The mutation causes a huge increase in testicular cancer incidence, from 5 percent to 94 percent. Although this dramatic rise was described in a mouse strain more than 30 years ago, it has taken until now for the identity of the gene itself to be discovered.
These results suggest that the Ter mutation may adversely affect essential aspects of primordial germ cell biology, and the authors explain that the work will have important implications for understanding of the genetic control of testicular germ cell tumors.
"Dead end is the earliest acting genetic defect that leads to these tumors," said Joseph Nadeau, Ph.D., a co-senior author of the paper and the Jewell Professor and Chair of Genetics at the Case Western Reserve University School of Medicine. "Interestingly, this defect causes these mice to develop tumors during fetal development. The mutation in the dead end gene increases susceptibility nearly 20 fold and is therefore one of the most potent inherited cancer genes," he said.
The researchers say that the gene appears to be involved in controlling RNA editing, which is a poorly understood process to change the RNA sequence in specific ways to build proteins.
"For the first time, we know the identity of one of the genes that controls inherited susceptibility. This gene and other functionally related genes might be used to diagnose at-risk individuals for more careful monitoring. And perhaps by understanding the role of RNA editing in the biology of the cancer stem cells we can develop improved therapeutics to treat and perhaps prevent these cancers,"said Nadeau.
"Our discovery also has implications for studies of stem cell biology. Many forms of testicular cancer, including the pediatric forms, originate from perhaps the most important stem cell, the primordial germ cell," he said.
Angabin Matin, Ph.D., the paper's other senior co-author and an assistant professor in the Department of Molecular Genetics at the University of Texas, MD Anderson Cancer Center in Houston, said, "Germ cell tumors arise from primordial germ cells, which become transformed into embryonal carcinoma cells (EC cells) before giving rise to the tumors. EC cells were observed to be pluripotent and have stem cell like properties in that they can be made to differentiate into many cell and tissue types and they have been used for this purpose before the derivation of embryonic stem cells (ES cells) directly from mouse embryos. The knowledge that loss of dead end allows EC cells to develop will provide clues as to how and why pluripotent cells arise."
Testicular cancer is the most common type of cancer among males between 15 to 30 years of age, and its incidence is increasing in western countries.
The researchers named the mutation Ter for teratoma, a form of testicular cancer.
The research institutions involved with the study are Case Western Reserve University's Department of Genetics, the Case Comprehensive Cancer Center, Duke University, University of Texas MD Anderson Cancer Center, NCI Frederick, and the Lawrence Berkeley National Laboratory.
Journal
Nature