Genetically Inferred Telomere Length Is Associated With Clonal Copy Number Alterations In Peripheral Leukocytes

Telomeres are DNA-protein structures at the ends of chromosomes essential in maintaining chromosomal stability. Telomeres shorten with each cell division due to incomplete replication of the 39 DNA end resulting in age-related telomere attrition. Very short telomeres induce cellular senescence and/or apoptosis, but cancer cells can bypass this mechanism by upregulating telomerase, TP53 and/or RB. Recent observational studies have identified associations between longer 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 links between telomere length and cancer risk by evaluating relationships between telomere length and (1) the acquisition of somatic copy number alterations (SCNAs), (2) the chromosomal distribution and copy number state of acquired SCNAs, and (3) the cellular fraction of clones carrying SCNAs. Genomic data were derived from 431,507 participants in the UK Biobank with genotyping array data (Affymetrix UK BiLEVE Axiom and Biobank Axiom arrays). Telomere length was genetically inferred using a polygenic risk score based on effect estimates and allelic counts of 20 common variants associated with leukocyte telomere length and subsequently standardized. SCNAs were called using raw genotyping array intensity data to detect allelic imbalances (BAF) and deviations from expected intensity (log R ratio) along with data on haplotype imbalances as implemented in MoChA. In total, 15,236 (3.5%) of individuals had a detectable clonal SCNA on an autosomal chromosome. Overall, longer genetically inferred telomere length was positively associated with the presence of an autosomal SCNA (OR=1.07, 95% CI=1.05-1.09, P=1.10 × 10−15). We noted no differences in estimates among strata of chromosomal event location (e.g., telomeric ends, interstitial or whole chromosome event; P= 0.34), suggesting no preference in the type of event associated with inferred telomere length. Likewise, event copy number status demonstrated similar effect sizes across strata of copy number state (e.g., gain, loss, neutral, and unknown events; P= 0.05). When investigating the relationship between inferred telomere length and proportion of cells affected by mosaic SCNAs, longer genetically inferred telomere length was associated with a higher cellular fraction of clones carrying SCNAs (β=0.004, 95% CI= 0.002-0.007, P= 5.60 × 10−4). Cumulatively, our population-based examination of inferred telomere length and SCNAs suggests inherited components of telomere length do not preferentially impact SCNA event location or copy number status, but rather are associated with cellular replicative potential possibly by promoting clonal expansion of leukocytes harboring SCNAs. Citation Format: Derek W. Brown, Shu-Hong Lin, Stephen J. Chanock, Sharon A. Savage, Mitchell J. Machiela. Genetically inferred telomere length is associated with clonal copy number alterations in peripheral leukocytes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1202.