Mutation in the PTEN/MMAC1 gene in archival low grade and high grade gliomas

Davies, Michael; Gibbs, F. E. M.; Halliwell, Nigel; Joyce, Kathy A.; Roebuck, Margaret M.; Rossi, Marco; Salisbury, J; Sibson, D. Ross; Tacconi, Leonello; Walker, Carol

doi:10.1038/sj.bjc.6690246

Cited by 45 publications

(35 citation statements)

References 22 publications

(27 reference statements)

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“…These findings contrast with those in breast cancer, where 10q23 LOH has been associated with adverse prognostic factors, including higher stage, higher tumour grade, and loss of oestrogen receptors Garcia et al, 1999). In gliomas, the presence of PTEN mutations correlated with high tumour grade (Rasheed et al, 1997;Duerr et al, 1998;Davies et al, 1999;Zhou et al, 1999). However, among high-grade glioblastomas, in which the incidence of PTEN mutation is highest, PTEN mutations do not appear to influence overall survival (Zhou et al, 1999).…”

Section: Discussioncontrasting

confidence: 48%

“…Somatic mutations of PTEN have been found in sporadic tumours of the breast Chen et al, 1999;Freihoff et al, 1999), thyroid , head and neck Shao et al, 1998), central nervous system (Liu et al, 1997;Rasheed et al, 1997;Teng et al, 1997;Wang et al, 1997;Bostrom et al, 1998;Chiariello et al, 1998;Duerr et al, 1998;Maier et al, 1998;Davies et al, 1999;Zhou et al, 1999), endometrium (Kong et al, 1997;Risinger et al, 1997;Tashiro et al, 1997;Simpkins et al, 1998;Mutter et al, 2000;Yaginuma et al, 2000), ovary (Tashiro et al, 1997;Teng et al, 1997;Obata et al, 1998;Saito et al, 2000), prostate Dong et al, 1998;Gray et al, 1998;Pesche et al, 1998;Suzuki et al, 1998;Feilotter et al, 1999), kidney Alimov et al, 1999), lung (Kohno et al, 1998;Yokomizo et al, 1998), and in melanomas Tsao et al, 1998) and non-Hodgkins lymphomas (Gronbaek et al, 1998;Nakahara et al, 1998;Sakai et al, 1998;Butler et al, 1999;Dahia et al, 1999). Whether loss of PTEN function plays a role in the development of Barrett's oesophagusassociated adenocarcinoma (BOAd) is not known.…”

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confidence: 99%

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Allelic loss of 10q23, the PTEN tumour suppressor gene locus, in Barrett’s oesophagus-associated adenocarcinoma

et al. 2001

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Summary PTEN is a putative tumour suppressor gene located on chromosome band 10q23. Mutations in PTEN have been identified in numerous human malignancies, including cancers of the brain, endometrium, ovary, and prostate. In this study, we screened 80 Barrett's oesophagus-associated adenocarcinomas (BOAd) for loss of heterozygosity (LOH) at 10q23, using the microsatellite markers D10S541, D10S219, and D10S551. Tumours demonstrating LOH were then screened for the presence or absence of PTEN mutations. LOH at one or more loci was identified in 17/80 (21%) cases. In none of these cases did we detect mutations in PTEN. The presence of LOH did not correlate with patient age, tumour stage, degree of differentiation, presence of perineural or vascular invasion, or overall survival. We conclude that LOH at chromosome 10q23 is uncommon in BOAd, is not associated with mutations in the PTEN tumour suppressor gene, and does not correlate with the clinical or pathologic features of these tumours. It is possible that PTEN is inactivated through other mechanisms in BOAd. MATERIALS AND METHODS Study group80 patients who had en bloc oesophageal resection at the Brigham and Women's Hospital and at the Beth Israel-Deaconess Hospital between 1973 and 1995 were identified. All patients had histologically confirmed BOAd, and none had received preoperative chemotherapy or radiation. All patients were treated surgically with an intent to cure.Selected clinical information (patient age, gender) and followup data were obtained from review of the patient's hospital charts and the hospital tumour registry, or from direct telephone interviews with the patient and/or his/her family when necessary. Follow-up time was calculated from the date of initial diagnosis to either the date of death or, for the patients who were still alive, to the date of the most recent clinical investigation. In the survival analysis, either death or tumour recurrence was considered a failure (event). Patients alive without disease at last follow-up were censored in the analysis. Pathologic analysisAll oesophageal resection specimens were received in the surgical pathology laboratory in the fresh state and fixed in 10% buffered formalin for subsequent tissue sectioning. Tissue sections were processed routinely, embedded in paraffin, and stained with haematoxylin and eosin (H & E).The following microscopic features were evaluated in all cases by one of the authors (RDO): 1) Pathologic stage according to the 1993 revised AJCC TNM classification (Fleming et al, 1997); 2) The presence or absence of lymphovascular invasion; 3) The presence or absence of perineural invasion; 4) Degree of tumour differentiation (well, > 95% of the tumour composed of glands; moderate, 50-95% of the tumour composed of glands; poor, < 50% of the tumour composed of glands). Molecular analysisSections from paraffin-embedded tumour specimens were cut. Tumour and normal tissue were identified and separated by microdissection. DNA extraction was performed using the QIAprep kit (Qiagen Inc, Chatswo...

