Second gene linked to familial testicular cancer

Specific variations or mutations in a particular can gene raise a man's risk of familial, or inherited, testicular germ-cell cancer, the most common form of this disease, according to new research by scientists at the National Institutes of Health. This is only the second gene to be identified that affects the risk of familial testicular cancer, and the first gene in a key biochemical pathway. The study appears in the July 2009 Cancer Research.

Researchers have suspected for years that heredity plays a role in some patients with testicular germ-cell cancer, although attempts to identify a single gene with very strong effects have been unsuccessful thus far. Scientists currently believe that multiple genes with weaker individual effects-but acting together-probably influence an individual's risk of familial testicular cancer.

Men with a family member who had a testicular germ cell cancer are at three-to six-fold greater risk than other men of developing testicular cancer. Although a family history of testicular cancer probably accounts for less than five percent of all testicular cancers, the careful study of rare familial cancer clusters has often led to important new understanding of the non-familial versions of the same cancer. There will be an estimated 8,400 new cases of testicular cancer diagnosed in 2009 with about 90 percent of them being germ-cell cancers, according to the National Cancer Institute (NCI).

"This study contributes to our understanding of why testicular germ cell cancer appears to run in families," said Raynard Kington, M.D., Acting NIH Director. "The findings may also lead to new ways to identify men at high risk, as well as more effective ways to prevent and treat testicular germ cell cancer."

The key pathway in this disease is the cyclic AMP pathway, which regulates how cells respond to such signals as hormones. Drugs that affect the cyclic AMP pathway are widely available, and, in theory, could affect progression of testicular cancer.

In this study, Anelia Horvath, Ph.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), performed the laboratory research and Larissa Korde, M.D., NCI, led the clinical cancer genetics study which identified the multiple-case testicular cancer families used for the DNA analysis. The NICHD and NCI are parts of NIH.

The researchers found that seven different mutations in the gene in question, PDE11A, created abnormal versions of the PDE11A enzyme that slowed down the enzyme's destruction of cyclic AMP.

"The mutations don't cause cancer directly, but instead appear to increase an individual's susceptibility to developing a tumor," explained the study's senior author, Constantine Stratakis, M.D., D.Sc., chief of NICHD's Section on Endocrinology and Genetics. "Almost one out of every five families we studied had a variation in the gene that affected its functioning."