Single-nucleotide polymorphisms of DNA damage response genes are associated with overall survival in patients with pancreatic cancer. Clin Cancer Res 2008 Apr 01;14(7):2042-8
Date
04/03/2008Pubmed ID
18381943Pubmed Central ID
PMC2423806DOI
10.1158/1078-0432.CCR-07-1520Scopus ID
2-s2.0-42249105871 (requires institutional sign-in at Scopus site) 48 CitationsAbstract
PURPOSE: The goals of this study were to determine if single-nucleotide polymorphisms in DNA damage repair genes and cell cycle regulating genes affect clinical response to combined gemcitabine radiation therapy and the overall survival (OS) of patients with pancreatic cancer.
EXPERIMENTAL DESIGN: We evaluated six single-nucleotide polymorphisms of the ATM, ATM and Rad3-related (ATR), CHEK1, and CHEK2 genes in 119 patients with potentially resectable pancreatic cancer who were enrolled in clinical trials at The University of Texas M. D. Anderson Cancer Center from February 1999 to January 2006, with follow-up until February 2007. Patients received neoadjuvant concurrent gemcitabine and radiation therapy with or without gemcitabine-cisplatin induction therapy. Genotypes were determined and tested for associations with OS by Kaplan-Meier estimation, the log-rank test, and Cox regression analysis. P values of <or=0.05 were considered significant.
RESULTS: The ATM G60A and CHEK1 G35A genotypes were significant (P<0.05), and the ATR C340T genotype borderline significantly (P=0.079) associated with OS. The hazard ratio of CHEK1 35AA was 2.01 (95% confidence interval, 1.20-3.37; P=0.007) compared with CHEK1 35GG/GA with adjustments for race, sex, diabetes status, CA19-9 level, and success of tumor resection. A significant combined genotype effect was observed between ATM 60GA/GG, ATR 340CT/CC, and CHEK1 35AA with median OS times of 31.0, 16.2, and 10.5 months for patients carrying <or=1, 2, and 3 deleterious alleles, respectively (P=0.004).
CONCLUSIONS: These observations suggest that polymorphic variations of DNA damage response genes affect clinical response to gemcitabine radiation therapy and OS of patients with resectable pancreatic cancer.
Author List
Okazaki T, Jiao L, Chang P, Evans DB, Abbruzzese JL, Li DAuthor
Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antineoplastic Combined Chemotherapy ProtocolsBiomarkers, Tumor
Carcinoma, Pancreatic Ductal
Cisplatin
DNA Damage
Deoxycytidine
Genotype
Humans
Kaplan-Meier Estimate
Pancreatic Neoplasms
Polymorphism, Single Nucleotide
Radiotherapy
