Change in Peripheral Blood Leukocyte Telomere Length and Mortality in Breast Cancer Survivors

Telomeres are protective structures that cap the end of eukaryotic chromosomes (1), comprising multiple 5′-TTAGGG-3′ repeats, ending in a single-stranded overhang of the G-rich sequence (2). Telomeres protect chromosome ends from end-to-end fusion, nucleolytic decay, degradation, and atypical recombination (3). Quantitative polymerase chain reaction (Q-PCR) offers a fast, high-throughput, and reproducible way to measure relative leukocyte telomere length (LTL), which correlates well with Southern blot measurements of absolute LTL (4). DNA from peripheral blood leukocytes is amplified for telomeric repeats and a single copy control gene, allowing calculation of the ratio of telomere copy number to single gene copy number (T/S ratio) (5). A lower T/S ratio reflects shorter LTL. Several studies (6–10), but not all (11–13), have reported associations between shorter LTL and increased risk for cancer, including breast cancer, and meta-analyses suggested a 1.4- to threefold increased risk of cancer in those with shortest vs longest telomeres (14,15). However, associations between shorter telomeres in patients with cancers compared with control subjects appear to be weaker in prospective than in retrospective studies (16). Few studies have examined associations between LTL and mortality in breast cancer survivors (17–19), and results have been conflicting. One study found no association between LTL and outcome (19); in another, longer LTL statistically significantly correlated with increased risk of all-cause mortality in a subgroup of patients with HER-2/neu–negative tumors (18). A case–control study reported that patients with node-positive tumors and shorter telomeres had increased survival compared with patients with longer telomeres (17). Finally, a recent population-based prospective study of 47102 individuals found increased hazard ratios (HRs) of early death after a diagnosis of any cancer (HR = 1.42; 95% confidence interval [CI] = 1.13 to 1.80) or breast cancer (HR = 1.20; 95% CI = 0.99 to 1.46) for shortest telomeres compared with longest (20). Longitudinal changes in LTL might be more informative than cross-sectional measurements because they reflect characteristics affecting rate of attrition in specific individuals: shortening of LTL over 2.5 years was related to greater cardiovascular mortality in men followed for 12 years (21). Here, we examined the association between longitudinal change of LTL and breast cancer–specific and all-cause mortality over a median of 11.2 years of follow-up in the Health Eating Activity and Lifestyle (HEAL) study, a cohort of breast cancer survivors diagnosed with stage I to stage IIIa breast cancer (22). We investigated these associations for baseline (mean = 6 months after diagnosis; n = 611), 30 months of follow-up (mean = 30 months after diagnosis; n = 478), and changes in LTL between those time points.