Somatic mutations in the neurofibromatosis 1 gene in human tumors

Liu, Ying; Bollag, Gideon; Clark, Robin; Stevens, Jeff; Conroy, Leah; Fults, Dan; Ward, Ken; Friedman, Eitan; Samowitz, Wade S.; Robertson, Margaret; Bradley, Paige K.; McCormick, Frank; White, Ray; Cawthon, Richard M.

doi:10.1016/0092-8674(92)90408-5

Cited by 341 publications

(178 citation statements)

References 28 publications

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“…Specifically, colon cancer and myelodysplasias are not more frequent in NF1 patients than in the control population. 6 In analogy to the NF1 gene, mutations of the retinoblastoma gene are frequently seen in sporadic small-cell lung cancers (SCLCs), although SCLC does not have a higher incidence among hereditary retinoblastoma patients. 51,52 On the other hand, eg, astrocytomas, which harbor an inactivating NF1 mutation, are seen in higher incidence among NF1 patients.…”

Section: Discussionmentioning

confidence: 99%

“…In one report on bladder cancer, potential mutations of codon 1423 of the NF1 gene were studied. In this codon, mutations have previously been reported in certain malignancies, 6 but no mutations were observed in 31 bladder cancer specimens studied by Uchida et al 17 Neurofibromin contains a domain that is related to the GTPase-activating protein (GAP) and accelerates the inactivation of proto-oncogene ras in various cell types 18 and apparently interacts with microtubules. 19,20 Thus, neurofibromin is likely to function as a regulator of cell growth and differentiation.…”

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confidence: 98%

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Urinary Bladder Transitional Cell Carcinogenesis Is Associated with Down-Regulation of NF1 Tumor Suppressor Gene in Vivo and in Vitro

Aaltonen

Boström

Söderström

et al. 1999

The American Journal of Pathology

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The NF1 gene product (neurofibromin) is known to act as a tumor suppressor protein by inactivating ras. The best documented factors involved in urinary bladder transitional cell carcinoma (TCC) are ras proto-oncogene activation and p53 suppressor gene mutations. This is the first study reporting alterations in NF1 gene expression in TCC. We examined NF1 gene expression in a total of 29 surgical urinary bladder TCC specimens representing grades 1 to 3 and in three cell lines , RT4 , 5637 , and T24 (representing grades 1 to 3 , respectively). Decreased NF1 gene expression was observed in 23 of 29 (83%) TCC specimens as estimated by immunohistochemistry , the decrease being more pronounced in high-grade tumors. NF1 mRNA levels were markedly lower in TCC tissue compared with adjacent non-neoplastic urothelium, as studied by in situ hybridization for grade 3 TCC.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

Urinary Bladder Transitional Cell Carcinogenesis Is Associated with Down-Regulation of NF1 Tumor Suppressor Gene in Vivo and in Vitro

Aaltonen

Boström

Söderström

et al. 1999

The American Journal of Pathology

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“…Mutations that inactivate the NF1 gene have been found in a variety of sporadic (Li et al, 1992;Andersen et al, 1993;Johnson et al, 1993) and neuro®bromatosis associated tumors (Legius et al, 1993;Stiller et al, 1994;Shen et al, 1996), including neuro®brosarcoma, pheochromocytoma, astrocytoma, neuroblastoma, melanoma, colon carcinoma, chronic myeloid leukemia, acute lymphoblastic leukemia and non-Hodgkin lymphoma. In addition to being mutated in tumors, Ras and NF1 are able to interact and function in the same proliferative pathway, suggesting a possible cooperating e ect for the deregulation of these two proteins in tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

