Featured Research

from universities, journals, and other organizations

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

Date:
April 3, 2014
Source:
St. Jude Children's Research Hospital
Summary:
Mutations in the tumor suppressor gene TP53 have been found in 90 percent of osteosarcomas, suggesting the alteration plays a key role early in development of the bone cancer. 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 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 genome sequencing 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 osteosarcoma, 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 mutations," Dyer said. "That would help us identify where to focus clinical research efforts."


Story Source:

The above story is based on materials provided by St. Jude Children's Research Hospital. Note: Materials may be edited for content and length.


Journal Reference:

  1. Xiang Chen, Armita Bahrami, Alberto Pappo, John Easton, James Dalton, Erin Hedlund, David Ellison, Sheila Shurtleff, Gang Wu, Lei Wei, Matthew Parker, Michael Rusch, Panduka Nagahawatte, Jianrong Wu, Shenghua Mao, Kristy Boggs, Heather Mulder, Donald Yergeau, Charles Lu, Li Ding, Michael Edmonson, Chunxu Qu, Jianmin Wang, Yongjin Li, Fariba Navid, Najat C. Daw, ElaineR. Mardis, RichardK. Wilson, JamesR. Downing, Jinghui Zhang, MichaelA. Dyer. Recurrent Somatic Structural Variations Contribute to Tumorigenesis in Pediatric Osteosarcoma. Cell Reports, 2014; DOI: 10.1016/j.celrep.2014.03.003

Cite This Page:

St. Jude Children's Research Hospital. "Tumor suppressor gene TP53 mutated in 90 percent of most common childhood bone tumor." ScienceDaily. ScienceDaily, 3 April 2014. <www.sciencedaily.com/releases/2014/04/140403131938.htm>.
St. Jude Children's Research Hospital. (2014, April 3). Tumor suppressor gene TP53 mutated in 90 percent of most common childhood bone tumor. ScienceDaily. Retrieved September 1, 2014 from www.sciencedaily.com/releases/2014/04/140403131938.htm
St. Jude Children's Research Hospital. "Tumor suppressor gene TP53 mutated in 90 percent of most common childhood bone tumor." ScienceDaily. www.sciencedaily.com/releases/2014/04/140403131938.htm (accessed September 1, 2014).

Share This




More Health & Medicine News

Monday, September 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Get on Your Bike! London Cycling Popularity Soars Despite Danger

Get on Your Bike! London Cycling Popularity Soars Despite Danger

AFP (Sep. 1, 2014) Wedged between buses, lorries and cars, cycling in London isn't for the faint hearted. Nevertheless the number of people choosing to bike in the British capital has doubled over the past 15 years. Duration: 02:27 Video provided by AFP
Powered by NewsLook.com
We've Got Mites Living In Our Faces And So Do You

We've Got Mites Living In Our Faces And So Do You

Newsy (Aug. 30, 2014) A new study suggests 100 percent of adult humans (those over 18 years of age) have Demodex mites living in their faces. Video provided by Newsy
Powered by NewsLook.com
Liberia Continues Fight Against Ebola

Liberia Continues Fight Against Ebola

AFP (Aug. 30, 2014) Authorities in Liberia try to stem the spread of the Ebola epidemic by raising awareness and setting up sanitation units for people to wash their hands. Duration: 00:41 Video provided by AFP
Powered by NewsLook.com
California Passes 'yes-Means-Yes' Campus Sexual Assault Bill

California Passes 'yes-Means-Yes' Campus Sexual Assault Bill

Reuters - US Online Video (Aug. 30, 2014) California lawmakers pass a bill requiring universities to adopt "affirmative consent" language in their definitions of consensual sex, part of a nationwide drive to curb sexual assault on campuses. Linda So reports. Video provided by Reuters
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins