Originally published as JCO Early Release 10.1200/JCO.2005.04.4206 on March 6 2006

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Single Nucleotide Polymorphisms of RecQ1, RAD54L, and ATM Genes Are Associated With Reduced Survival of Pancreatic Cancer

Donghui Li, Marsha Frazier, Douglas B. Evans, Kenneth R. Hess, Christopher H. Crane, Li Jiao, James L. Abbruzzese

From the Departments of Gastrointestinal Medical Oncology, Epidemiology, Surgical Oncology, Biostatistics, and Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Donghui Li, PhD, Department of Gastrointestinal Medical Oncology—Unit 426, The University of Texas M.D. Anderson Cancer Center, PO Box 301402, Houston, TX 77230-1402; e-mail: dli{at}mdanderson.org

PURPOSE: Our goal was to determine whether single nucleotide polymorphisms (SNPs) in DNA repair genes influence the clinical outcome of pancreatic cancer.

PATIENTS AND METHODS: We evaluated 13 SNPs of eight DNA damage response and repair genes in 92 patients with potentially resectable pancreatic adenocarcinoma. All patients were treated with neoadjuvant concurrent gemcitabine and radiotherapy with or without a component of induction gemcitabine/cisplatin at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from February 1999 to August 2004 and observed through August 2005. Response to the pretreatment was assessed by evaluating time to tumor progression and overall survival. Kaplan-Meier plot, log-rank test, and Cox regression were used to compare survival of patients according to genotype.

RESULTS: The RecQ1 A159C, RAD54L C157T, XRCC1 R194W, and ATM T77C genotypes had a significant effect on the overall survival with log-rank P values of .001, .004, .001, and .02, respectively. A strong combined effect of the four genotypes was observed. Patients with none of the adverse genotypes had a mean survival time of 62.1 months, and those with one, two, or three or more at-risk alleles had median survival times of 27.5, 14.4, and 9.9 months, respectively (log-rank P < .001). There is a significant interaction between the RecQ1 gene and other genotypes. All four genes except XRCC1 remained as independent predictors of survival in multivariate Cox regression models adjusted for other clinical predictors.

CONCLUSION: These observations support the hypothesis that polymorphic variants of DNA repair genes affect clinical prognosis of patients with pancreatic cancer.

Supported by National Institutes of Health (NIH) RO1 Grant No. CA098380 (D.L.), SPORE P20 Grant No. CA101936 (J.L.A.), NIH Cancer Center Core Grant No. CA16672, and a research grant from the Lockton Research Funds (D.L.).

Presented in part at the 13th SPORE Investigators Workshop, Washington, DC, July 9-12, 2005.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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