SMARCAL1 is a new osteosarcoma predisposition gene

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, 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. SMARCAL1 is a new osteosarcoma predisposition gene. J Natl Cancer Inst. 2025 Sep 25:djaf278. doi: 10.1093/jnci/djaf278. Epub ahead of print. PMID: 40996338; PMCID: PMC12702491.

Osteosarcoma, the most common childhood bone tumor, can occur in rare cancer predisposition syndromes; however, most are sporadic with no known predisposing factors. We investigated the frequency of SMARCAL1 putative pathogenic variants in our large ongoing study of 2119 osteosarcoma patients, their relation to patient characteristics, and the population prevalence. Our analysis uncovered a higher frequency of SMARCAL1 pathogenic variants across 3 osteosarcoma patient sets (1.8%, n = 2119) than in 2625 comparably sequenced cancer-free individuals (0.3%; P < .001). Patients with SMARCAL1 pathogenic variants had statistically significantly improved overall survival compared with patients without these variants (hazard ratio [HR] = 0.36, 95% confidence interval [CI] = 0.14 to 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.