title: The ERCC1 N118N polymorphism does not change cellular ERCC1 protein expression or platinum sensitivity.
abstract: Genetic polymorphisms in ERCC1 are thought to contribute to altered sensitivity to platinum-based chemotherapy. Although ERCC1 N118N (500 C>T, rs11615) is the most studied polymorphism, the impact of this polymorphism on platinum-based chemotherapy remains unclear. This is the first study in which the functional impact of ERCC1 N118N on gene expression and platinum sensitivity was explored. The aim of this study is to investigate if the reduced codon usage frequency of AAT, which contains the variant allele of the silent mutation, has functional impact on ERCC1 in a well-controlled biological system. Specifically, the ERCC1 cDNA clone with either the C or T allele was introduced into an ERCC1 deficient cell line, UV20, and assayed for the effect of the two alleles on ERCC1 transcription, translation and platinum sensitivity. Both ERCC1 mRNA and protein expression levels increased upon cisplatin treatment, peaking at 4h post-treatment, however there were no differences between the two alleles (p>0.05). Cells complemented with ERCC1 showed significantly higher survival proportion than the parental cell line following platinum exposure (p<0.0001), although no differences were observed between the cells transfected with the wild type or the polymorphic allele. These data suggest that N118N itself is not related to the phenotypic differences in ERCC1 expression or function, but rather this polymorphism may be linked to other causative variants or haplotypes.
authors.affiliation: Molecular Pharmacology Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.forename: Kelie
authors.initials: K
authors.lastname: Reece
authors.forename: Tristan
authors.initials: T
authors.lastname: Sissung
authors.forename: Eddie
authors.initials: E
authors.lastname: Reed
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Price
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin