Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cowden syndrome is an autosomal dominant condition of multiple hamartomas. Patients with this phakomatosis have an increased risk of breast cancer and thyroid tumours. Lhermitte-Duclos disease is usually a sporadic condition of cerebellar ganglion cell hypertrophy, ataxia, mental retardation, and self-limited seizure disorder. We describe a three generation family with Cowden syndrome and Lhermitte-Duclos disease. Karyotyping performed on the peripheral lymphocytes of the proband and her affected mother showed a 46,XX complement. Single strand conformational polymorphism analysis failed to show any germline p53 mutations as a cause of the syndrome in this family.
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PMID:Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy? 807 72

Cowden syndrome (CS) or multiple hamartoma syndrome (MIM 158350) is an autosomal dominant disorder with an increased risk for breast and thyroid carcinoma. The diagnosis of CS, as operationally defined by the International Cowden Consortium, is made when a patient, or family, has a combination of pathognomonic major and/or minor criteria. The CS gene has recently been identified as PTEN, which maps at 10q23.3 and encodes a dual specificity phosphatase. PTEN appears to function as a tumour suppressor in CS, with between 13-80% of CS families harbouring germline nonsense, missense, and frameshift mutations predicted to disrupt normal PTEN function. To date, only a small number of tumour suppressor genes, including BRCA1, BRCA2, and p53, have been associated with familial breast or breast/ovarian cancer families. Given the involvement of PTEN in CS, we postulated that PTEN was a likely candidate to play a role in families with a "CS-like" phenotype, but not classical CS. To answer these questions, we gathered a series of patients from families who had features reminiscent of CS but did not meet the Consortium Criteria. Using a combination of denaturing gradient gel electrophoresis (DGGE), temporal temperature gel electrophoresis (TTGE), and sequence analysis, we screened 64 unrelated CS-like subjects for germline mutations in PTEN. A single male with follicular thyroid carcinoma from one of these 64 (2%) CS-like families harboured a germline point mutation, c.209T-->C. This mutation occurred at the last nucleotide of exon 3 and within a region homologous to the cytoskeletal proteins tensin and auxilin. We conclude that germline PTEN mutations play a relatively minor role in CS-like families. In addition, our data would suggest that, for the most part, the strict International Cowden Consortium operational diagnostic criteria for CS are quite robust and should remain in place.
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PMID:Germline PTEN mutations in Cowden syndrome-like families. 983 31

Germline mutations of the TP53 tumor suppressor gene account for the predisposition to cancer observed in many Li-Fraumeni syndrome (LFS) families. A causative genetic factor in the remaining families that harbor no TP53 mutations remains to be elucidated. The PTEN phosphatase tumor suppressor gene is mutated in human cancers observed in LFS. There also exists some phenotypic overlap in the occurrence of cancers in LFS and Cowden's disease (CD), for which germline PTEN mutations are believed to be responsible. We hypothesized that PTEN may be altered in some TP53-wild-type LFS families. We examined LFS primary patient lymphocytes for PTEN alterations using SSCP and sequence analysis. A novel intronic deletion was found in two unrelated individuals, adjacent to the splice acceptor site of PTEN exon 4. Based on an in vitro mRNA processing assay this alteration is predicted to be a polymorphism. The in vivo effects of this proximal splice site deletion are unknown and a genetic cause for the cancers in these families remains to be elucidated. Germline mutations of PTEN were not detected in other families, suggesting that alterations of this tumor suppressor gene do not account for the cancers observed in the subset of LFS individuals with wild-type germline TP53.
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PMID:Identification of a novel PTEN intronic deletion in Li-Fraumeni syndrome and its effect on RNA processing. 1112 Mar 38

Assessing the risk of breast and ovarian cancer starts with obtaining a complete and accurate family history. This can reveal evidence of inherited cancer risk. The highest risk of cancer is associated with germ-line abnormalities in several genes, including BRCA1, BRCA2, and TP53. Moderate-risk genes associated with syndromes that are inherited in an autosomal dominant pattern (such as Cowden's disease, hereditary non-polyposis colorectal cancer, Muir-Torre syndrome, and Peutz-Jeghers syndrome) exhibit lower penetrance and thus less risk of breast and/or ovarian cancer. Low-risk genes likely require significant environmental exposure, and although they are associated with the lowest risk of cancer, they account for more cancer than high- and moderate-risk genes. Lifetime risks for breast or ovarian cancer can be estimated. The Gail and Claus models, the more widely utilized models for calculation of lifetime breast cancer risk, are discussed. Models are also available for determining the likelihood of finding a BRCA1/2 mutation (the BRCAPRO and Myriad models). Appropriate candidates for testing include affected individuals who are most likely to have a hereditary form of cancer. Testing should proceed only after a thorough discussion of the risks, benefits, and limitations of testing. Risk-reducing options are available to women with a strong family history of breast and ovarian cancer. These options include high-risk screening, chemoprevention, and prophylactic surgery.
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PMID:Risk of breast and ovarian cancer in women with strong family histories. 1149 90

