A replicated patient-specific component of tumour telomere length across two pan-cancer cohorts

Bulk telomere length measured from tumour sequencing is routinely read as a property of the cancer cells. A tumour specimen is a mixture, however, and the patient who supplies it has a telomere length of their own. Here I re-analyse published pan-cancer telomere estimates and ask how much of a tumour’s telomere length is the patient’s.

A calibration step comes first. Whole-genome and low-pass estimates recover the known cross-sectional attrition of leukocyte telomeres with age (−26.6 bp per year in blood normals), whereas whole-exome estimates do not: adjusted for cancer type, sequencing centre and sex the exome slope is −0.6 bp per year, and in 684 blood-normal aliquots sequenced by both assays the whole-genome estimate declines at −38.9 bp per year while the exome estimate from the same DNA does not decline at all (difference −41.5 bp per year, P = 3 × 10⁻¹⁰). Because exome data are 78.6% of the resource, downstream analyses use only the calibrated libraries.

Within those, tumour telomere length tracks the patient’s matched normal (Spearman ρ = +0.395; 22 of 23 cancer types positive), and this replicates in a second consortium measured with a different estimator (PCAWG ρ = +0.472, 24 of 24 histologies). Entering cancer type, sequencing centre and library type as fixed effects leaves β = 0.385, and the coefficient is unmoved by age, sex, purity, leukocyte fraction, ploidy, coverage and continental ancestry (range 0.406–0.429). Pure normal-cell admixture is rejected as the sole explanation: the mixture model requires β_H = 1 and β_H×p = −1, and both are rejected jointly ( P = 0.001).

Tumour purity, leukocyte fraction and age each explain only ∼1–3% of within-cohort variance, and none alters the cross-cancer ranking. The between-cohort coefficient is not interpretable: it appears to show one-to-one correspondence with tissue-of-origin telomere length, but that value depends on which tissue supplies the reference and on the spread of the predictor, and falls to 0.44 with an organ-matched solid-tissue normal.

Bulk tumour telomere length is therefore a composite phenotype containing a replicated patient-specific component. Telomere biomarker studies should carry matched normal telomere length as a covariate rather than treating tumour telomere length as tumour-intrinsic.