The finding may allow for earlier detection or development of targeted therapies.
Researchers have discovered a new genetic link to the most common type of bone cancer among children and young adults.
Inherited mutations in the SMARCAL1 gene are significantly associated with osteosarcoma risk, an analysis of nearly 200 DNA damage repair genes showed.
"Osteosarcoma is a poster child for a highly genomically unstable tumor, which is one reason why outcomes are so poor," Richa Sharma, MD, pediatric hematologist and oncologist at Cleveland Clinic Children's, told Healio. "This is one of the few germline associations identified for osteosarcoma, which is a big deal for the patients who suffer from this cancer. This could play a big role in early detection, and diving deep and understanding the biology should lead us down the road of targeting pathways controlled by these genetic changes in cancer."
Prior research suggests that up to 18% of children with cancer harbor pathogenic variants in established cancer-predisposing genes, according to study background.
Most studies of inheritable susceptibility to cancer focus on a gene list of 70 to 110 well-established cancer predisposition genes, Sharma said.
Heritable mutations in DNA damage repair genes -- which are known cancer drivers when mutated in the tumor -- have not been evaluated comprehensively and systematically for cancer-predisposing signals in children.
Sharma and colleagues aimed to examine a large set of DNA repair genes in an unbiased manner rather than relying on a short gene list of known DNA repair cancer predisposition genes.
The researchers analyzed genetic information from 5,993 children with cancer and 14,477 cancer-free adults. Their analysis focused on 189 DNA damage repair genes, which they evaluated for germline predisposing variants.
When investigators identified genes with pathogenic variants statistically enriched among children with cancer, they aimed to validate them among 1,497 more childhood cancer cases across three independent cohorts.
The gene-cancer association with SMARCAL1 in osteosarcoma was significant in the discovery cohort, with variants identified in six of 230 cases (2.6%; FDRlogistic = .0189), as well as in the three independent validation cohorts: the Childhood Cancer Survivor Study (eight of 275 cases; 2.9%; PFisher < .0001), the German Childhood Cancer Registry (four of 135 cases; 3%; PFisher = .002) and a cohort from the INFORM precision medicine program in Germany (four of 217 cases; 1.8%; PFisher = .012).
"Several cancer predisposition genes have relatively low prevalence," Sharma said. "But this prompts an important question: How does this gene predispose to cancer and, in our case, osteosarcoma, one of the most malignant cancers among children? If I learn how this specific gene contributes to osteosarcoma development, could I learn something about the overall tumor biology?
"This opens a window of opportunity," Sharma added. "Because SMARCAL1 is known to be mutated in several other high-grade cancers among adults and children, understanding the role of SMARCAL1 in cancer development also opens a bigger window to better understanding its role in several other types of cancer, which could ultimately lead to targeted therapies."
Osteosarcoma accounts for 2% to 3% of childhood cancers, according to American Cancer Society. Approximately half of the 1,000 new cases diagnosed each year occur among children and adolescents.
Survival rates range from 60% to 75% for those with localized disease, but 5% to 30% for those with metastatic disease, according to society statistics.
Standard treatment often includes surgery and chemotherapy. Radiation may be used in cases when surgery is not possible or a tumor cannot be fully resected. Only one new drug has been approved in the past several decades.
There are few genes known to predispose to osteosarcoma and, because it is a highly unstable tumor, understanding how it develops remains a challenge. The discovery of a novel cancer-predisposing gene in osteosarcoma is very exciting and paves the way for better screening and potentially effective therapies, Sharma said.
Further analysis of patients with heritable SMARCAL1 mutations will provide insights about how this impacts the carriers' outcomes and penetrance of osteosarcoma.
Sharma and colleagues also intend to further study the biology of SMARCAL1 and its role in tumor formation and progression in osteosarcoma.
"Our objective was to find new cancer predisposition genes, and it is hard to accomplish this if you are using a list of genes that already are associated with cancer," Sharma said. "Looking for novelty requires a novel approach, which is what our study employs and what we need to strive for. Thinking bigger -- and outside the box -- by asking a biologically relevant question in cancer type-agnostic manner is what led us to discovering novel cancer disposition genes."