Germline Shelterin Loss of Function Predisposes to Lipoma and Uterine Leiomyoma: Population Evidence Bearing on Shelterin-Associated Sarcoma Risk

Purpose Germline shelterin variants were linked to sarcoma in a case-enriched cohort. Whether shelterin loss of function predisposes to mesenchymal neoplasia in the general population is unknown. Methods We analyzed rare-variant collapsing associations for five shelterin genes across neoplasm phenotypes in UK Biobank exomes, with Genebass as a second pipeline. Prespecified shelterin and centrosome gene sets were tested by permutation-calibrated statistics against a TP53/RB1/NF1 positive control. Carrier risks were compared with telomere-lengthening predictions. Results Lipoma risk was increased in TERF1 (odds ratio [OR], 3.32; P = 8.4 x10⁻⁸), POT1, and TERF2IP carriers, and uterine leiomyoma risk in all four core shelterin genes, most strongly POT1 (OR, 2.23; P = 4.0 x 10⁻⁵); POT1 and TINF2 reproduced in Genebass. TERF1 was also associated with thyroid cancer and monoclonal gammopathy. Neither gene set nor the positive control was associated with self-reported sarcoma. Telomere lengthening accounted for POT1-associated chronic lymphocytic leukemia risk but not myeloma or TINF2-associated thyroid cancer, where observed risk exceeded prediction five- to seven-fold. Conclusion Shelterin loss of function is a population-level risk factor for lipoma and uterine leiomyoma, the benign counterparts of liposarcoma and leiomyosarcoma. TERF1 joins POT1 and TINF2 as long-telomere cancer genes. Sarcoma-specific penetrance remains untested.