Telomere length, telomere‐related genes, and breast cancer risk: The breast cancer health disparities study

Abstract

Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere-related genes with cancer. We evaluated associations between telomere-related genes, TL, and breast cancer risk in an admixed population of US non-Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL-related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL-related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (ORadj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER−/PR+) tumors and TERT rs2735940 (ORadj 0.73, 95% CI 0.59, 0.91) with ER−/PR− tumors. These data provide support for an association between TL and TL-related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry.

Genetic variants in the TEP1 gene are associated with prostate cancer risk and recurrence

“…18 These results support the presence of biological interactions between telomere attrition and age on PCa development and recurrence (Figure 3). Accounting for risk factors and TEP1 polymorphisms and prostate cancer C Gu et al their potential interactions with genetic factors could result in improved discrimination in risk stratification.…”

“…Genetic variants of TEP1 have been previously examined in relation to bladder, hepatocellular and breast cancer risk. 18,22,29 This SNP is non-synonymous and causes a substitution of proline to serine (Ser1195Pro), which is likely to affect TEP1 structure and influence telomerase, as well as BLM helicase activity. Telomere shortening can initiate tumor growth and constrain PCa progression.…”

“…35 Four previous studies have examined the association between genetic variants in the TNKS2 genes and cancer risk, and the results have not been entirely consistent. 18,[36][37][38] However, only one study has investigated the effect of TNKS2 polymorphisms on cancer prognosis. In this study, TNKS2 rs2066276 located in the promoter of the TNKS2 gene, in partial linkage disequilibrium with rs1539042 (r 2 = 0.41 and D' = 1), showed a significant correlation with histologic grade of but not susceptibility to breast cancer.…”

Gender and telomere length: Systematic review and meta-analysis

“…However, the picture might be more complex: While short leukocyte telomere length has been associated with cardiovascular risk factors (Benetos et al, 2001; Bekaert et al, 2007; Fitzpatrick et al, 2007; Nordfjall et al, 2008b; Shiels et al, 2011) and cardiovascular disease (Brouilette et al, 2007; Fitzpatrick et al, 2007), it did not predict risk for enhanced cancer incidence in carefully controlled prospective studies (Weischer et al, 2013) and for some cancers including breast cancer, long rather than short telomeres were associated with increased risk (Pellatt et al, 2013). While males die at a higher rate at virtually every age (Austad, 2006), associations of telomere length with mortality have shown contradictory results (Cawthon et al, 2003; Bischoff et al, 2006; Fitzpatrick et al, 2011).…”

Telomere Length in White Blood Cell DNA and Lung Cancer: A Pooled Analysis of Three Prospective Cohorts

“…However, most of these findings were derived from retrospective case-control studies, which may have shown telomere length shortening as a consequence of tumor progression. In contrast, there is growing evidence that longer telomere length is associated with increased risk for cancers (7–13). It has also been suggested that the direction of the association between telomere length and cancer may vary by cancer types (14).…”