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 collect DNA samples and clinical data from prostate cancer families, with the goal of localizing and characterizing prostate cancer susceptibility genes. The candidate tumor suppressor gene PTEN (also called MMAC1) has recently been shown to be somatically altered in several common malignancies, including cancers of the brain, kidney, skin, thyroid, endometrium, breast, and prostate. Germ-line mutations in this gene, which maps to chromosome 10q23, have been associated with Cowden disease, an autosomal dominant cancer predisposition syndrome that is characterized by multiple hamartomas. Although prostate cancer is not typically associated with Cowden disease, previous studies of sporadic prostate cancers demonstrate loss of heterozygosity at 10q23 loci in approximately 25% of cases. We, therefore, hypothesized that germ-line mutations in the PTEN gene may predispose to prostate cancer in a subset of families, particularly those in which cancers of the breast, kidney, and/or thyroid also segregate. To test this hypothesis, DNA was isolated from whole blood of 11 prostate cancer patients from 10 unrelated families. Four of the 10 families met the previously established clinical criteria for hereditary prostate cancer. Eight of the II men had at least one second primary malignancy, including cases of neuroendocrine cancer, glioblastoma multiforme, melanoma, kidney, and thyroid cancer. Although we identified some common as well as some unique polymorphisms, no nonsense or missense mutations were identified in any of the 11 samples. To further examine the possibility 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 gene in these 10 men also revealed no mutations or novel polymorphisms. We conclude that germ-line mutations in the PTEN are unlikely to contribute in a significant way to the inherited predisposition to prostate cancer.

Similarities of cutaneous and breast pathology in Cowden's Syndrome.

Cowden's Syndrome (CS), or multiple hamartoma syndrome, is an autosomal dominant disorder characterized by mucocutaneous lesions, multiple benign tumors of internal organs and an increased risk of breast cancer. Here, we describe and illustrate in detail the benign breast pathology of 59 breast cases from 19 women with CS. Fibrosis is a significant characteristic of the breasts of patients with CS. Fibroadenomas appear to hyalinize at an early age and are frequently complex. The specimens demonstrate a spectrum of dense hyalinization of both the lobule and the stroma, and hyaline nodules appear to be the most characteristic lesion. This hyalinization process shares striking similarities with keloids, as well as the sclerotic nodules seen in the skin of CS individuals. Ductal carcinoma in CS was common, and it appeared to be associated with stromal hyalinization. Other frequently found benign features are adenosis and cysts. Of interest, the features of the benign breast disease in CS show certain similarities with senescent lobules, fibrous mastopathy of diabetes mellitus, and mammary hamartomas. These observations provide a framework for pathologists to identify this underrecognized syndrome.

The genetic basis of Cowden's syndrome: three novel mutations in PTEN/MMAC1/TEP1.

Cowden's syndrome (CS) is an autosomal dominant disorder associated with an increased risk of developing benign and malignant tumors in a variety of tissues, including the skin, thyroid, breast and brain. Women with CS are felt to have an increased risk of developing breast cancer, and virtually all women with CS develop bilateral fibrocystic disease of the breast. Recently, a series of germline mutations have been identified from CS families in a gene known as PTEN/MMAC1/TEP1. In this study, we used heteroduplex analysis and direct sequencing analysis and identified three novel germline mutations in the PTEN/MMAC1/TEP1 coding sequence from unrelated individuals with CS. We report a de novo transition (T-->C) at nucleotide 335 in exon 5. This missense mutation resulted in a leucine to proline (CTA to CCA) change at codon 112. We also describe a novel splice site mutation (801+2T-->G) in intron 7 that caused exon skipping in PTEN/MMAC1/TEP1 mRNA. The third mutation we report is a missense mutation, consisting of a transition (T-->C) at nucleotide 202 in exon 3, resulting in a tyrosine to histidine (TAC to CAC) change at codon 68. Finally, we also detected a rare polymorphism in exon 7 of the PTEN/MMAC1/TEP1 coding sequence. These data confirm the observation that mutations of the PTEN/MMAC1/TEP1 coding sequence are responsible for at least some cases of CS, and further define the spectrum of mutations in this autosomal dominant disorder.

Clinical and pathological features of breast disease in Cowden's syndrome: an underrecognized syndrome with an increased risk of breast cancer.

Cowden's syndrome (CS), or multiple hamartoma syndrome, is an autosomal dominant disorder associated with benign skin tumors and an increased risk of breast cancer. In an effort to understand the basic mechanisms regulating the development of breast cancer in this patient population, as well as to define diagnostic aspects of the disorder, we describe for the first time the clinical and pathological spectrum of breast disease in CS. We obtained the clinical histories and examined the histopathology of 59 cases from 19 women with CS sent to us from a variety of institutions. The 19 women showed a spectrum of benign histopathological findings, including ductal hyperplasia, intraductal papillomatosis, adenosis, lobular atrophy, fibroadenomas, and fibrocystic change. Seventeen (89%) showed features suggestive of a breast hamartoma. Fourteen women (74%) showed malignant disease, most of which was ductal carcinoma. Twelve patients (86%) showed ductal carcinoma in situ (DCIS), and 12 (86%) showed infiltrating ductal carcinoma. One patient had only DCIS and another patient showed both infiltrating tubular carcinoma and lobular carcinoma in situ. Ten patients (71%) actually showed foci of tumor involving densely fibrotic, hamartomatous areas. In summary, we show that women with CS have a spectrum of exuberant benign and malignant breast pathology. A common benign breast lesion in CS is a densely fibrotic hyalinized nodule, whereas the most frequent breast malignancy is ductal carcinoma.

The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases.

Cowden syndrome (CS) is an autosomal dominant disorder associated with the development of hamartomas and benign tumors in a variety of tissues, including the skin, thyroid, breast, endometrium, and brain. It has been suggested that women with CS are at increased risk for breast cancer. A locus for CS was recently defined on chromosome 10 in 12 families, resulting in the identification of the CS critical interval, between the markers D10S215 and D10S541. More recently, affected individuals in four families with CS have been shown to have germ-line mutations in a gene known as "PTEN," or "MMAC1," which is located in the CS critical interval on chromosome 10. In this study, we report three novel MMAC1 mutations in CS and demonstrate that MMAC1 mutations are associated with CS and breast cancer. Furthermore, we also show that certain families and individuals with CS do not have mutations in the coding sequence of MMAC1. Finally, we did not detect MMAC1 mutations in a subpopulation of individuals with early-onset breast cancer, suggesting that germ-line mutations in this gene do not appear to be common in this group.