carboplatin / Q000009:adverse effects / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use; D018450:Disease Progression; D005971:Glutamates / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D006147:Guanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics; D000068437:Pemetrexed; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin; D002945:Cisplatin