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Section: Discussioncontrasting

confidence: 48%

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confidence: 99%

Allelic loss of 10q23, the PTEN tumour suppressor gene locus, in Barrett’s oesophagus-associated adenocarcinoma

et al. 2001

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“…25,26 PTEN was mutated or deleted homozygously in glioma, endometrial, and breast carcinoma tumors. [27][28][29] It was reported that PTEN mutations were identified in small cell carcinomas, but not in non-small-cell carcinomas. 30,31 We found that the frequency of the loss of expression of PTEN was higher in high-grade neuroendocrine carcinoma than in classic large cell carcinoma or carcinoid tumor, and the differences were significant; however, the difference was not significant between large cell neuroendocrine carcinoma and small cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis

et al. 2006

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The distinction between pulmonary large cell neuroendocrine carcinoma and small cell carcinoma is difficult in some cases. Some propose that these carcinomas should be classified as one high-grade neuroendocrine carcinoma. We examined biological features of small cell carcinoma (n ¼ 23), large cell neuroendocrine carcinoma (n ¼ 17), and classic large cell carcinoma (n ¼ 12). The average ratio of nuclear diameter of the tumor cells to that of lymphocytes for small cell carcinoma was smaller than that for large cell neuroendocrine carcinoma (Po0.0001). The frequencies of the expressions of CD56, mASH1, TTF-1, and p16 were higher and that of NeuroD was lower in small cell carcinoma than in large cell neuroendocrine carcinoma. The frequency of loss of heterozygosity at 3p was higher in high-grade neuroendocrine carcinomas than in classic large cell carcinoma (P ¼ 0.0002). Allelic losses at D5S422 (5q33) were more frequent in small cell carcinoma than in large cell neuroendocrine carcinoma (P ¼ 0.0091). Mean fractional regional loss indices of the tumors were 0.38, 0.65, and 0.72 for patients with classic large cell carcinoma, large cell neuroendocrine carcinoma, and small cell carcinoma, respectively (P ¼ 0.0003). Five-year overall survivals of patients with classic large cell carcinoma, large cell neuroendocrine carcinoma and small cell carcinoma in stage I were 67, 73, 60%, respectively. Patients with NeuroD expression had better survivals, and those with p63 expression had poorer survivals in large cell neuroendocrine carcinoma. Patients with TTF-1 expression had poorer survivals in small cell carcinoma. Our data suggest that large cell neuroendocrine carcinoma and small cell carcinoma are different morphologically, phenotypically, and genetically, although there are some overlapping features. Although further studies are needed to analyze the biological behavior of high-grade neuroendocrine carcinomas including sensitivity to chemotherapy, the pathological distinction of large cell neuroendocrine carcinoma from small cell carcinoma may be necessary to treat the patients with neuroendocrine tumors.

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“…Clinical trials with tumstatin, therefore, might benefit from stratification of patients based on PTEN status. This type of stratification could easily be done in glioblastoma multiforme, only 30% of which exhibit PTEN alterations (45)(46)(47). Alternatively, the present work suggests that inhibition of the Akt/mTOR axis by agents, such as epidermal growth factor receptor inhibitors or rapamycin, might further sensitize tumors to the direct antitumor actions of T3.…”

Section: Discussionmentioning

confidence: 99%

The PTEN/Akt Pathway Dictates the Direct αVβ3-Dependent Growth-Inhibitory Action of an Active Fragment of Tumstatin in Glioma Cells In vitro and In vivo

et al. 2006

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The collagen type IV cleavage fragment tumstatin and its active subfragments bind to integrin A V B 3 and inhibit activation of focal adhesion kinase, phophoinositol-3 kinase, Akt, and mammalian target of rapamycin (mTOR) in what is thought to be an endothelial cell-specific manner. The resultant endothelial cell apoptosis accounts for the ability of tumstatin to function as an endogenous inhibitor of angiogenesis and an indirect suppressor of tumor growth. We hypothesized that the inability of tumstatin to directly suppress tumor cell growth might be the result of the constitutive activation of the Akt/mTOR pathway commonly seen in tumors. Consistent with this idea, several integrin A V B 3 -expressing glioma cell lines with PTEN mutations and high levels of phospho-Akt (pAkt) were unaffected by exposure to an active fragment of tumstatin (T3), whereas A V B 3 -expressing glioma cell lines with a functional PTEN/low levels of pAkt exhibited T3-induced growth suppression that could be bypassed by small interfering RNA-mediated suppression of PTEN, introduction of a constitutively expressed Akt, or introduction of the Akt and mTOR target eukaryotic translation initiation factor 4E. The direct tumor-suppressive actions of T3 were further shown in an A V B 3 -deficient in vivo mouse model in which T3, while unable to alter the tumstatininsensitive vasculature contributed by the A V B 3 -deficient host, nonetheless suppressed the growth and proliferative index of i.c. implanted A V B 3 -expressing PTEN-proficient glioma cells. These results show that tumstatin, previously considered to be only an endogenous inhibitor of angiogenesis, also directly inhibits the growth of tumors in a manner dependent on Akt/ mTOR activation. (Cancer Res 2006; 66(23): 11331-40)

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Mutation in the PTEN/MMAC1 gene in archival low grade and high grade gliomas

Cited by 45 publications

References 22 publications

Allelic loss of 10q23, the PTEN tumour suppressor gene locus, in Barrett’s oesophagus-associated adenocarcinoma

Allelic loss of 10q23, the PTEN tumour suppressor gene locus, in Barrett’s oesophagus-associated adenocarcinoma

Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis

The PTEN/Akt Pathway Dictates the Direct αVβ3-Dependent Growth-Inhibitory Action of an Active Fragment of Tumstatin in Glioma Cells In vitro and In vivo

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