Single nucleotide polymorphisms of RecQ1, RAD54L, and ATM genes are associated with reduced survival of pancreatic cancer

Abstract

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.

Figure 1

Overall survival curves by genotypes. P values of the log rank test were 0.02 and 0.004 for RecQ1 AC or CC versus AA genotype; 0.16 and 0.002 for RAD54L CT or TT versus CC genotype; 0.04 and 0.001 for XRCC1 CT or TT versus CC genotype; and 0.009 and 0.85 for ATM TC or CC versus TT genotype.

Figure 2

Combined effect of RecQ1 159 AC/CC, RAD54L 157 CT/TT, XRCC1 194CT/TT, and ATM-77 TC on overall survival (upper panel). The number of 0–3 indicates number of adverse genotypes. P(LR) = 0.03, 0.007, and 0.001 for patients carrying 1, 2 or 3 adverse genotypes compared with those having none. Combined effect of RAD54L, XRCC1 and ATM genotypes in patients carrying the RecQ1 159 AA genotype (middle panel) or the RecQ1 AC/CC genotypes (lower panel). Note the strong protective effect of RecQ1 AA genotype on survival. The likelihood ratio P value for the statistical interaction between RecQ1 and the number of other adverse genotypes was 0.0035.