SMARCAL1 is a new osteosarcoma predisposition gene.

Authors

Rafati M, Guenther LM, Egolf LE, Gianferante DM, Kim J, Wang K, Zhu B, Spector LG, Anderson N, Janeway KA, Barkauskas DA, Hawkins DS, Patiño-Garcia A, Lupo PJ, Scheurer ME, Morton L, Armstrong GT, Sapkota Y, Gramatges MM, Serra M, ...show more Hattinger C, Scotlandi K, Andrulis IL, Wunder JS, Ballinger ML, Thomas DM, Yeager M, Dean M, Stewart DR, Vogt A, Liu J, Hicks BD, Huang WY, Landi MT, Lori A, Diver WR, Savage SA, Chanock SJ, Mirabello L

Affiliations

• Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, MD, USA.
• Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
• Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
• Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
• Department of Population and Public Health Sciences, Keck School of Medicine of the University of Southern California, Los Angeles, CA.
• Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA.
• Department of Pediatrics/Medical Genomics Unit and Program in Solid Tumors, Cima-Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN) Pamplona, IdiSNA, Spain.
• Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA.
• Division of Hematology and Oncology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
• Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Abstract

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.