Genetically predicted telomere length is associated with clonal somatic copy number alterations in peripheral leukocytes

Abstract

Telomeres are DNA-protein structures at the ends of chromosomes essential in maintaining chromosomal stability. Observational studies have identified associations between telomeres and elevated cancer risk, including hematologic malignancies; but biologic mechanisms relating telomere length to cancer etiology remain unclear. Our study sought to better understand the relationship between telomere length and cancer risk by evaluating genetically-predicted telomere length (gTL) in relation to the presence of clonal somatic copy number alterations (SCNAs) in peripheral blood leukocytes. Genotyping array data were acquired from 431,507 participants in the UK Biobank and used to detect SCNAs from intensity information and infer telomere length using a polygenic risk score (PRS) of variants previously associated with leukocyte telomere length. In total, 15,236 (3.5%) of individuals had a detectable clonal SCNA on an autosomal chromosome. Overall, higher gTL value was positively associated with the presence of an autosomal SCNA (OR = 1.07, 95% CI = 1.05–1.09, P = 1.61×10−15). There was high consistency in effect estimates across strata of chromosomal event location (e.g., telomeric ends, interstitial or whole chromosome event; Phet = 0.37) and strata of copy number state (e.g., gain, loss, or neutral events; Phet = 0.05). Higher gTL value was associated with a greater cellular fraction of clones carrying autosomal SCNAs (β = 0.004, 95% CI = 0.002–0.007, P = 6.61×10−4). Our population-based examination of gTL and SCNAs suggests inherited components of telomere length do not preferentially impact autosomal SCNA event location or copy number status, but rather likely influence cellular replicative potential. risk; however, exactly how telomere length impacts cancer risk is unknown. We investigated potential associations between telomere length and somatic copy number alterations (SCNAs), as SCNAs are associated with cancer risk and may be responsible for some of the observed association between telomere length and cancer. We analyzed blood-derived DNA from over 430,000 participants in a large UK based study and identified an association between elevated telomere length (as inferred from genetic variants) and increased frequency of SCNAs. We did not find any difference in the relationship between telomere length and SCNAs based on specific regions of chromosomes impacted or whether chromosomes were lost or gained. However, we did note that longer predicted telomere length is associated with higher proportions of cells containing a SCNA. Although further studies are needed, our results provide new evidence indicating SCNAs may be a potential mechanism by which telomere length could impact cancer risk.