Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

NIH Researchers Identify Novel Genes that may Drive Rare, Aggressive Form of Uterine Cancer

Published: Tuesday, March 05, 2013
Last Updated: Tuesday, March 05, 2013
Bookmark and Share
Serous endometrial tumors account for some of the most difficult to treat cancers of the uterine lining.

Researchers have identified several genes that are linked to one of the most lethal forms of uterine cancer, serous endometrial cancer.

The researchers describe how three of the genes found in the study are frequently altered in the disease, suggesting that the genes drive the development of tumors.

The findings appear in the Oct. 28, 2012, advance online issue of Nature Genetics. The team was led by researchers from the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health.

Cancer of the uterine lining, or endometrium, is the most commonly diagnosed gynecological malignancy in the United States.

Also called endometrial cancer, it is diagnosed in about 47,000 American women and leads to about 8,000 deaths each year.

Each of its three major subtypes - endometrioid, serous and clear-cell - is caused by a different constellation of genetic alterations and has a different prognosis.

Endometrioid tumors make up about 80 percent of diagnosed tumors. Surgery often is a complete cure for women with the endometrioid subtype, since doctors usually diagnose these cases at an early stage.

Compared to other subtypes, the 2 to 10 percent of uterine cancers that comprise the serous subtype do not respond well to therapies.

The five-year survival rate for serous endometrial cancer is 45 percent, compared to 65 percent for clear-cell and 91 percent for endometrioid subtypes. Serous and clear-cell endometrial tumor subtypes are clinically aggressive and quickly advance beyond the uterus.

"Serous endometrial tumors can account for as much as 39 percent of deaths from endometrial cancer," said Daphne W. Bell, Ph.D., an NHGRI investigator and the paper's senior author. Dr. Bell heads the Reproductive Cancer Genetics Section of NHGRI's Cancer Genetics Branch.

To determine which genes are altered in serous endometrial cancer, Dr. Bell and her team undertook a comprehensive genomic study of tumors by sequencing their exomes, the critical 1 to 2 percent of the genome that codes for proteins.

"Exome sequencing is a powerful tool for revealing important insights about this form of cancer that exacts such a high toll for thousands of women," said NHGRI Scientific Director Dan Kastner, M.D., Ph.D. "This study pinpoints genetic alterations that may be essential for onset and progression of uterine cancers and may eventually lead to new therapeutic targets."

Dr. Bell's team focused on the rarer, more aggressive forms of endometrial cancer. They began their study by examining serous tumor tissue and matched normal tissue from 13 patients.

National Cancer Institute and Massachusetts General Hospital pathologists processed the 26 tissue samples, which subsequently underwent whole-exome sequencing at the NIH Intramural Sequencing Center.

With the exome data in hand, the researchers filtered through millions of data points to locate alterations, or mutations. They disqualified from the analysis any mutation found in a tumor and its matched healthy tissue, looking expressly for mutations that occurred exclusively in the tumor cells. They also eliminated one of the 13 tumors from analysis because its exome had hundreds more unique mutations than any other tumor.

The researchers detected more than 500 somatic mutations within the remaining 12 tumors. They next looked for genes that were mutated in more than one of the tumors. An alteration that occurs in more than one tumor is more likely to be relevant to the development of the cancer than a unique alteration.

"When you identify a set of mutations, they could either be drivers that have caused the cancer or incidental passengers that are of no consequence; our goal is to identify the drivers," Dr. Bell explained. "One way to do this is to home in on genes that are mutated in more than one tumor, because we know from experience that frequently mutated genes are often driver genes."

The team felt confident that alterations in nine genes could be driver genes in serous endometrial cancer. Three of the nine genes had previously been recognized by researchers in the cancer genetics field as a cause of serous endometrial cancer.

To get a clearer picture of driver gene status among the other six genes, the researchers sequenced each gene in 40 additional serous endometrial tumors. They discovered that three of the six genes - CHD4, FBXW7 and SPOP - are altered at a statistically high frequency in serous endometrial cancer.

The team also found that this set of three genes is mutated in 40 percent of the serous endometrial cancer tumors and in 15 to 26 percent of the other endometrial cancer subtypes.

Probing still further, the researchers looked for the same genes highlighted by their exome sequencing study within databases that organize genes according to their biological function. They found an enrichment of genes involved in chromatin remodeling, the dynamic process by which the contents of the cell nucleus, including DNA, are packaged and modified.

Chromatin remodeling enables tightly packaged DNA to be accessed for the expression of genes. Intriguingly, CHD4 was one of the genes that formed the chromatin-remodeling cluster.

"We sequenced the other genes that make up this cluster and, as a set, these genes are frequently mutated in both serous and clear-cell endometrial tumors," said Dr. Bell.

They also noted frequent mutations in genes that regulate a process known as ubiquitin-mediated protein degradation. The process targets unneeded proteins for destruction, and thus prevents them from accumulating within the cell.

Left to accumulate, some of the target proteins are known to drive cancer formation. FBXW7 and SPOP are both known to play a role in binding to the unneeded proteins and targeting them for destruction.

Many of the FBXW7 gene mutations that Dr. Bell's team identified are known in other cancers to be driver mutations that prevent the FBXW7 protein from binding to its target protein. Dr. Bell believes that altered SPOP may behave the same way. "All the mutations we found in SPOP are in the region that binds the target proteins" she said. "We suspect the mutations in SPOP might lead to the accumulation of the unneeded proteins within the cell. But that has to be tested."

