Single-Nucleotide Polymorphisms of DNA Damage Response Genes Are Associated with Overall Survival in Patients with Pancreatic Cancer
Open Access
- 1 April 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 14 (7), 2042-2048
- https://doi.org/10.1158/1078-0432.ccr-07-1520
Abstract
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 ≤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 ≤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.Keywords
This publication has 29 references indexed in Scilit:
- Cancer Statistics, 2007CA: A Cancer Journal for Clinicians, 2007
- Consensus report of the International Society of Gastrointestinal Oncology on therapeutic progress in advanced pancreatic cancerCancer, 2006
- Borderline Resectable Pancreatic Cancer: Definitions, Management, and Role of Preoperative TherapyAnnals of Surgical Oncology, 2006
- Single Nucleotide Polymorphisms of RecQ1, RAD54L, and ATM Genes Are Associated With Reduced Survival of Pancreatic CancerJournal of Clinical Oncology, 2006
- Polymorphisms of DNA repair genes and risk of non-small cell lung cancerCarcinogenesis: Integrative Cancer Research, 2005
- Gemcitabine-Induced Activation of Checkpoint Signaling Pathways That Affect Tumor Cell SurvivalPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2005
- Role of Checkpoint Kinase 1 in Preventing Premature Mitosis in Response to GemcitabineCancer Research, 2005
- Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage CheckpointsAnnual Review of Biochemistry, 2004
- ATM and related protein kinases: safeguarding genome integrityNature Reviews Cancer, 2003
- Activation of mammalian Chk1 during DNA replication arrestThe Journal of cell biology, 2001