Abstract 1633: A phenotype risk score to define patients with a 'long-telomeropathy' and at risk for a novel cancer-like syndrome
Authors: hebbring scott , Alaire Patrick 
Published: March 2024

Introduction: In human populations, telomere length (TL) displays a large inter-individual variability. At the population level, the most predictive variable for TL is age. Rare loss-of-function mutations in telomere maintenance genes are known to cause telomeropathies, a group of deadly diseases triggered by critically short telomeres. Over the last few decades, GWASs have uncovered many common variants associated with TL. More recently, a small number of PheWASs have suggested short-TL is associated with risk for a wide spectrum of phenotypes whereas long-TL is primarily associated with increased risk for several different neoplasms. We hypothesized that genetic variation contributing to long-TL may cause a unique and heritable telomeropathy, distinguishable from classical telomeropathies, that we refer to as a long-telomeropathy resulting in a cancer-like syndrome. To test this hypothesis, we studied telomere genetics in two large independent cohorts linking genomics with electronic health records data.

Methods: Discovery cohort consisted of approximately 70,398 individuals from the All of Us (AoU) Research Program. Marshfield Clinic’s PMRP Biobank of 19,443 individuals served as a replication set. Previously published GWAS results (161 common variant) were utilized to produce a weighted polygenic risk score for TL (TL-PRS). A PheWAS of TL-PRS in AoU identified 19 significant phenotypes that passed a Bonferroni-adjusted p-value threshold (P&lt;2.71E-5). Notably, risk for all 19 phenotypes were associated with long-TL and were categorized as neoplasm or neoplasm-like phenotypes. PheWAS results were used to generate a phenotype risk score for long-telomeropathy (longTL-PheRS), and this model was replicated in PMRP.

Results: The validated longTL-PheRS was used to screen rare variants that may contribute to increased risk for a telomere dependent cancer-like syndrome. When focusing on 293 telomere related genes in AoU, SKAT identified ATM (P=8.8E-7) and DCLRE1B (P&lt;1E-10) as statistically significant risk genes. Whereas ATM has been previously implicated in multiple cancer types, DCLRE1B has not. SKAT results were influenced largely by a single missense variant in each gene [P=2.43E-15 (ATM, p.Leu2307Phe) and =1.78E-12 (DCLRE1B, p.Asn510Tyr)]. Neither variant was previously reported as pathogenic.

Conclusion: Many decades of research in telomere biology has demonstrated the health consequences associated with telomere shortening. This study builds on a growing body of evidence that long telomeres also have significant negative health implications. Individuals who have a genetic predisposition to long telomeres influenced by both common and rare variants may be at risk for a spectrum of tumors. These findings may lead to new diagnostic or preventative measures for individuals at risk for a long-telomeropathy and a cancer-like syndrome.

Citation Format: scott hebbring, Patrick Alaire. A phenotype risk score to define patients with a 'long-telomeropathy' and at risk for a novel cancer-like syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1633.