Tumor suppressor gene TP53 mutated in 90 percent of most common childhood bone tumor

April 3, 2014, St. Jude Children's Research Hospital
Tumor suppressor gene TP53 mutated in 90 percent of most common childhood bone tumor
Michael Dyer, Ph.D., is a Howard Hughes Medical Institute investigator and member of the St. Jude Department of Developmental Neurobiology. Credit: St. Jude Children's Research Hospital

The St. Jude Children's Research Hospital—Washington University Pediatric Cancer Genome Project found mutations in the tumor suppressor gene TP53 in 90 percent of osteosarcomas, suggesting the alteration plays a key role early in development of the bone cancer. The research was published today online ahead of print in the journal Cell Reports.

The discovery that TP53 is altered in nearly every osteosarcoma also helps to explain a long-standing paradox in osteosarcoma treatment, which is why at standard doses radiation therapy is largely ineffective against the tumor. The findings follow the first whole of osteosarcoma, which is diagnosed in about 400 children and adolescents annually, making it the most common pediatric bone tumor.

"Osteosarcoma treatment has remained largely unchanged for more than 20 years, and cure rates are stalled at about 70 percent. This study lays a foundation for new therapies and more immediately identifies numerous mutations in TP53 missed by previous studies that did not include whole genome sequencing," said co-corresponding author Michael Dyer, Ph.D., a Howard Hughes Medical Institute investigator and member of the St. Jude Department of Developmental Neurobiology. Jinghui Zhang, Ph.D., member of the St. Jude Department of Computational Biology, is the other corresponding author.

TP53 carries instructions for assembling the p53 protein, which plays a role in DNA repair and cell death. Inactivation of p53 helps tumor cells survive radiation therapy. Previous studies estimated that TP53 was mutated in a quarter to half of osteosarcomas, suggesting that a significant proportion of patients with this tumor should respond to radiation. That was not the case, Dyer said.

"With whole-genome sequencing, we are gaining new insights into the way various mutations in TP53 promote the development of osteosarcomas," said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. "This information will be very helpful in designing treatment protocols."

The study involved whole genome sequencing of 34 osteosarcoma tumors from 32 patients. The patients' normal genomes were also sequenced.

The research revealed that 55 percent of TP53 mutations were caused by structural variations. These alterations occur when chromosomes break and are reassembled. Osteosarcoma is just the second cancer with TP53 mutations resulting from chromosomal rearrangements rather than point mutations, which are small changes in the DNA that makes up the gene. "This suggests that the cell that gives rise to osteosarcoma may either be particularly susceptible to chromosomal breaks or better able to tolerate breaks when they occur," Dyer said.

In addition to TP53, sequencing showed osteosarcoma tumors were riddled with structural variations that affected numerous other cancer genes. These are genes that, when altered, are known or suspected of causing cancer. All but one of the tumors had at least one structural variation in a cancer gene. The list included recurring mutations in the genes ATRX and RB1, which are altered in other pediatric solid tumors. The suspected cancer gene DLG2 was also mutated in half of osteosarcomas.

Half the tumors also included unusually large numbers of DNA point mutations that were clustered near chromosomal breaks. This localized hypermutation, known as kataegis, was first identified in 2012 in breast cancer. The hypermutated regions identified in this study did not include TP53, ATRX or other genes frequently altered in , but Dyer said the finding is another indication of the genome instability that is a hallmark of this cancer.

The study also yielded a new test to streamline identification of TP53 structural variations. The test could be used to screen for the alterations in other cancers or in tumor samples stored in tissue banks. "This test makes it possible to ask if patients with p53 structural variations have different outcomes than patients with other TP53 ," Dyer said. "That would help us identify where to focus clinical research efforts."

The test was developed by Armita Bahrami, M.D., an assistant member of the St. Jude Department of Pathology. She and Xiang Chen, Ph.D., a staff scientist in the Computational Biology department, are the paper's co-first authors.

The study was part of the Pediatric Cancer Genome Project, which was launched in 2010 to harness advances in genome sequencing technology to improve understanding and treatment of some of the most aggressive and least understood childhood cancers. Since then, the project has sequenced the complete normal and tumor genomes of 700 young patients.

Explore further: Gene sequencing project finds family of drugs with promise for treating childhood tumor

Related Stories

Gene sequencing project finds family of drugs with promise for treating childhood tumor

December 9, 2013
Drugs that enhance a process called oxidative stress were found to kill rhabdomyosarcoma tumor cells growing in the laboratory and possibly bolstered the effectiveness of chemotherapy against this aggressive tumor of muscle ...

Gene sequencing project discovers common driver of a childhood brain tumor

February 19, 2014
The St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project has identified the most common genetic alteration ever reported in the brain tumor ependymoma and evidence that the alteration ...

Gene identified as a new target for treatment of aggressive childhood eye tumor

January 11, 2012
New findings from the St. Jude Children's Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP) have helped identify the mechanism that makes the childhood eye tumor retinoblastoma so aggressive. ...

Study finds new genetic defects in high-risk childhood leukemia subtypes with chromosomal loss

January 20, 2013
Research led by St. Jude Children's Research Hospital scientists has identified a possible lead in treatment of two childhood leukemia subtypes known for their dramatic loss of chromosomes and poor treatment outcomes.

Genetic errors identified in 12 major cancer types

October 16, 2013
Examining 12 major types of cancer, scientists at Washington University School of Medicine in St. Louis have identified 127 repeatedly mutated genes that appear to drive the development and progression of a range of tumors ...

Gene sequencing project finds new mutations to blame for a majority of brain tumor subtype

May 30, 2013
(Medical Xpress)—The St. Jude Children's Research Hospital – Washington University Pediatric Cancer Genome Project has identified mutations responsible for more than half of a subtype of childhood brain tumor that takes ...

Recommended for you

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

Researchers develop swallowable test to detect pre-cancerous Barrett's esophagus

January 17, 2018
Investigators at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center have developed a simple, swallowable test for early detection of Barrett's esophagus that offers promise ...

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.