Posted September 18, 2014
Tomas Walsh, Ph.D., University of Washington
For women who have inherited mutations in cancer predisposition genes such as BRCA1 or BRCA2, the risk of developing breast and/or ovarian cancer is greatly increased. BRCA1 and BRCA2 are genes responsible for repairing damaged DNA and helping to ensure the stability of a cell's genetic material. Recently, other genes involved in regulating DNA damage, such as BRIP1, RAD51C, and RAD51D, have also been implicated in genetic susceptibility to ovarian cancer.
Screening for these gene mutations has been a useful tool for preventing a subset of ovarian cancers, as women carrying these mutations can elect to have preventive surgery before the cancer develops. Even though women with known cancer predisposition gene mutations only account for a small subset of ovarian cancer cases, more individuals with ovarian cancer may have a strong family history of the disease in the absence of a known genetic mutation. Dr. Tomas Walsh, of the University of Washington, recipient of an FY09 OCRP Idea Development Award, sought to identify additional ovarian cancer-predisposing DNA repair genes that may be present in these high-risk families. To accomplish this, he used high-throughput, whole genome sequencing, looking at the sequence of the entire set of genes. Dr. Walsh identified five families with a strong history of breast and ovarian cancer that do not have any of the known cancer predisposition gene mutations and selected two members of each family with ovarian cancer for whole genome sequencing.
Dr. Walsh identified familial mutations in a gene called checkpoint kinase 1 (CHEK1), which coordinates the cellular DNA damage response and helps control cell division. He then screened large sets of other ovarian cancer samples and identified additional damaging CHEK1 mutations. These results suggest for the first time that CHEK1 may be a new ovarian cancer susceptibility gene. Further studies could lead to screening for CHEK1 mutations in high-risk families and may lead to the prevention of an additional subset of ovarian cancer.