Person:

Wong, Jason

Telomeres are repetitive non-coding DNA sequences at the ends of chromosomes that provide protection against chromosomal instability. Telomere length and stability are influenced by proteins, including telomerase which is partially encoded by the TERT gene. Genetic variation in the TERT gene is associated with ovarian cancer risk, and predicts survival in lung cancer and glioma. We investigated whether genetic variation in five telomere maintenance genes was associated with survival among 1480 cases of invasive epithelial ovarian cancer in the population-based New England Case-Control Study. Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals. Overall we observed no significant associations between SNPs in telomere maintenance genes and mortality using a significance threshold of p=0.001. However, we observed some suggestive associations in subgroup analyses. Future studies with larger populations may further our understanding of what role telomeres play in ovarian cancer survival.

Background

Telomeres protect chromosomal ends, shorten with cellular division, and signal cellular senescence but unchecked telomere attrition can lead to telomere dysfunction, upregulation of telomerase, and carcinogenesis. Shorter telomeres in peripheral blood leukocytes (PBLs) have been associated with elevated cancer risk. Further, genetic variants in and around the TERT gene have been implicated in carcinogenesis.

Methods

We measured relative telomere length (RTL) in PBLs of 911 cases and 948 controls from the New England Case Control Study, a population-based study of ovarian cancer. In addition, we assessed germline genetic variation in five telomere maintenance genes among 2112 cases and 2456 controls from the New England Case Control Study and the Nurses’ Health Study, a prospective cohort study. Odds ratios and 95% confidence intervals were estimated using logistic regression.

Results

Overall, we observed no differences in telomere length between cases and controls. Compared to women with RTL in the longest tertile, women with RTL in the shortest tertile had no increase in risk (OR=1.01, 95% CI: 0.80, 1.28). However, several SNPs in the TERT gene, including RS2736122, RS4246742, RS4975605, RS10069690, RS2736100, RS2853676, RS7726159, were significantly associated with ovarian cancer risk. We observed a significant gene-level association between TERT and ovarian cancer risk (p=0.00008).

Conclusion

Our observations suggest genetic variation in the TERT gene may influence ovarian cancer risk, but the association between average telomere length in PBLs and ovarian cancer remains unclear.

Impact

The role of telomeres in ovarian carcinogenesis remains unsettled and warrants further investigation.