title: A Xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer.
abstract: The Xeroderma pigmentosum group D (XPD) protein is an essential participant in nucleotide excision repair and basal transcription. There is evidence that three common polymorphisms of the XPD gene (C156A, Asp312Asn, and Lys751Gln) may be associated with differential DNA repair activity. Because increased DNA repair plays an important role in chemoresistance to platinum-based compounds, we assessed the aforementioned polymorphisms in 73 patients with metastatic colorectal cancer and determined their outcome to 5-fluorouracil/oxaliplatin. Among those tested for the Lys751Gln polymorphism, 24% (5 of 21) patients with the Lys/Lys genotype responded, versus 10% (4 of 39) and 10% (1 of 10) of those with the Lys/Gln and Gln/Gln genotypes (P = 0.015). The median survival for those with the Lys/Lys genotype was 17.4 (95% CI 7.9, 26.5) versus 12.8 (95% CI 8.5, 25.9) and 3.3 (95% CI 1.4, 6.5) months for patients with the Lys/Gln and Gln/Gln respectively (P = 0.002). The polymorphisms C156A and Asp312Asn of the XPD gene were not associated with response to 5-fluorouracil/oxaliplatin nor with survival. However, a linkage was observed between the Lys751 allele and the C156 allele (P = 0.028), and between the Lys751Lys genotype and the Asp312Asp genotype (P < 0.001). We conclude that XPD Lys751Gln polymorphism may be an important marker in the prediction of clinical outcome to platinum-based chemotherapy.
authors.affiliation: Los Angeles County/University of Southern California Medical Center, Department of Medicine, Los Angeles, California 90033, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Park
authors.forename: J
authors.initials: J
authors.lastname: Stoehlmacher
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: D D
authors.initials: DD
authors.lastname: Tsao-Wei
authors.forename: S
authors.initials: S
authors.lastname: Groshen
authors.forename: H J
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003062:Codon; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004265:DNA Helicases; D004260:DNA Repair / Q000502:physiology; D004268:DNA-Binding Proteins; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011506:Proteins / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate; D014157:Transcription Factors; D016896:Treatment Outcome; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D011506:Proteins; D014157:Transcription Factors; D000077150:Oxaliplatin; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D005472:Fluorouracil