Genetic variants in the telomere maintenance pathway as predictors of second primary tumors and recurrence of early-stage head and neck cancer.

Abstract

1504 Background: Telomere is critical for chromosome stability. Telomere shortening has been associated with cancer development. In this study, we evaluated genetic variants in the telomere maintenance pathway as predictors for the risk of second primary tumor (SPT) or recurrence in early-stage head and neck squamous cell carcinoma (HNSCC) patients. Methods: We genotyped 427 single nucleotide polymorphisms (SNP) from 41 telomere maintenance pathway genes in a nested 1:2 case-control study of 150 early stage HNSCC patients with SPT/recurrence and 300 patients without. Individual and cumulative effects and interactions of these SNPs on SPT/recurrence were assessed. Results: In the Cox proportional hazards model, patients carrying the variant genotypes of rs9562605, located in the BRCA2 gene, were associated with a 0.5-fold (95% CI 0.4- 0.8) reduced risk of SPT/recurrence, and longer median SPT/recurrence-free survival time (MST) (> 93 months) than those with wild-type genotype (81.6 months) (p = 2.4 × 10-3). A cumulative effect analysis was performed by combining the unfavorable genotypes of the 53 significant SNPs with p < 0.05. A progressively increasing SPT/recurrence risk was observed as the number of unfavorable genotypes increased (p for trend < 0.0001). Specifically, compared to the subjects with fewer than 19 unfavorable genotypes, subjects with more than 30 unfavorable genotypes had 19.7-fold (95% CI 9.6-40.4) increased risk and significantly shorter MST (28.2 months vs. > 93 months, log-rank p = 2.0 × 10-24). From survival tree analysis, rs10849605 was the first split with the smallest p-value (2.5 × 10-3). Node 18 ranked the highest risk group (HR > 3.7, 95% CI 9.6-568.4, MST = 13.4 months) as compared to the reference node, node 1 (MST > 93 months) (log-rank p = 1.1 × 10-23). Conclusions: The study identified several promising SNPs and further demonstrated that the combination of multiple SNPs and their interactions may be useful to predict clinical outcome of early-stage head and neck cancer. No significant financial relationships to disclose.