Skip to main content

Study Finds 28 Percent of Osteosarcoma Patients Have High-Penetrance Germline Mutations

NEW YORK – A retrospective study published today in JAMA Oncology by the National Cancer Institute reported that 28 percent of osteosarcoma patients harbored a pathogenic or likely pathogenic genetic variant associated with cancer.

Researchers led by NCI investigator Lisa Mirabello said their findings suggest the need to refine preventive and early detection strategies for osteosarcoma patients and possibly the need for cascade genetic testing to assess risk in family members. 

Osteosarcoma is a rare bone cancer, appearing in about 900 new cases annually in the US. The cancer seems to occur in patients during puberty, where sudden growth spurts can give way to cancer.

When it is diagnosed early and treated with a combination of chemotherapy and surgery, survival rates are around 70 percent. But metastatic osteosarcoma is associated with survival rates falling below 30 percent. Researchers have been searching for ways to make osteosarcoma patient treatment more targeted.

The study assembled 1,244 osteosarcoma patients from 10 participating centers and studies. They assessed 238 cancer-susceptibility genes followed by tumor mutational burden testing for an additional 736 genes, then they compared the frequency of pathogenic or likely pathogenic variants in patients against a control group of 1,062 individuals without cancer, as well as with 27,173 cancer patients in the Exome Aggregation Consortium (ExAC) database with non-Finnish European ancestry.

The researchers then grouped the genes according to inheritance patterns, such as autosomal dominant, recessive, or X, Y-linked. Further, they identified genes associated with osteosarcoma through the Human Genome Epidemiology (HuGE) phenopedia and manually curated published reports.

The investigators also identified pediatric cancer-associated genes through the Catalogue of Somatic Mutations in Cancer and annotation of published osteosarcoma somatic data.

They classified variants as pathogenic, likely pathogenic, of uncertain significance, likely benign, or benign.

Researchers performed whole-exome sequencing on 1,004 out of the 1,244 patients, and 240 were used as a replication set. They also sequenced the 1,062 individuals in the control group. The team found that 28 percent of patients with osteosarcoma had a pathogenic or likely pathogenic variant in a cancer-susceptibility gene, and 18.4 percent of those variants occurred in an autosomal-dominant gene, which indicates that the person needed to only have one mutant copy of the gene from either parent to develop the disease..

Researchers stated that this frequency of observed autosomal-dominant gene mutations in osteosarcoma patients is higher than previously reported for any other pediatric cancer. The frequency was also higher than the variants observed in the control group (12.1 percent).

The pathogenic or likely pathogenic frequency was higher among European patients with osteosarcoma compared to individuals in the ExAC group. European patients with osteosarcoma had a higher risk of carrying a pathogenic or likely pathogenic variant in MEN1, VHL, POT1, and APC.

The youngest patients also had the highest frequency of these genes, with 24.5 percent of patients between 0 and 10 years old carrying one of these mutated autosomal-dominant genes.

Additionally, the team was able to confirm previous observations of high frequency, pathogenic germline variants in TP53, which is tied to Li-Fraumeni syndrome and is associated with heightened risk to a host of various inherited cancers. The data from this study suggests that germline TP53 variants are associated with osteosarcoma diagnosis at a younger age, an axial skeleton tumor location, and worse survival.

Pathogenic or likely pathogenic variants in TP53 were the most frequent of all autosomal-dominant genes in this study. Almost all patients in the study who had theTP53 variants were younger than 30 at the time of diagnosis, and only one patient was 39 at diagnosis.

In this study, 2.2 percent of patients had a pathogenic or likely pathogenic variant in a gene other than TP53 that is linked to a cancer-predisposing syndrome and associated with the occurrence of osteosarcoma, including RB1, RECQL4, RPL35A(OMIM180468), RPL5(OMIM603634), RPS19(OMIM603474), RPS7(OMIM603658), and WRN (OMIM277700).

This data also confirmed that the likely pathogenic variants in RB1, APC, MSH2, and PALB2 have an increased presence in osteosarcoma, which is in line with previous findings in osteosarcoma patients. Further, researchers found germline risk associations between osteosarcoma and ATRX variants, which have been previously implicated as somatic driver mutations in osteosarcoma.

The team also identified several new candidate osteosarcoma-susceptibility genes that they noted should be further studied including CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX. CDKN2A variants had the second highest frequency in osteosarcoma patients, but the researchers noted that this gene has not been previously associated with any pediatric cancers, only melanoma and pancreatic cancer.

Two patients had pathogenic DKC1 variants, which are known to cause dyskeratosis congenita and are associated with a higher risk of solid tumors but were not previously associated with osteosarcoma.

"Our findings have important implications for the genetic testing of patients, especially younger patients, who are newly diagnosed with osteosarcoma because these patients were more likely to have a potentially clinically relevant disease-associated pathogenic/likely pathogenic variant," Mirabello et. al wrote in the paper. "We note that individuals harboring Li-Fraumeni syndrome–associated TP53 mutations benefit from active screening, which could translate into improved outcomes."