Studies identify SMARCAL1 as a novel osteosarcoma predisposition gene

Children may be at a higher risk of developing cancer based on DNA variants in their healthy cells. Recent studies revealed that 5%-18% of children with cancer have variants in known cancer-predisposing genes. While genes involved in recognizing and repairing DNA damage are known to be mutated in tumor cells, it has been unclear how variants in these genes, when present in normal or germline cells, predispose children to certain cancers.

Osteosarcoma is the most common malignant bone tumor in children and young adults. Patients with localized disease have a 70%-75% probability of survival, while those with metastatic disease have only 30% five-year survival. There have been hints of hereditary predisposition to the disease, most commonly secondary to germline mutations in TP53. However, other than TP53 mutations, the genetic variant landscape was largely unknown.

A study published in the Journal of Clinical Oncology, co-led by Kim Nichols, MD, Division of Cancer Predisposition director and Department of Oncology member, shed light on what fuels osteosarcoma and other cancer types. The researchers performed the first comprehensive analysis of DNA damage repair gene variants, examining 189 genes for the presence of germline predisposing variants among 5,993 childhood cancer cases.

The analysis showed that variations in SMARCAL1, a gene that encodes an important DNA repair protein, are associated with increased osteosarcoma risk. Furthermore, several osteosarcoma tumors from patients with germline SMARCAL1 variants exhibited mutations in their other copy of SMARCAL1, connecting complete loss of SMARCAL1 protein function with osteosarcoma formation. The analysis also confirmed several known predisposing variants in other malignancies, such as BARD1 in neuroblastoma, increasing confidence in the results. Results also highlighted novel associations in ependymoma, high-grade glioma, and medulloblastoma, though at a lower frequency than SMARCAL1 for osteosarcoma. 

“These findings provide new clues into the development of osteosarcoma, an aggressive cancer for which there has been little improvement in therapy for decades,” said Nichols. “Additionally, genetic testing for germline SMARCAL1 gene changes will help identify individuals who might benefit from screening to detect new osteosarcoma tumors at their earliest, most curable stages.”

A complementary study, co-led by Lillian Guenther, MD, Department of Oncology, further cemented SMARCAL1 as a significant predisposition gene. The research, published in the Journal of the National Cancer Institute, leveraged germline sequencing data from the Clinical Genetics Branch at the National Cancer Institute and found that loss-of-function variants of SMARCAL1 confer a statistical increase in osteosarcoma risk compared to matched healthy controls. They also found that SMARCAL1 germline variants, while predisposing to osteosarcoma, are associated with favorable overall survival in patients receiving treatment, emphasizing the clinical importance of this variant.

The independent studies, both confirming SMARCAL1 as a significant osteosarcoma predisposition gene, strengthen confidence in the finding. The insights gained from these studies, along with future research, may provide opportunities to develop novel therapeutics and possibly preventive interventions. For now, this new knowledge empowers clinicians to improve patient outcomes through tumor surveillance.