Corrigan A, Walker J L, Wickramasinghe S, Hernandez M A, Newhouse S J, Folarin A A, Lewis C M, Sanderson J D, Spicer J, Marinaki A M
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.
Department of Medical and Molecular Genetics, King's College London, 8th Floor Tower Wing, Guy's Hospital, London, UK.
Pharmacogenomics J. 2014 Oct;14(5):411-7. doi: 10.1038/tpj.2014.13. Epub 2014 Apr 15.
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.
鉴定影响培美曲塞耐受性的多态性，可能会带来个体化治疗方案并改善生活质量。使用Illumina Human Exome v1.1 BeadChip对11个候选基因中的28个多态性进行基因分型，并测试它们与接受培美曲塞/铂类双联化疗的非小细胞肺癌和间皮瘤患者（n = 136）临床结局的相关性。GGH rs11545078与治疗前四个周期内≥3级毒性的发生率降低相关（比值比（OR）0.25，P = 0.018），以及≥3级血液学毒性降低（OR 0.13，P = 0.048）。DHFR rs1650697使≥3级毒性风险增加（OR 2.14，P = 0.034）。此外，FOLR3 rs61734430与治疗中期影像学评估时疾病进展的可能性增加相关（OR 4.05，P = 0.023）。SLC19A1内的多态性（rs3788189、rs1051298和rs914232）与总生存期相关。本研究证实了先前的药物遗传学关联，并鉴定出培美曲塞毒性的新标志物。
