Telomeres protect chromosomal integrity, and telomere length (TL) is influenced by environmental and genetic factors. While short-telomeres are linked to rare telomeropathies, this study explored the hypothesis that a "long-telomeropathy" is associated with a cancer-predisposing syndrome. Using genomic and health data from 113,861 individuals, a trans-ancestry polygenic risk score for TL (PRS ) was developed. A phenome-wide association study (PheWAS) identified 65 tumor traits linked to elevated PRS . Using this result, a trans-ancestry phenotype risk score for a long-TL (PheRS ) was develop and validated. Rare variant analyses revealed 13 genes associated with PheRS . Individuals who were carriers of these rare variants had a predisposition for long-TL validating original hypothesis. Most of these genes were new to both cancer and telomere biology. In conclusion, this study identified a novel tumor-predisposing syndrome shaped by both common and rare genetic variants, broadening the understanding of telomeropathies to those with a predisposition for long telomeres.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623752PMC
http://dx.doi.org/10.1101/2024.11.26.24318007DOI Listing

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