Genetic variation in telomere maintenance genes and survival after colorectal cancer diagnosis

Abstract

Introduction: Telomeres are the repetitive nucleotide sequences capping the end of chromosomes and are regulated by telomerase. Both telomere length and telomerase initiate carcinogenesis and prognosis in patients diagnosed with cancer, including colorectal cancer (CRC). Genome-wide association studies (GWAS) have identified several loci related to telomere length or telomerase activity, but the association between those single nucleotide polymorphisms (SNPs) and survival after CRC diagnosis remains uncertain. Smoking and sex influence telomere/telomerase, so we also investigate the gene-smoking and gene-sex interaction with CRC survival. Methods: We conducted large gene-wide study with 4896 invasive CRC cases from Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Common variants within 13 genes involved in telomere maintenance (TERT, TERC, TERF1, TERF2, TINF2, TERF2IP, ACD, POT1, TNKS, TNKS2, TNKS1BP1, TEP1 and PINX1) were included. Multivariate Cox proportional hazard models were fit to analyze the association between these variants and overall and CRC-specific survival, with additional stratification analyses according to smoking status, smoking pack-years and sex. Likelihood ratio tests were used to test the significance of interaction terms. P-values were adjusted for multiple comparison by Bonferroni method. Results: Several SNPs within TERT, TERF1, TNKS, TNKS1BP1, TEP1 and TERF2 were associated with overall and/or CRC-specific survival at the p-value threshold of 0.05. After Bonferroni adjustment, the association between rs7200950 (ACD) and CRC-specific survival was significantly modified by categorical smoking pack-years (adjusted P=0.049 for interaction). The minor allele at rs74429678 (POT1) increased CRC-specific mortality in women (HR: 1.33, 95%CI: 1.07-1.65) but not in men (HR: 0.75, 95%CI: 0.52-0.97); the minor allele at rs2975843 (TERF1) increased overall mortality in women (HR: 1.08, 95%CI: 0.99-1.18) but not in men (HR: 0.84, 95%CI: 0.75-0.92). Gene-wide significant interaction was also detected between sex and rs75676021 (POT1, adjusted P=0.023 for interaction). Conclusion: Our study reported the gene-wide statistically significant interaction between genes involved in telomere maintenance and smoking pack-years (ACD) and sex (POT1, TERF1), respectively. Our study also suggested an association between candidate genes and overall/CRC-specific survival. Validation of these findings by other large studies and further functional annotation on those SNPs may be warranted.