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 i
|Contact: Raymond MacDougall|
NIH/National Human Genome Research Institute