" "
Satellite Banner
Genomics
Scientific Community
 
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 2,900+ scientific posters on ePosters
  • More than 4,200+ 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

Tick Genome Reveals Secrets of a Successful Bloodsucker
NIH-funded study could lead to new tick control methods.
Tuesday, February 09, 2016
Genomic Signature Shared by Five Types of Cancer
National Institutes of Health researchers have identified a striking signature in tumor DNA that occurs in five different types of cancer.
Monday, February 08, 2016
Cancer Drug Target Visualized at Atomic Resolution
New study using cryo-electron microscopy shows how potential drugs could inhibit cancer.
Thursday, February 04, 2016
Genome-Wide Study Yields Markers of Lithium Response
An international consortium of scientists has identified a stretch of chromosome that is associated with responsiveness to the mood-stabilizing medication lithium among patients with bipolar disorder.
Monday, February 01, 2016
Schizophrenia’s Strongest Known Genetic Risk Deconstructed
Suspect gene may trigger runaway synaptic pruning during adolescence – NIH-funded study.
Thursday, January 28, 2016
NIH Genome Sequencing Program Targets the Genomic Bases of Common, Rare Disease
The National Institutes of Health will fund a set of genome sequencing and analysis centers whose research will focus on understanding the genomic bases of common and rare human diseases.
Friday, January 15, 2016
Three Glaucoma-Related Genes Discovered
NIH-funded genetics analysis of glaucoma is largest to date.
Tuesday, January 12, 2016
International Study Reveals New Genetic Clues to AMD
NIH-funded research provides framework for future studies of AMD biology, therapy.
Tuesday, December 22, 2015
Dementia Linked to Deficient DNA Repair
Mutant forms of breast cancer factor 1 (BRCA1) are associated with breast and ovarian cancers but according to new findings, in the brain the normal BRCA1 gene product may also be linked to Alzheimer’s disease.
Tuesday, December 01, 2015
Batten Disease may Benefit from Gene Therapy
NIH-funded animal study suggests one-shot approach to injecting genes.
Friday, November 13, 2015
NIH Researchers Link Single Gene Variation to Obesity
Variation in the BDNF gene may affect brain’s regulation of appetite, study suggests.
Saturday, October 31, 2015
Researchers Identify Potential Alternative to CRISPR-Cas Genome Editing Tools
New Cas enzymes shed light on evolution of CRISPR-Cas systems.
Saturday, October 31, 2015
Potential Alternative to CRISPR-Cas Genome Editing Tools
New Cas enzymes shed light on evolution of CRISPR-Cas systems.
Friday, October 23, 2015
Charting Genetic Variation Across the Globe
An international team of scientists has created the world’s largest catalog of human genetic differences in populations around the globe.
Tuesday, October 20, 2015
Gene Therapy Staves Off Blindness from Retinitis Pigmentosa in Canine Model
NIH-funded study suggests therapeutic window may extend to later-stage disease.
Tuesday, October 20, 2015
Scientific News
Common Cell Transformed into Master Heart Cell
By genetically reprogramming the most common type of cell in mammalian connective tissue, researchers at the University of Wisconsin—Madison have generated master heart cells — primitive progenitors that form the developing heart.
Genetic Mutation that Prevents Diabetes Complications
The most significant complications of diabetes include diabetic retinal disease, or retinopathy, and diabetic kidney disease, or nephropathy. Both involve damaged capillaries.
Could the Food we Eat Affect Our Genes?
Almost all of our genes may be influenced by the food we eat, according to new research.
Neanderthal DNA Influences Human Disease Risk
Large-scale, evolutionary analysis compares genetic data alongside electronic health records.
Improving Regenerative Medicine
Lab-created stem cells may lack key characteristics, UCLA research finds.
Tick Genome Reveals Secrets of a Successful Bloodsucker
NIH has announced that decipher the genome of the blacklegged tick which could lead to new tick control methods.
"Dark Side" of the Transcriptome
New approach to quantifying gene "read-outs" reveals important variations in protein synthesis and has implications for understanding neurodegenerative diseases.
Individuals' Medical Histories Predicted by their Noncoding Genomes
Researchers have found that analyzing mutations in regions of the genome that control genes can predict medical conditions such as hypertension, narcolepsy and heart problems.
New Source of Mutations in Cancer
Recently, a new mutation signature found in cancer cells was suspected to have been created by a family of enzymes found in human cells called the APOBEC3 family.
Advancing Synthetic Biology
Living systems rely on a dizzying variety of chemical reactions essential to development and survival. Most of these involve a specialized class of protein molecules — the enzymes.
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
2,900+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,200+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!