St. Jude co-led multi-institution collaboration uncovers a predisposition gene for osteosarcoma

Osteosarcoma is the most common malignant bone tumor in children and young adults. There have been hints of hereditary predispositions to the disease, the most common of which is TP53 gene loss, but osteosarcoma’s relative rarity makes it difficult to put together a large-enough patient group with germline genetic information to make statistically meaningful inferences. 

A multi-institution study co-led by Lillian Guenther, MD, Department of Oncology, leveraged germline sequencing housed in the Clinical Genetics Branch at the National Cancer Institute, containing over 2,000 osteosarcoma cases, which represents the largest collection of osteosarcoma cases with germline data reported to date. 

They discovered that SMARCAL1 loss-of-function variants conferred a statistical increase in osteosarcoma risk compared to matched healthy controls, establishing it as a significant predisposition gene. Furthermore, they found that SMARCAL1 germline variants are associated with a favorable overall survival in patients with osteosarcoma. The findings were published in September in the Journal of the National Cancer Institute. 

“Our findings on SMARCAL1 are a step forward in our understanding of the underpinnings of osteosarcoma development,” Guenther said. “Furthermore, the discovery that SMARCAL1 variants are associated with survival will hopefully lead to improved prognostication for pat

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