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 3,900+ scientific posters on ePosters
  • More Than 5,300+ 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

Study to Assess Shorter-Duration Antibiotics in Children
Physicians plan a clinical trial to evaluate whether short course anti-biotics are effective at treating CAP in children.
Wednesday, November 30, 2016
First New HIV Vaccine Study for Seven Years Begins
South Africa hosts historic clinical trial of experimental HIV vaccine aiming to safely prevent HIV infection.
Wednesday, November 30, 2016
Antibody Protects Mice from Zika Infection
Researchers develop human-derived antibody protected pregnant mice and their developing fetuses from Zika infection.
Wednesday, November 23, 2016
Food Additives Promote Inflammation, Colon Cancer
Dietary emulsifiers promoted colon cancer in a mouse model by altering gut microbes and increasing gut inflammation.
Wednesday, November 23, 2016
Protein-Folding Gene Helps Heal Wounds
Researchers identified a protein that dramatically accelerates wound healing in animal models.
Wednesday, November 23, 2016
More Immunotherapy Options Approved for Lung Cancer
The FDA has approved a new immunotherapy drug for certain patients with non-small cell lung cancer.
Monday, November 21, 2016
Big Data for Infectious Disease Surveillance
NIH-led effort examines use of big data from health records and other digital sources for uses in infectious disease surveillance.
Tuesday, November 15, 2016
Potential Therapies Against Drug-Resistant Bacteria Identified
Researchers create new identification method for drug and drug combinations that may combat resistant infections.
Thursday, November 10, 2016
Testing Zika Vaccine in Humans Begins
The first of five planned clinical trials to test ZPIV vaccine in humans has begun.
Tuesday, November 08, 2016
Genetic Markers Predict Malaria Treatment Failure
By comparing 297 parasite genomes to a reference malaria parasite genome, researchers have identified two genetic markers that are strongly associated with the parasites’ ability to resist piperaquine.
Monday, November 07, 2016
Cannabinoid Receptor Structure Revealed
Scientists provided a detailed view of the primary molecule through which cannabinoids exert their effects on the brain. The findings might help guide the design of more targeted medicines with fewer side effects.
Wednesday, November 02, 2016
NIH Researchers Unveil New Wound-Healing Role for Protein-Folding Gene in Mice
The study found that topical treatment of an Hsp60-containing gel dramatically accelerates wound closure in a diabetic mouse model.
Friday, October 28, 2016
Ebola-Affected Countries Receive NIH Support
The National Institutes of Health has established a new program to further research capacity to study Ebola and other epidemics.
Thursday, October 27, 2016
Skin Patch to Treat Peanut Allergy
NIH-funded study suggests peanut protein patch is a safe and convenient method of treatment.
Thursday, October 27, 2016
Gene Editing Corrects Sickle Cell Mutation
Researchers demonstrate a potential pathway to developing gene-editing treatments for sickle cell disease.
Wednesday, October 26, 2016
Scientific News
Big Genetics in BC: The American Society for Human Genetics 2016 Meeting
Themes at this year's meeting ranged from the verification, validation, and sharing of data, to the translation of laboratory findings into actionable clinical results.
Stem Cells in Drug Discovery
Potential Source of Unlimited Human Test Cells, but Roadblocks Remain.
Cancer Genetics: Key to Diagnosis, Therapy
When applied judiciously, cancer genetics directs caregivers to the right drug at the right time, while sparing patients of unnecessary or harmful treatments.
BGI Sequences Gingko Tree, Revealing Large, Highly Repetitive Genome
Researchers at BGI have sequenced the more than 10-gigabase ginkgo genome to find a high number of repetitive sequences as well as a number of gene clusters that appear to be involved in defense mechanisms.
Survey of New York City Soil Uncovers Medicine-Making Microbes
Microbes have long been an invaluable source of new drugs. And to find more, we may have to look no further than the ground beneath our feet.
Accelerating the Detection of Foodborne Bacterial Outbreaks
The speed of diagnosis of foodborne bacterial outbreaks could be improved by a new technique developed by researchers at the Georgia Institute of Technology.
Making Personalized Medicine a Reality
Groundbreaking technique developed at McMaster University is helping to pave the way for advances in personalized medicine.
Scientists Identify Unique Genomic Features in Testicular Cancer
The findings may shed light on factors in other cancers that influence their sensitivity to chemotherapy.
Top 10 Life Science Innovations of 2016
2016 has seen the release of some truly innovative products. To help you digest these developments, The Scientist have listed their top picks for the year.
BioCision Forms MedCision
The new company will focus on technologies for the management and automation of vital clinical processes.
Scroll Up
Scroll Down
Skyscraper Banner

SELECTBIO Market Reports
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
3,900+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,300+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!