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Aurora-A and p16 Polymorphisms Contribute to an Earlier Age at Diagnosis of Pancreatic Cancer in Caucasians

Authors' Affiliations: Departments of ¹ Epidemiology, ² Gastrointestinal Medical Oncology, ³ Molecular Pathology, ⁴ Cancer Genetics, and ⁵ Surgical Oncology, M. D. Anderson Cancer Center, and ⁶ Program in Human and Molecular Genetics, Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas

Requests for reprints: Marsha L. Frazier, Department of Epidemiology, Unit 1365, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Boulevard, Houston, TX 77030. Phone: 713-792-3393; Fax: 713-563-0999; E-mail: mlfrazier{at}mail.mdanderson.org.

Purpose: Aurora-A and p16 play a major role in cell cycle checkpoint regulation. Both of them are important in the maintenance of centrosome duplication. Therefore, we hypothesized that polymorphisms in the two genes may interact or work together to influence the finely tuned mechanisms of cell cycle regulation that these proteins regulate. The purpose of this study was to investigate the association of the Aurora-A (T91A), and p16 (C540G and C580T) polymorphisms with age at diagnosis of pancreatic cancer.

Experimental Design: We genotyped 148 Caucasian patients with a diagnosis of pancreatic cancer for the Aurora-A and p16 polymorphisms using pyrosequencing. We tested the association between age at diagnosis and the Aurora-A and p16 genotypes by comparing Kaplan-Meier curves, evaluating the homogeneity of the curves using the log-rank test. We used Cox proportional hazard regression analysis to estimate the association between time to diagnosis and genotype, adjusting for gender.

Results: Patients with the Aurora-A polymorphic genotypes had a median age at diagnosis with pancreatic cancer that was 2.8 years earlier than those with the wild-type genotype [log-rank, P = 0.015; hazard ratio (HR), 1.55; 95% confidence intervals (95% CI), 1.09-2.20]. There was no significant association between the p16 genotypes and age at diagnosis. However, the Aurora-A and p16 C580T polymorphisms combined had a synergistic effect on age-associated risk for early diagnosis of pancreatic cancer. Compared with patients with wild-type genotypes for both genes, the median age at diagnosis for patients with one or two polymorphic alleles for both genes was 12.6 years earlier (log-rank, P = 0.0002; HR, 3.88; 95% CI, 1.94-7.76). No significant associations between the polymorphisms and the cancer metastatic status or survival after diagnosis were found.

Conclusions: Our findings suggest that the Aurora-A polymorphism contributes to a significantly earlier age at diagnosis of pancreatic cancer, and that Aurora-A and p16 C580T polymorphisms synergistically contribute to an earlier age at diagnosis of pancreatic cancer.

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