Germline mutations of the PTEN tumor-suppressor gene, on 10q23, cause Cowden syndrome, an inherited hamartoma syndrome with a high risk of breast, thyroid and endometrial carcinomas and, some suggest, melanoma. To date, most studies which strongly implicate PTEN in the etiology of sporadic melanomas have depended on cell lines, short-term tumor cultures and noncultured metastatic melanomas. The only study which reports PTEN protein expression in melanoma focuses on cytoplasmic expression, mainly in metastatic samples. To determine how PTEN contributes to the etiology or the progression of primary cutaneous melanoma, we examined cytoplasmic and nuclear PTEN expression against clinical and pathologic features in a population-based sample of 150 individuals with incident primary cutaneous melanoma. Among 92 evaluable samples, 30 had no or decreased cytoplasmic PTEN protein expression and the remaining 62 had normal PTEN expression. In contrast, 84 tumors had no or decreased nuclear expression and 8 had normal nuclear PTEN expression. None of the clinical features studied, such as Clark's level and Breslow thickness or sun exposure, were associated with cytoplasmic PTEN expressional levels. An association with loss of nuclear PTEN expression was indicated for anatomical site (p = 0.06) and mitotic index (p = 0.02). There was also an association for melanomas to either not express nuclear PTEN or to express p53 alone, rather than both simultaneously (p = 0.02). In contrast with metastatic melanoma, where we have shown previously that almost two-thirds of tumors have some PTEN inactivation, only one-third of primary melanomas had PTEN silencing. This suggests that PTEN inactivation is a late event likely related to melanoma progression rather than initiation. Taken together with our previous observations in thyroid and islet cell tumors, our data suggest that nuclear-cytoplasmic partitioning of PTEN might also play a role in melanoma progression.
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PMID:Nuclear PTEN expression and clinicopathologic features in a population-based series of primary cutaneous melanoma. 1194 93

Not since the discovery of p53 has another molecule received as much attention as PTEN. In the 5 years since the discovery of PTEN, encoding a dual specificity phosphatase tumor suppressor on 10q23, it has been shown to be a susceptibility gene for an inherited cancer syndrome, Cowden syndrome, and for several developmental disorders; it has been shown to play a prominent role in normal murine and human development; and it has been shown to be instrumental in cell cycle arrest, apoptosis, and/or possibly cell migration and cytoskeletal affairs. Initial work on cancer cell lines had suggested that PTEN caused every type of cancer because it was reported that a relatively high frequency of a variety of cancer cell lines, whether derived from solid tumors or hematological malignancies, had homozygous or compound heterozygous genetic alterations involving PTEN. Such data, together with the germ-line human and murine model data, suggested that PTEN mutations occurred "early" in sporadic tumorigenesis. However, subsequent painstaking work in noncultured primary tumors and in careful in vitro overexpression studies over the last 4 years demonstrated that the mechanism of PTEN inactivation can be varied and might be cell type dependent. Furthermore, apart from sporadic endometrial carcinoma, PTEN alteration in noncultured sporadic neoplasias likely occurs "late," promoting progression and metastasis. The article by Davies et al. (Clin Cancer Res., 8: 1904-1914, 2002) sheds light on all of these issues when they report on data that derive from a "triple threat" strategy, i.e., in vitro, in vivo, and ex vivo, to demonstrate that adenoviral infection of PTEN into PTEN-null PC3 prostate cancer cell lines results in decreased metastatic potential without significantly altering tumor size via the predominant mechanism of G(1) cell cycle arrest but not apoptosis.
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PMID:The expanding role of PTEN in neoplasia: a molecule for all seasons? Commentary re: M. A. Davies, et al., Adenoviral-mediated expression of MMAC/PTEN inhibits proliferation and metastasis of human prostate cancer cells. Clin. Cancer Res., 8: 1904-1914, 2002. 1206 Jun 35

We report a 54-year-old woman with Cowden's disease (CD) who was found to carry a novel germline mutation in the PTEN gene. The mutation (c.334C-->G) introduced a splice donor site within exon 5 that caused the expression of an aberrant transcript lacking 159 nucleotides corresponding to codons 112-164. Clinically, the patient showed multiple benign hamartomatous lesions of the skin, papillomatosis of the lips and oral mucosa, polyposis coli and bilateral fibrocystic disease of the breast. In addition, she developed different types of malignant neoplasms, including bilateral carcinomas of the breast and malignant melanomas of the skin. Molecular genetic analysis of a benign skin hamartoma and an invasive ductal breast carcinoma revealed loss of heterozygosity (LOH) at microsatellite markers on chromosome 10 in the carcinoma but not in the hamartoma. The breast carcinoma additionally carried a somatic TP53 point mutation (c.466C-->G; R156G) that was associated with LOH on 17p and nuclear p53 protein accumulation. Taken together, our findings indicate that benign hamartomas in CD may develop without loss of the second (wild-type) PTEN allele, whereas the pathogenesis of malignant tumours, such as breast carcinomas, appears to require the complete inactivation of Pten as well as further alterations such as the loss of p53-dependent growth control.
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PMID:Cowden's disease: clinical and molecular genetic findings in a patient with a novel PTEN germline mutation. 1278 40