The current findings build on the team's 2011 study that showed for the first time that alterations in the PIK3R1 gene occur in all subtypes of endometrial cancer and are most frequent in the more common endometrioid subtype.

"This discovery really changes our understanding of some of the genetic alterations that may contribute to this disease," Dr. Bell said, acknowledging that the findings are limited by the small number of tumors subjected to exome sequencing.

She noted that it is too early to make a direct connection between their findings and prospects for treatments for this aggressive form of uterine cancer.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,100+ scientific posters on ePosters
  • More Than 4,500+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Nanoparticles Target, Transform Fat Tissue
Nanoparticles designed to target white fat and convert it to calorie-burning brown fat slowed weight gain in obese mice without affecting food intake. This proof-of-concept work could lead to new therapies to treat obesity.
Wednesday, May 25, 2016
Visual Impairment, Blindness Cases in U.S. Expected to Double by 2050
Researchers at NIH have suggested that there is a need for increased screening and interventions to identify and address treatable causes of vision loss.
Friday, May 20, 2016
Drug Might Help Treat Sepsis
A DNA enzyme called Top1 plays a key role in turning on genes that cause inflammation in mouse and human cells in response to pathogens. A drug blocking this enzyme rescued mice from lethal inflammatory responses, suggesting a potential treatment for sepsis.
Wednesday, May 18, 2016
NIH Funds New Studies on Ethical, Legal and Social Impact of Genomic Information
Four new grants from the National Institutes of Health will support research on the ethical, legal and social questions raised by advances in genomics research and the increasing availability of genomic information.
Wednesday, May 18, 2016
Large-scale HIV Vaccine Trial to Launch in South Africa
NIH-funded study will test safety, efficacy of vaccine regimen.
Wednesday, May 18, 2016
New HIV Vaccine Target Discovered
NIH-Led team have discovered a new vaccine target site on HIV.
Tuesday, May 17, 2016
Researchers Identify Genetic Links to Educational Attainment
Researchers at NIH have suggested that the large genetics analyses may be able to help discover biological pathways as well.
Thursday, May 12, 2016
Investigational Malaria Vaccine Protects Healthy U.S. Adults
Researchers at NIH have found that the malaria vaccine protected a small number of healthy, malaria-naïve adults in the U.S. from infection for more than one year after immunization.
Tuesday, May 10, 2016
Ketamine Metabolism Lifts Depression
NIH-funded team finds rapid-acting, non-addicting agent in mouse study.
Thursday, May 05, 2016
Finding Factors That Protect Against Flu
A clinical trial examining the body’s response to seasonal flu suggests new approaches for evaluating the effectiveness of seasonal flu vaccines.
Wednesday, April 27, 2016
Factors Influencing Influenza Vaccine Effectiveness Uncovered
The long-held approach to predicting seasonal influenza vaccine effectiveness may need to be revisited, new research suggests.
Thursday, April 21, 2016
Study Finds Factors That May Influence Influenza Vaccine Effectiveness
Researchers at NIH have suggested that the long-held approach to predicting seasonal influenza vaccine effectiveness may need to be revisited.
Wednesday, April 20, 2016
Serotonin Transporter Structure Revealed
Researchers determined the 3-D structure of the serotonin transporter and visualized how two common antidepressants interact with the protein.
Wednesday, April 20, 2016
Improving Flu Vaccine Effectiveness
NIH study finds factors that may influence influenza vaccine effectiveness.
Wednesday, April 20, 2016
Submissions Open for the Cancer Moonshot Program
NCI opens online platform to submit ideas about research for Cancer Moonshot.
Tuesday, April 19, 2016
Scientific News
The Rise of 3D Cell Culture and in vitro Model Systems for Drug Discovery and Toxicology
An overview of the current technology and the challenges and benefits over 2D cell culture models plus some of the latest advances relating to human health research.
World’s Largest Coral Gene Database
‘Genetic toolkit’ will help shed light on which species survive climate change.
A Boost for Regenerative Medicine
Growing tissues and organs in the lab for transplantation into patients could become easier after scientists discovered an effective way to produce three-dimensional networks of blood vessels, vital for tissue survival yet a current stumbling block in regenerative medicine.
Breast Cancer Drug Hope
A drug for breast cancer that is more effective than existing medicines may be a step closer thanks to new research.
Untangling Disease-Related Protein Misfolding
Work advances understanding of genetic forms of thrombosis, emphysema, cirrhosis of the liver, neurodegenerative diseases and inflammation, among others.
Early Genetic Changes in Premalignant Colorectal Tissue Identified
Findings point to drivers of early cancer development, targets for cancer prevention therapies.
Harnessing Nature’s Vast Array of Venoms for Drug Discovery
Scripps scientists have developed a method for rapidly identifying venoms.
Nanoparticles Target, Transform Fat Tissue
Nanoparticles designed to target white fat and convert it to calorie-burning brown fat slowed weight gain in obese mice without affecting food intake. This proof-of-concept work could lead to new therapies to treat obesity.
New Cancer Fighters Emerge From Lab
Rice University lab simplifies total synthesis of anti-cancer agent.
Scientists Find Evidence That Cancer Can Arise Changes
Researchers at Rockefeller University have found a mutation that affects the proteins that package DNA without changing the DNA itself can cause a rare form of cancer.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,100+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,500+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!