Open AccessJournal Article
PTEN/MMAC1 Mutations in Endometrial Cancers
TLDR
Data indicate that PTEN/MMAC1 is more commonly mutated than any other known gene in endometrial cancers, and may be responsible for several familial neoplastic disorders.Abstract:
Endometrial carcinomas represent the most common gynecological cancer in the United States, yet the molecular genetic events that underlie the development of these tumors remain obscure Chromosome 10 is implicated in the pathogenesis of endometrial carcinoma based on loss of heterozygosity (LOH), comparative genomic hybridization, and cytogenetics Recently, a potential tumor suppressor gene, PTEN/MMAC1 , with homology to dual-specificity phosphatases and to the cytoskeletal proteins tensin and auxillin was identified on chromosome 10 This gene is mutated in several types of advanced tumors that display frequent LOH on chromosome 10, most notably glioblastomas Additionally, germ-line mutations of PTEN/MMAC1 are responsible for several familial neoplastic disorders, including Cowden disease and Bannayan-Zonana syndrome Because this locus is included in the region of LOH in many endometrial carcinomas, we examined 70 endometrial carcinomas for alterations in PTEN/MMAC1 Somatic mutations were detected in 24 cases (34%) including 21 cases that resulted in premature truncation of the protein, 2 tumors with missense alterations in the conserved phosphatase domain, and 1 tumor with a large insertion These data indicate that PTEN/MMAC1 is more commonly mutated than any other known gene in endometrial cancersread more
Citations
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New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway
TL;DR: A series of publications over the past year now suggest a mechanism by which PTEN loss of function results in tumors, and PTEN appears to negatively control the phosphoinositide 3-kinase signaling pathway for regulation of cell growth and survival by dephosphorylating the 3 position ofosphoinositides.
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Pten is essential for embryonic development and tumour suppression.
TL;DR: The notion that PTEN haploinsufficiency plays a causal role in CD, LDD and BZS pathogenesis is supported, and it is demonstrated that Pten is a tumour suppressor essential for embryonic development.
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The lipid phosphatase activity of PTEN is critical for its tumor supressor function
Michael P. Myers,I. Pass,Ian H. Batty,J. Van Der Kaay,Javor P. Stolarov,Brian A. Hemmings,Michael Wigler,C P Downes,Nicholas K. Tonks +8 more
TL;DR: It is reported that a missense mutation in PTEN, PTEN-G129E, which is observed in two Cowden disease kindreds, specifically ablates the ability of PTEN to recognize inositol phospholipids as a substrate, suggesting that loss of the lipid phosphatase activity is responsible for the etiology of the disease.
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Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems
Katrina Podsypanina,Lora Hedrick Ellenson,Adriana Nemes,Jianguo Gu,Masahito Tamura,Kenneth M. Yamada,Carlos Cordon-Cardo,Giorgio Catoretti,Peter E. Fisher,Ramon Parsons +9 more
TL;DR: Examination of peripheral lymphoid tissue including lymphoid aggregates associated with polyps revealed that the normal organization of B and T cells was disrupted in heterozygous animals, suggesting that PTEN is a regulator of apoptosis and proliferation that behaves as a "landscaper" tumor suppressor in the gut and a "gatekeeper" tumor suppressionor in other organs.
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The Biology and Clinical Relevance of the PTEN Tumor Suppressor Pathway
TL;DR: It is raised the possibility that drugs targeting these kinases, or PI3K itself, might have significant therapeutic activity in PTEN-null cancers and phase I and phase II trials of inhibitors of mTOR are underway.
References
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Journal ArticleDOI
PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer
Jing Li,Clifford Yen,Danny Liaw,Katrina Podsypanina,Shikha Bose,Steven I. Wang,Janusz Puc,Christa Miliaresis,Linda Rodgers,Richard W. McCombie,Sandra H. Bigner,Beppino C. Giovanella,Michael Ittmann,B. Tycko,Hanina Hibshoosh,Michael Wigler,Ramon Parsons +16 more
TL;DR: The PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions as discussed by the authors.
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Identification of a candidate tumour suppressor gene, MMAC1 , at chromosome 10q23.3 that is mutated in multiple advanced cancers
Peter A. Steck,Mark A. Pershouse,Samar A. Jasser,W. K. A. Yung,Huai Lin,Azra H. Ligon,Lauren A. Langford,Michelle Baumgard,T. Hattier,Thaylon Davis,Cheryl Frye,Rong Hu,Bradley D. Swedlund,David H. F. Teng,Sean V. Tavtigian +14 more
TL;DR: The results identify a strong candidate tumour suppressor gene at chromosome 10q23.3, whose loss of function appears to be associated with the oncogenesis of multiple human cancers.
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Inactivation of the Type II TGF-β Receptor in Colon Cancer Cells with Microsatellite Instability
Sanford D. Markowitz,Jing Wang,Lois Myeroff,Ramon Parsons,Lu Zhe Sun,James Lutterbaugh,Robert S. Fan,Elizabeth Zborowska,Kenneth W. Kinzler,Bert Vogelstein,Bert Vogelstein,Michael G. Brattain,James K V Willson +12 more
TL;DR: Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-beta receptor (RII) gene, which links DNA repair defects with a specific pathway of tumor progression.
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Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome
Danny Liaw,Deborah J. Marsh,Jing Li,Patricia L. M. Dahia,Steven I. Wang,Z. Zheng,Shikha Bose,K. M. Call,Hui C. Tsou,Monica Peacocke,Charis Eng,Ramon Parsons +11 more
TL;DR: Mutational analysis of PTEN in CD kindreds has identified germline mutations that are predicted to disrupt the protein tyrosine/dual-specificity phosphatase domain of this gene, and implies that PTEN may play a role in organizing the relationship of different cell types within an organ during development.
Journal Article
Replication Errors in Benign and Malignant Tumors from Hereditary Nonpolyposis Colorectal Cancer Patients
Lauri A. Aaltonen,Päivi Peltomäki,Jukka-Pekka Mecklin,Heikki Järvinen,Jeremy R. Jass,Jane Green,Henry T. Lynch,Patrice Watson,Gustav Tallqvist,Matti Juhola,Pertti Sistonen,Stanley R. Hamilton,Kenneth W. Kinzler,Bert Vogelstein,Albert de la Chapelle +14 more
TL;DR: The involvement of mismatch repair deficiency in the premalignant stage of tumorigenesis in HNPCC cases is suggested, and it is suggested that mismatch repair genes (MSH2 or others) are defective in the germline of nearly all these patients.