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 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.