Corporate Banner
Satellite Banner
Scientific Community
Become a Member | Sign in
Home>News>This Article

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
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 2,600+ scientific posters on ePosters
  • More than 3,800+ 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 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

Cellular Factors that Shape the 3D Landscape of the Genome Identified
Researchers have identified 50 cellular factors required for the proper 3D positioning of genes by using novel large-scale imaging technology.
Tuesday, August 18, 2015
Tell-tale Biomarker Detects Early Breast Cancer in NIH-funded Study
The study published online in the issue of Nature Communications.
Thursday, August 13, 2015
Study Shows Promise of Precision Medicine for Most Common Type of Lymphoma
The study appeared online July 20, 2015, in Nature Medicine.
Tuesday, July 21, 2015
Potential Therapeutic for Blinding Eye Disease
NIH research points to microglia as potential therapeutic target in retinitis pigmentosa.
Thursday, July 02, 2015
NCI-MATCH Trial will Link Targeted Cancer Drugs to Gene Abnormalities
Precision medicine trial will open to patient enrollment in July.
Tuesday, June 09, 2015
Linking Targeted Cancer Drugs to Gene Abnormalities
Investigators at the NIH have announced a series of clinical trials that will study drugs or drug combinations that target specific genetic mutations.
Wednesday, June 03, 2015
Lipid Nanoparticle Therapeutic Treats Ebola in Monkeys
A newly designed agent was effective in treating monkeys infected with a deadly Ebola virus strain.
Wednesday, May 06, 2015
Possible Treatment for Lethal Pediatric Brain Cancer
NIH-funded preclinical study suggests epigenetic drugs may be used to treat leading cause of pediatric brain cancer death.
Tuesday, May 05, 2015
NIH Study Finds Genetic Link for Rare Intestinal Cancer
Researchers recommend screening for people with family history.
Friday, April 17, 2015
Novel Approach Gives Insights Into Tumor Development
Scientists used a powerful new technique to turn off all the genes in mouse lung cancer cells and test how they affect tumor growth and metastasis.
Tuesday, March 24, 2015
Strengthening the Immune System’s Fight Against Brain Cancer
NIH-funded research suggests novel way to improve vaccine efficacy in brain tumors.
Friday, March 20, 2015
Range of Molecular Alterations in Head and Neck Cancers Uncovered
TCGA tumor genome sequencing analyses offer new insights into the effects of HPV and smoking, and find genomic similarities with other cancers.
Thursday, January 29, 2015
NIH Researchers Tackle Thorny Side of Gene Therapy
Pre-clinical studies in mice reveal ways to reduce cancer risk with modified treatment.
Wednesday, January 21, 2015
NIH Exceptional Responders to Cancer Therapy Study Launched
Study to investigate the molecular factors of tumors associated with exceptional treatment responses of cancer patients to drug therapies.
Friday, September 26, 2014
NIH Announces the Launch of 3 Integrated Precision Medicine Trials
ALCHEMIST is for patients with certain types of early-stage lung cancer.
Tuesday, August 26, 2014
Scientific News
Researchers Disguise Drugs As Platelets to Target Cancer
Researchers have for the first time developed a technique that coats anticancer drugs in membranes made from a patient’s own platelets.
A New Single-Molecule Tool to Observe Enzymes at Work
A team of scientists at the University of Washington and the biotechnology company Illumina have created an innovative tool to directly detect the delicate, single-molecule interactions between DNA and enzymatic proteins.
Milestone Single-Biomolecule Imaging Technique May Advance Drug Design
The first nanometer resolved image of individual tobacco mosaic virions shows the potential of low-energy electron holography for imaging biomolecules at a single particle level; a milestone in structural biology and a potential new tool for drug design.
Opening the Door to Safer, More Precise Cancer Therapies
New method regulates when, and how strongly, cancer-killing therapeutic T cells are activated.
Biologists Find Unexpected Role for Amyloid-Forming Protein
Yeast protein could offer clues to how Alzheimer’s plaques form in the brain.
Revolutionary Gene-editing Technique to Stop AIDS Virus in Its Tracks
UNLV personalized medicine researchers seeking patent on potential HIV cure. Their technique uses a plant protein widely used in agriculture industry.
Viruses Join Fight Against Harmful Bacteria
Engineered viruses could combat human disease and improve food safety.
Tracking Changes in DNA Methylation In Real Time At Single-Cell Resolution
Whitehead Institute researchers have developed a methodology to monitor changes in DNA methylation over time in individual cells.
Virus Re-Engineered to Deliver Targeted Therapies
Researchers stripped a virus of its infectious machinery and turned its benign core into a delivery vehicle that can target sick cells while leaving healthy tissue alone.
Exposure to Pesticides In Childhood Linked to Cancer
Young children who are exposed to insecticides inside their homes may be slightly more at risk for developing leukemia or lymphoma during childhood, according to a meta-analysis by Harvard T.H. Chan School of Public Health researchers.

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
2,600+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos