Researchers identify mutations that may drive serous endometrial cancer
Exome sequencing of serous endometrial cancer
- Date : 29 Oct 2012
- Topic : Gynaecologic malignancies
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 tumours. The findings appear in the October 28, 2012, advance online issue of Nature Genetics. The team was led by researchers from the USA National Human Genome Research Institute (NHGRI), part of the National Institutes of Health.
Each of its three major subtypes of endometrial cancer (endometrioid, serous and clear-cell) is caused by a different constellation of genetic alterations and has a different prognosis. Endometrioid tumours make up about 80% of diagnosed tumours. Compared to other subtypes, the 2 to 10% 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%, compared to 65% for clear-cell and 91% for endometrioid subtypes. Serous and clear-cell endometrial tumour subtypes are clinically aggressive and quickly advance beyond the uterus.
To determine which genes are altered in serous endometrial cancer, Dr. Daphne Bell, who heads the Reproductive Cancer Genetics Section of NHGRI's Cancer Genetics Branch and the paper's senior author, and her team undertook a comprehensive genomic study of tumours by sequencing their exomes, the critical 1 to 2% of the genome that codes for proteins.
The study pinpoints genetic alterations that may be essential for onset and progression of uterine cancers
Dr. Bell's team focused on the rarer, more aggressive forms of endometrial cancer. They began their study by examining serous tumour 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 Centre.
With the exome data in hand, the researchers filtered through millions of data points to locate mutations. They disqualified from the analysis any mutation found in a tumour and its matched healthy tissue, looking expressly for mutations that occurred exclusively in the tumour cells. They also eliminated one of the 13 tumours from analysis because its exome had hundreds more unique mutations than any other tumour.
The researchers detected more than 500 somatic mutations within the remaining 12 tumours. They next looked for genes that were mutated in more than one of the tumours. An alteration that occurs in more than one tumour is more likely to be relevant to the development of the cancer than a unique alteration.
One way to identify driver mutations is to home them in on genes that are mutated in more than one tumour, because from experience is known 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 tumours. 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% of the serous endometrial cancers and in 15 to 26% 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 remodelling, the dynamic process by which the contents of the cell nucleus, including DNA, are packaged and modified. Chromatin remodelling enables tightly packaged DNA to be accessed for the expression of genes. Intriguingly, CHD4 was one of the genes that formed the chromatin-remodelling cluster.
The researchers 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 tumours. 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. The researchers believe that altered SPOP may behave the same way. All the mutations they found in SPOP are in the region that binds the target proteins. They 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.
The findings are limited by the small number of tumours subjected to exome sequencing and it is too early to make a direct connection between findings and prospects for treatments for this aggressive form of uterine cancer.
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