Abstract 1571: Telomere maintenance variants and survival after colorectal cancer: Smoking- and sex-specific associations
Authors: Hardikar Sheetal , Yin Hang , Lindstroem Sara , Hsu Li , Anderson Kristin , Banbury Barbara , Berndt Sonja I. , Chan Andrew T. , Giovanucci Edward L. , Harrison Tabitha A. , Joshi Amit D. , Hongmei Nan , Potter John D. , Sakoda Lori C. , Slattery Martha L. , Schoen Robert E. , White Emily , Peters Ulrike , Newcomb Polly A. 
Published: August 2019

Background: Telomeres play an important role in determining colorectal cancer (CRC) prognosis; telomere length varies by smoking status and sex. The association between variation in telomere maintenance genes and survival after CRC remains uncertain; evidence on the interaction between these genes and prognostic factors, such as smoking and sex, is also lacking.

Methods: We selected candidates from a subset of the large genome-wide International Survival Analysis in Colorectal Cancer Consortium (ISACC). Common variants (MAF &gt;5%) in 13 telomere maintenance genes (TERT, TERC, TERF1, TERF2, TINF2, TERF2IP, ACD, POT1, TNKS, TNKS2, TNKS1BP1, TEP1, PINX1) were examined. Cox proportional hazard models adjusted for age, sex, study, and genetic ancestry were used to analyze associations of these variants with overall and CRC-specific survival, with additional stratification analyses by prognostic factors, including smoking status and sex. Likelihood ratio tests evaluated the significance of interaction terms. P-values were adjusted for multiple comparisons by the Bonferroni method within each gene.

Results: Eight SNPs within TERT, TERF1, TNKS, TNKS1BP1, TEP1 and TERF2 were associated with overall and CRC-specific survival at the P-value threshold of 0.05. The association between rs73202875 (TNKS) and CRC-specific survival varied significantly by smoking pack-years (adjusted Pinteraction =0.024, never smokers vs. ≥45 smoking pack-years). Significant interactions by sex were observed such that the minor allele at rs2975843 (TERF1) was associated with poorer overall and CRC-specific survival in women, but not in men (adjusted Pinteraction =0.002 and 0.019, respectively). The minor allele at rs74429678 (POT1) was associated with increased CRC-specific mortality in women but not in men [HR (95% CI) =1.33(1.07-1.65) and 0.75(0.52-0.97), respectively; adjusted Pinteraction =0.002]. A significant interaction was also observed for overall survival between sex and rs75676021 (POT1, adjusted Pinteraction =0.023).

Conclusion: This study showed statistically significant associations between candidate genes in the telomere maintenance pathway with overall and CRC-specific survival. Additionally, we observed a statistically significant interaction for telomere maintenance genes with smoking pack-years (TNKS) and sex (POT1, TERF1), respectively. Validation of these findings in other large studies is warranted; further functional annotation of these SNPs should be conducted.

Citation Format: Sheetal Hardikar, Hang Yin, Sara Lindstroem, Li Hsu, Kristin Anderson, Barbara Banbury, Sonja I. Berndt, Andrew T. Chan, Edward L. Giovanucci, Tabitha A. Harrison, Amit D. Joshi, Nan Hongmei, John D. Potter, Lori C. Sakoda, Martha L. Slattery, Robert E. Schoen, Emily White, Ulrike Peters, Polly A. Newcomb. Telomere maintenance variants and survival after colorectal cancer: Smoking- and sex-specific associations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1571.