NF1 inactivation cooperates with N-Ras in in vivo lymphogenesis activating Erk by a mechanism independent of its Ras-GTPase accelerating activity

et al. 1998

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We crossed transgenic mice overexpressing the N-ras proto-oncogene (RasTg) with mice carrying one inactivated copy of the NF1 tumor suppressor gene (NF1+/ 7) to assess their possible cooperation in tumorigenesis. We have found a signi®cant increase in the incidence of lymphomas in animals with both lesions (RasTg NF1+/ 7), as compared with animals with single lesions. The mechanism of this cooperation appears to be independent of the NF1 GTPase activating activity since the level of Ras-GTP in primary cultures of tumor tissue do not di er among animals with double and with single lesions. Nevertheless, the ®nding of signi®cantly higher levels of Erk-1 and Erk-2 activation in lymphomas in the RasTg NF1+/7 than in the RasTg group suggests that this cooperative e ect may be in part explained by increased signaling through the Erk pathways. Consistent with a role for Erk activation in transformation is the additional observation that Erk-1 and Erk-2 activation is signi®-cantly increased in lymphomas as compared with normal spleen. This activation is likely to occur by phosphorylation of previously synthesized and inactive Erk proteins since, despite di erences in activation, Erk-1 and Erk-2 expression is similar in normal and lymphoid tissue in all groups. The observed cooperation in in vivo lymphomagenesis between N-ras overexpression and NF1 inactivation emphasizes the importance of searching for additional functions for the NF1 protein and of intensifying the screening for NF1 mutations in human lymphomas.

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“…No meningioma with a normal neurofibromin expression level and impaired GAP activity was found, suggesting that GRD of neurofibromin in these tumours was functionally intact. Therefore, it is likely that the inactivating mutations described in GRD of neurofibromin in other tumour types (Li et al, 1992) are absent or are rare in meningiomas.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, loss of function of GAPs to negatively regulate the activity of p21 ras might be important in the tumorigenesis process. Supporting this idea, mutations of the NFl gene and reduced neurofibromin expression and catalytic activity were described in NFl-associated tumours and sporadic tumours of various types (Li et al, 1992;von Deimling et al, 1995). Decreased expression of p120 GAP or its shorter placental isoform has been demonstrated in benign and malignant human trophoblastic tumours (Stahle-Backdhal et al, 1995).…”

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confidence: 91%

Reduced expression of neurofibromin in human meningiomas

Sundaram

Lee²,

Harwalkar³

et al. 1997

Br J Cancer

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Summary Meningiomas are common, mostly benign, tumours arising from leptomeningeal cells of the meninges, which frequently contain mutations in the neurofibromatosis type 2 (NF2) gene. In this study, we analysed a protein product of the neurofibromatosis type 1 (NF1) gene, neurofibromin, in human established leptomeningeal cells LTAg2B, in 17 sporadic meningiomas and in a meningioma from a patient affected by NF2. The expression level of neurofibromin was determined by immunoblotting and immunoprecipitation with anti-neurofibromin antibodies. The functional status of neurofibromin was analysed through its ability to stimulate the intrinsic GTPase activity of p21 ras. In the cytosolic extracts of four sporadic meningiomas and in the NF2-related meningioma, the expression level and the GTPase stimulatory activity of neurofibromin were drastically reduced compared with the level present in the human brain, human established leptomeningeal cells LTAg2B and the remaining 13 meningiomas. Our results suggest that neurofibromin is expressed in leptomeningeal cells LTAg2B and in most meningiomas, i.e. tumours derived from these cells. The reduced expression and GTPase stimulatory activity of neurofibromin was found in about 23% of meningiomas and in the single NF2-related meningioma analysed. These results suggest that decreased levels of neurofibromin in these tumours may contribute to their tumorigenesis.

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Somatic mutations in the neurofibromatosis 1 gene in human tumors

Cited by 341 publications

References 28 publications

Urinary Bladder Transitional Cell Carcinogenesis Is Associated with Down-Regulation of NF1 Tumor Suppressor Gene in Vivo and in Vitro

Urinary Bladder Transitional Cell Carcinogenesis Is Associated with Down-Regulation of NF1 Tumor Suppressor Gene in Vivo and in Vitro

NF1 inactivation cooperates with N-Ras in in vivo lymphogenesis activating Erk by a mechanism independent of its Ras-GTPase accelerating activity

Reduced expression of neurofibromin in human meningiomas

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