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A higher than expected fraction of adolescent osteosarcoma patients carry a gene mutation that is often inherited

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NCI Press Office


A new study shows that inherited variations in a known tumor suppressor gene among children and adolescents with osteosarcoma, a cancer of the bone, are more common than previously thought. Older patients who are also susceptible to this malignancy were not found to carry mutations in the gene, known as TP53. The study, finding that the genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, was published online April 20, 2015, in the Journal of the National Cancer Institute. Lisa Mirabello, Ph.D., of the National Cancer Institute’s (NCI) Division of Cancer Epidemiology and Genetics, led the research. NCI is part of the National Institutes of Health.

The incidence of osteosarcoma peaks between the ages of 10 and 19. This cancer often arises in people with Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome that is most often caused by germline or inherited mutations in the TP53 gene. LFS results in a constellation of tumors, often occurring at very young ages. Osteosarcoma can also occur in families that are not known to have LFS. The role of inherited TP53 mutations in osteosarcoma patients not known to have LFS is not very well understood.

To try to gain a better understanding of the contribution of TP53 mutations in osteosarcoma, study researchers sequenced the TP53 gene in a random set of 765 osteosarcoma patients, the largest population evaluated for these mutations to date. For all patients, DNA was taken for sequencing from cells found in the blood or in tissue in the mouth. DNA from tumors was not available.

“We found a higher than expected prevalence of TP53 mutations in young patients. In particular, we observed mutations known to be associated with Li-Fraumeni syndrome as well as rare and potentially highly damaging novel genetic changes,” said Dr. Mirabello. “Some of these changes were associated with risk of metastasis at diagnosis, as well as lower survival independent of the presence of metastatic disease.”

Among the young (less than age 30) osteosarcoma patients in the study, 3.8 percent carried an LFS-associated mutation in the TP53 gene and 5.7 percent carried a rare TP53 variation of the gene, for a total prevalence of TP53 mutations of 9.5 percent, significantly higher than the previously reported prevalence of about 3 percent. None of the older osteosarcoma patients carried an LFS-associated mutation.  

Because the osteosarcoma patients were identified based on prior studies, the researchers did not have information on family history of cancer. The finding that nearly 4 percent of pediatric osteosarcoma cases have a LFS-associated germline TP53 mutation is important because these individuals, and possibly their family members, may be at risk of developing other LFS-associated cancers.

"The findings highlight the potential importance of sequencing the germline DNA in patients with pediatric osteosarcoma, because the germline analysis might uncover new cases of Li-Fraumeni syndrome,” said Doug Lowy, M.D., acting director, NCI. 

Testing for germline TP53 mutations is also important because individuals with LFS have a substantial risk for a second cancer. Knowing that level of risk could help clinicians offer genetic counseling and cancer screening so subsequent malignancies may be detected at an earlier stage and potentially improve patient survival. Additionally, 90 percent of osteosarcomas that develop in young people do not have germline TP53 mutations and further research is needed to understand those cases. 


Reference: Mirabello, L. et al., 2015. Germline TP53 variants and susceptibility to osteosarcoma. JNCI. Online April 20, 2015. DOI:xxx