June 5, 2002 DURHAM, N.C. -- In a study to be published in the June 6, 2002, issue of the journal Oncogene, researchers at Duke University Medical Center have identified the first gene known to be highly correlated to testicular cancer.
The gene, called hiwi, belongs to the piwi family of genes discovered in 1997 in the laboratory of Haifan Lin, Ph.D., an associate professor of cell biology at Duke and senior author of the new study in Oncogene, a science journal published by the Nature Publishing Group.
Lin's new research, which was funded by the National Institutes of Health, shows that 63 percent of men, who inherit the overactive form of the hiwi gene, could develop seminoma, which is a testicular cancer that originates from reproductive cells.
According to the National Cancer Institute, testicular cancer accounts for about 1 percent of all cancers in men. Testicular cancer is the most common form of cancer in Caucasian men between the ages of 15 and 45, Lin said.
Testicular tumors usually occur in reproductive cells, which are called germ cells. The tumors are usually malignant and are grouped into two main classes: seminoma and nonseminoma. Nonseminomas tend to be more aggressive than seminomas and in most cases, quickly spread to the lymph nodes.
Lin found that in seminomas, the reproductive stem cells expressed the hiwi gene at an unusually high rate. The cells then divided and multiplied at an equally high rate, which, Lin said, is an indication of the development of cancer. On the other hand, Lin suspects that an underactive or non-active hiwi gene can cause sterility in men because the same gene in drosophila and mice, called piwi and miwi, respectively, are known to cause sterility, said Lin who also is affiliated with Duke's Comprehensive Cancer Research Center.
The gene activity in the cancer samples was up to 16 times higher than that of a healthy patient. Although the patient sample size is small, the data is so overwhelmingly clear that the findings are considered statistically significant, Lin said.
"There are several other genes known to be associated with testicular cancer at very low frequencies (10 percent or lower). This is the first study to establish a high level correlation between a gene and seminoma," Lin said.
Although hiwi is the first gene known to be highly correlated to seminoma, scientists are close to identifying other genes suspected of playing a role in other testicular cancers. In February 2000, cancer researchers in the United Kingdom, announced they had located, but not yet identified, a gene on a region of chromosome X that is associated with testicular cancer. The gene, TGCT1, can increase a men's risk of testicular cancer by up to 50 times. Other researchers have located testicular cancer susceptibility to chromosome 19 in mice.
Lin's new research is based on testicular cancer samples from 35 patients in which 12 of 19 patients, or 63 percent of the sample size, expressed the hiwi gene in abnormally high levels. The hiwi gene was mapped to a region on the long arm of chromosome 12, which was previously linked by Lin's collaborators in the Netherlands to the development of seminomas and other testicular cancers.
Over-expression of the hiwi gene was not detected in nonseminomas. Nor was over-expression detected in spermatocytic seminomas, which are testicular tumors that originate from germ cells, but they are not malignant. Also, testicular tumors caused by over proliferation of the somatic cells, the non-reproductive cells in the testes, were not found to be correlated with the hyperactivity of the hiwi gene.
Lin attributes his recent discoveries to the use of Drosophila, or fruit flies, as a pioneering model for dissecting the genetic mechanism that controls stem cell division. Drosophila is a favorite organism of researchers in labs. Its genome is smaller -- only 12,000 genes compared to 30,000 to 40,0000 in humans -- and the genes are easier to manipulate in the lab, Lin said.
"Because of its small genome, Drosophila only has room for genes with essential biological functions, such as those that are important for stem cell production. So, by working with fruit flies, we have effectively narrowed down the search for important stem cell genes to one-third of the human genome, yet it's the most important one-third of the genome," Lin said.
In 1997, Lin and collaborators at Duke identified the first member of the family of genes called piwi, in Drosophila. The piwi genes, they learned, played a key role in stem cell division and in controlling the proliferation and differentiation of tissues. The loss of function of the piwi gene in fruit flies can deplete the reproduction of stem cells, resulting in sterility, Lin said. Over production of piwi can cause tumors in the reproductive systems of the fruit flies.
Lin's research group has since identified the same gene in nematodes (called prg's, which is short for "piwi related genes"); miwi in mice; and hiwi in humans. The piwi family is the only family of genes known to be required for stem cell function in to both animal and plant kingdoms. They also identified two previously identified genes in plants as a member of the piwi family: zwille and argonaute.
"Our research in Drosophila lead to the discovery of the human homologue, hiwi, and our work on piwi genes in Drosophila and later in mice lead to the understanding of hiwi function in humans. We suspected that abnormally overactive forms of these genes would probably lead to cancer, which is why did this most recent study. We could not have done this work if it were not for the research in Drosophila," Lin said.
In addition to learning more about the biology and genetics of testicular cancer, Lin's research could lead to genetic testing to predict the potential for developing seminoma. It also could lead to new treatments in affected individuals by genetically reprogramming the reproductive cells to multiply at safe levels to prevent seminomas. There is also the possibility of developing stem cell therapy to cure infertility due to defects in hiwi-related regulatory processes, Lin said.
### The study's co-authors include Dan Qiao, lead author of the paper and a post-doctoral fellow in cell biology at Duke University Medical Center (DUMC); Wei Deng, also of DUMC Department of Cell Biology; and Anne-Marie Zeeman and Leendert H.J. Looijenga of the University Hospital Rotterdam.
Other financial contributors for this study included the David and Lucile Packard Foundation of Los Altos, California, and the Dutch Cancer Society.
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