<i>SMARCAL1</i> is a new osteosarcoma predisposition gene
Osteosarcoma, the most common childhood bone tumor, can occur in rare cancer predisposition syndromes; however, most cases are sporadic with no known predisposing factors. We investigated the frequency of SMARCAL1 putative pathogenic variants in our large ongoing study of 2,119 osteosarcoma cases, their relation to patient characteristics, and the population prevalence. Our analysis uncovered a higher frequency of SMARCAL1 pathogenic variants across three osteosarcoma case sets (1.8%, n = 2,119) than in 2,625 comparably sequenced cancer-free controls (0.3%; P < .001). Cases with SMARCAL1 pathogenic variants had significantly improved overall survival compared to cases without these variants (hazard ratio 0.36, 95% CI 0.14-0.96, P = .034). In the UK Biobank (469,557 exomes), there was a 33-fold increased risk of osteosarcoma in individuals with SMARCAL1 pathogenic variants. These results identify SMARCAL1 as a new osteosarcoma predisposition gene and thus warrant follow-up to identify the mechanisms by which SMARCAL1 contributes to the etiology of osteosarcoma.
Authors
- Ana Patiño‐García (ORCID: https://orcid.org/0000-0002-4066-8203)
- Lindsay McOmber Morton (ORCID: https://orcid.org/0000-0001-9767-2310)
- Jay S. Wunder (ORCID: https://orcid.org/0000-0002-5978-9400)
- Sharon A. Savage (ORCID: https://orcid.org/0000-0001-6006-0740)
- Michael E. Scheurer (ORCID: https://orcid.org/0000-0002-8379-6088)
- Maryam Rafati (ORCID: https://orcid.org/0000-0001-7118-3412)
- Katia Scotlandi (ORCID: https://orcid.org/0000-0001-6114-9499)
- W Ryan Diver
- Donald A. Barkauskas (ORCID: https://orcid.org/0000-0002-2339-719X)
- Massimo Serra (ORCID: https://orcid.org/0000-0003-0742-1177)
- Yadav Sapkota (ORCID: https://orcid.org/0000-0001-5943-9454)
- Maria Monica Gramatges (ORCID: https://orcid.org/0000-0002-0947-104X)
- Logan G. Spector (ORCID: https://orcid.org/0000-0003-2516-0222)
- Katherine A. Janeway (ORCID: https://orcid.org/0000-0001-6000-3594)
- Bin Zhu
- Michael Dean (ORCID: https://orcid.org/0000-0003-2234-0631)
- Douglas R. Stewart (ORCID: https://orcid.org/0000-0001-8193-1488)
- Gregory T. Armstrong (ORCID: https://orcid.org/0000-0001-8722-4207)
- Philip J. Lupo (ORCID: https://orcid.org/0000-0003-0978-5863)
- Belynda D. Hicks (ORCID: https://orcid.org/0000-0001-8014-4888)
- Mandy L. Ballinger (ORCID: https://orcid.org/0000-0002-9706-0514)
- Lillian M. Guenther (ORCID: https://orcid.org/0000-0002-5906-7504)
- Douglas S. Hawkins (ORCID: https://orcid.org/0000-0003-3602-1375)
- Laura E. Egolf (ORCID: https://orcid.org/0000-0002-7103-4801)
- Claudia Maria Hattinger (ORCID: https://orcid.org/0000-0002-9316-5095)
- Aurélie Vogt (ORCID: https://orcid.org/0000-0003-1257-3095)
- Jia Liu (ORCID: https://orcid.org/0000-0001-9474-4139)
- Kevin Wang (ORCID: https://orcid.org/0000-0002-9343-6473)
- Jung Kim (ORCID: https://orcid.org/0000-0001-6274-2841)
- David M. Thomas (ORCID: https://orcid.org/0000-0002-9845-5892)
- D. Matthew Gianferante (ORCID: https://orcid.org/0000-0003-4126-2093)
- Wen‐Yi Huang (ORCID: https://orcid.org/0000-0002-4440-3368)
- Meredith Yeager (ORCID: https://orcid.org/0000-0003-3871-2225)
- Nathan Anderson
- Adriana Lori
- Stephen J. Chanock
- Irene L. Andrulis
- Maria Teresa Landi (ORCID: https://orcid.org/0000-0003-4507-329X)
Institutions
- University of Southern California (US)
- American Cancer Society (US)
- Seattle Children's Hospital (US)
- University of Minnesota (US)
- New South Wales Department of Health (AU)
- St. Jude Children's Research Hospital (US)
- Harvard University (US)
- Emory University (US)
- University of Toronto (CA)
- University of Washington (US)
- Lunenfeld-Tanenbaum Research Institute (CA)
- UNSW Sydney (AU)
- Seattle Children's Hospital (US)
- Istituto Ortopedico Rizzoli (IT)
- Frederick National Laboratory for Cancer Research (US)
- Sinai Health System (CA)
- Clinica Universidad de Navarra (ES)
- National Cancer Institute (US)
- Children's Healthcare of Atlanta (US)
- Texas Children's Hospital (US)
- Center for Cancer Research (US)
- Department of Health and Human Services (US)
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US)
- Division of Cancer Epidemiology and Genetics
- Universidad de Navarra (ES)
Publication Details
- Journal
- JNCI Journal of the National Cancer Institute
- Published
- 2025-09-20
- DOI
- https://doi.org/10.1093/jnci/djaf278
- Citations
- 1
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 1.05