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New Study Highlights Pathogenic Germline Variants in Patients With Osteosarcoma


A major study of patients with osteosarcoma suggests new pathogenic and likely pathogenic germline variants associated with the bone cancer.

More than one-quarter of patients with osteosarcoma carry a particular germline variant in a cancer-susceptibility gene, according to new research of more than 1200 patients.

The study, published in JAMA Oncology, could have implications for early detection and treatment of the disease, as well as for precautionary genetic testing of family members of patients with the variant.

Osteosarcoma is a rare bone cancer that destroys tissue and can weaken bones. Fewer than 1000 people are diagnosed with the cancer in the United States each year, most of whom are between the ages of 10 and 30. However, the disease makes up an estimated 2% of all childhood cancers.

A large team of researchers, including Lisa Mirabello, PhD, of the National Cancer Institute (part of the National Institutes of Health), sought to better understand the cancer’s genetic connections. They noted that the cancer occurs frequently in cases of cancer predisposition syndromes that are defined by highly penetrant germline mutations. However, they noted that germline genetic susceptibility to osteosarcoma outside of these syndromes is not well understood.

The team decided to investigate the matter by performing whole-exome sequencing or targeted sequencing on 1244 patients with osteosarcoma. The sequencing took place over 3 years, from 2014 to 2017, at 10 international cancer centers. Those patients’ DNA were then compared with the DNA of 1062 patients without cancer who underwent whole-genome sequencing as participants in 4 participating studies, and to the DNA of 27,713 individuals in the Exome Aggregation Consortium’s database.

The investigators looked at 238 high-interest cancer susceptibility genes and 736 additional candidate genes. “Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons,” wrote Mirabello and colleagues, adding that the results were then compared with the Exome Aggregation Consortium’s data.

An analysis using only patients with European ancestry showed “a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group,” the authors write.

Pathogenic or likely pathogenic cancer susceptibility genes were found in 28% of the patients with osteosarcoma, “of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene.

The authors also noted that the frequency of pathogenic or likely pathogenic variants was higher than expected in genes such as CDKN2A, MEN1, VHL, and others that had not previously been linked to osteosarcoma.

The authors conclude by noting a number of potential clinical implications of their findings. For one, the data suggest that genetic testing of newly diagnosed patients could be important because such patients are more likely to have pathogenic or likely pathogenic variants, particularly if the patient is at the younger end of the spectrum.

Mirabello and colleagues also note that these data could be helpful in the early detection of patients with a predisposition toward this cancer.

“Our data underscore the high frequency of potentially actionable cancer risk variants in patients with osteosarcoma, suggesting a need for further preventive and early detection strategies as well as a consideration of cascade genetic testing for the patient and the entire family,” they conclude.


Mirabello L, Zhu B, Koster R, et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma [published online March 19, 2020]. JAMA Oncol. doi:10.1001/jamaoncol.2020.0197.

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