New insights into the genetic basis of carcinogenesis have been obtained by modern molecular biological techniques. Several susceptibility genes are known. The hereditary breast and ovarian cancer syndrome (germline mutations in BRCA1 and BRCA2) and endometrial cancer in the context of the hereditary non-polyposis colorectal cancer syndrome (HNPCC), germline mutations in mismatch-repair genes, are the most frequent hereditary cancer syndromes in gynaecology. Mutations in TP53 (Li-Fraumeni syndrome) and PTEN (Cowden's disease), associated with increased risk of breast cancer, are responsible for a smaller portion of familial breast cancer. The risk of inheritance and disease can be identified and defined by investigating family history, risk calculation programs, and genetic testing. Afterwards, options of primary, secondary, and tertiary prevention can be formulated. Presently, prophylactic surgery is the only option proven by clinical trials that can reduce the mortality of hereditary breast and ovarian cancer.
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PMID:[Prophylactic surgery of mammary and ovarian carcinoma]. 1623 64

PTEN (phosphatase and tensin homologue, deleted on chromosome 10) is a tumor suppressor with dual phosphatase activity and mutations of its gene, PTEN, have been associated with many sporadic cancers and heritable neoplasia syndromes, including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. However, accumulating evidence now shows that PTEN may have novel functions other than as a phosphatase. In the present study, we show that PTEN is able to autoregulate its expression through the stabilization of another tumor suppressor p53. We further show that PTEN enhances p53 transactivation, a relationship that requires the interaction between PTEN and p53 and is PTEN phosphatase independent. We show that cell lines from Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients with germ line PTEN promoter mutations in the vicinity of the p53-binding motifs have altered p53 regulation. This seems to be due to reduced PTEN stability and decreased PTEN-p53 interactions. Our data provide clues to better understand the regulation of PTEN expression and the possible mechanisms of the pathogenesis of the subset of Cowden syndrome individuals with germ line promoter variation and who lack mutations in the PTEN coding region and splice sites. Importantly, this mechanism also holds for those sporadic tumors that lack intragenic mutations but have hemizygous deletion of PTEN, which includes the promoter region as manifested by loss-of-heterozygosity of 10q markers. The importance of our observations is underlined by the broad spectrum of neoplasias that harbor somatic PTEN or p53 alterations, or both.
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PMID:PTEN autoregulates its expression by stabilization of p53 in a phosphatase-independent manner. 1642 3

PTEN, a dual-phosphatase tumor suppressor, is inactivated in Cowden syndrome (CS), characterized by high risk of breast and thyroid cancer, and in variety of sporadic cancers. Despite the importance of alternative splicing, very limited information on its role in PTEN and associated cancers is available. We identified eight novel PTEN splice variants (SVs) that retained intron 3 regions (3a, 3b, 3c); intron 5 regions (5a, 5b, 5c); excluded part of exon 5 (DelE5) or all of exon 6 (DelE6), respectively. Analysis of SVs in 12 sporadic breast cancers revealed full-length (FL)-PTEN transcript reduction in 10; SVs 3b, 3c and 5c not expressed in 7, 6 and 4, respectively, and under-expressed in the rest. In contrast, SV-5b was over-expressed in breast cancers. PTEN SV analysis in 16 CS/CS-like patients and eight controls revealed that SV-5a is under-expressed and SV-3a over-expressed in the germline of CS/CS-like individuals when compared with controls. Although SV-5a expression decreased P-Akt level and cyclin D1 promoter activity, SVs 5b and 5c increased cyclin D1 promoter activity. Thus, SV-5a behaving like FL-PTEN corroborates our observation that SV-5a is under-expressed in CS when compared with controls. Similarly, SV-5b functionally counters PTEN's action and is over-expressed in sporadic breast cancers. Furthermore, we demonstrate that expression of these SVs is under the regulation of p53. Our observations suggest that differential expression of PTEN and its SVs could play a role in the pathogenesis of sporadic breast cancers and CS, and may lend a novel way of making a rapid molecular diagnosis of CS without mutation analysis.
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PMID:Differential expression of novel naturally occurring splice variants of PTEN and their functional consequences in Cowden syndrome and sporadic breast cancer. 1643 56


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