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

  • B. D. Lin
  • K. H.-L. Chan
  • Z. Zhang
  • L. Zhi
  • A. Y. Leow
  • J. C. Chi
  • M. Y. Zhou
  • N. Bui
  • K. Ganjoo
  • M. Pan1
  1. 1Stanford University School of Medicine
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Abstract

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-), 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-); 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.

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Cite

BibTeXRIS
BibTeX
@misc{lin2026germline,
  title = {{Germline Shelterin Loss of Function Predisposes to Lipoma and Uterine Leiomyoma: Population Evidence Bearing on Shelterin-Associated Sarcoma Risk}},
  author = {B. D. Lin and K. H.-L. Chan and Z. Zhang and L. Zhi and A. Y. Leow and J. C. Chi and M. Y. Zhou and N. Bui and K. Ganjoo and M. Pan},
  howpublished = {medRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.03.26367209},
  url = {https://www.medrxiv.org/content/10.64898/2026.11.03.26367209v1},
  note = {CC BY-NC},
}
RIS
TY  - UNPB
TI  - Germline Shelterin Loss of Function Predisposes to Lipoma and Uterine Leiomyoma: Population Evidence Bearing on Shelterin-Associated Sarcoma Risk
AU  - B. D. Lin
AU  - K. H.-L. Chan
AU  - Z. Zhang
AU  - L. Zhi
AU  - A. Y. Leow
AU  - J. C. Chi
AU  - M. Y. Zhou
AU  - N. Bui
AU  - K. Ganjoo
AU  - M. Pan
PY  - 2026
DA  - 2026/11/03
PB  - medRxiv
DO  - 10.64898/2026.11.03.26367209
UR  - https://www.medrxiv.org/content/10.64898/2026.11.03.26367209v1
AB  - 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-), 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-); 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.
ER  -