Absence of PTEN germ-line mutations in men with a potential inherited predisposition to prostate cancer

Epidemiological studies have demonstrated that men with a family history of prostate cancer are at an increased risk for this disease. This important observation has led a number of research teams, including our own, to colle ct DNA samples and clinical data from prostate cancer families, with the go al of localizing and characterizing prostate cancer susceptibility genes. T he candidate tumor suppressor gene PTEN (also called MMAC1) has recently be en shown to be somatically altered in several common malignancies, includin g cancers of the brain, kidney, skin, thyroid, endometrium, breast, and pro state. Germ-line mutations in this gene, which maps to chromosome 10q23, ha ve been associated with Cowden disease, an autosomal dominant cancer predis position syndrome that is characterized by multiple hamartomas, Although pr ostate cancer is not typically associated with Cowden disease, previous stu dies of sporadic prostate cancers demonstrate loss of heterozygosity at 10q 23 loci in similar to 25% of cases. We, therefore, hypothesized that germ-l ine mutations in the PTEN gene may predispose to prostate cancer in a subse t of families, particularly those in which cancers of the breast, kidney, a nd/or thyroid also segregate. To test this hypothesis, DNA was isolated fro m whole blood of 11 prostate cancer patients from 10 unrelated families. Fo ur of the 10 families met the previously established clinical criteria for hereditary prostate cancer. Eight of the 11 men had at least one second pri mary malignancy, including cases of neuroendocrine cancer, glioblastoma mul tiforme, melanoma, kidney, and thyroid cancer. Although we identified some common as well as some unique polymorphisms, no nonsense or missense mutati ons were identified in any of the 11 samples. To further examine the possib ility that PTEN mutations contribute to prostate cancer predisposition, we also studied the probands from each of 10 families with early-onset and/or multiple individuals with prostate cancer. Sequence analysis of the PTEN ge ne in these 10 men also revealed no mutations or novel polymorphisms. We co nclude that germ-line mutations in the PTEN are unlikely to contribute in a significant way to the inherited predisposition to prostate cancer.