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Mutação em NRAS causa uma síndrome autoimune linfoproliferativa humana; NRAS mutation causes a human autoimmune lymphoproliferative syndrome

Oliveira Filho, João Bosco de
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 21/08/2008 Português
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A subfamília p21 RAS de pequenas GTPases, incluindo KRAS, HRAS e NRAS, participa de muitas redes de sinalização, incluindo proliferação celular, organização do citoesqueleto e apoptose, e é o alvo mais freqüente de mutações ativadoras em câncer. Mutações germinativas em KRAS e HRAS causam graves anormalidades desenvolvimentais levando às síndromes de Noonan, cárdio-facial-cutânea e Costello, porem mutações ativadoras germinativas em NRAS não foram descritas até hoje. A síndrome autoimune linfoproliferativa (ALPS) é o mais comum defeito genético de apoptose linfocitária, cursando com autoimunidade e acúmulo excessivo de linfócitos, particularmente do tipo T + CD4- CD8-. As mutações causadoras de ALPS descritas até hoje afetam a apoptose mediada por Fas, uma das vias extrínsecas de apoptose. Nós demonstramos aqui que os principais achados clínicos de ALPS, bem como uma predisposição para tumores hematológicos, podem ser causados por uma mutação heterozigota ativadora G13D no oncogene NRAS, sem causar prejuízo na apoptose mediada por Fas. O aumento na quantidade intracelular de NRAS ativo, ligado a GTP, induziu a um aumento da sinalização na via RAF/MEK/ERK, o que suprimiu a expressão da proteína pró-apoptótica BIM...

NRAS mutation causes a human autoimmune lymphoproliferative syndrome

Oliveira, João B.; Bidère, Nicolas; Niemela, Julie E.; Zheng, Lixin; Sakai, Keiko; Nix, Cynthia P.; Danner, Robert L.; Barb, Jennifer; Munson, Peter J.; Puck, Jennifer M.; Dale, Janet; Straus, Stephen E.; Fleisher, Thomas A.; Lenardo, Michael J.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
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The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization, and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous, and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4−, CD8− αβ T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving TNF receptor superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling, which markedly decreases the proapoptotic protein BIM and attenuates intrinsic...

Oncogenic NRAS rapidly and efficiently induces CMML- and AML-like diseases in mice

Parikh, Chaitali; Subrahmanyam, Ramesh; Ren, Ruibao
Fonte: The American Society of Hematology Publicador: The American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 01/10/2006 Português
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Activating mutations in RAS, predominantly NRAS, are common in myeloid malignancies. Previous studies in animal models have shown that oncogenic NRAS is unable to induce myeloid malignancies effectively, and it was suggested that oncogenic NRAS might only act as a secondary mutation in leukemogenesis. In this study, we examined the leukemogenicity of NRAS using an improved mouse bone marrow transduction and transplantation model. We found that oncogenic NRAS rapidly and efficiently induced chronic myelomonocytic leukemia (CMML)– or acute myeloid leukemia (AML)– like disease in mice, indicating that mutated NRAS can function as an initiating oncogene in the induction of myeloid malignancies. In addition to CMML and AML, we found that NRAS induced mastocytosis in mice. This result indicates that activation of the RAS pathway also plays an important role in the pathogenesis of mastocytosis. The mouse model for NRAS leukemogenesis established here provides a system for further studying the molecular mechanisms in the pathogenesis of myeloid malignancies and for testing relevant therapies.

Palmitoylation of oncogenic NRAS is essential for leukemogenesis

Cuiffo, Benjamin; Ren, Ruibao
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 29/04/2010 Português
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Activating mutations of NRAS are common in acute myeloid leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndrome. Like all RAS proteins, NRAS must undergo a series of post-translational modifications for differential targeting to distinct membrane subdomains. Although farnesylation is the obligatory first step in post-translational modifications of RAS, to date, successes of therapies targeting farnesyl protein transferase are modest. Other RAS modifications, such as palmitoylation, are required for optimal plasma membrane association of RAS proteins. However, the relative importance of these latter modifications of RAS in leukemogenesis is not clear. We have previously shown that expression of oncogenic NRAS using a bone marrow transduction and transplantation model efficiently induces a chronic myelomonocytic leukemia- or acute myeloid leukemia-like disease in mice. Here we examined the role of palmitoylation in NRAS leukemogenesis using this model. We found that palmitoylation is essential for leukemogenesis by oncogenic NRAS. We also found that farnesylation is essential for NRAS leukemogenesis, yet through a different mechanism from that of palmitoylation deficiency. This study demonstrates, for the first time...

NRAS Mutations Are Rare in Colorectal Cancer

Irahara, Natsumi; Baba, Yoshifumi; Nosho, Katsuhiko; Shima, Kaori; Yan, Liying; Dias-Santagata, Dora; Iafrate, A. John; Fuchs, Charles S.; Haigis, Kevin M.; Ogino, Shuji
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/2010 Português
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Activating mutations in members of the RAS oncogene family (KRAS, HRAS and NRAS) have been found in a variety of human malignancies, suggesting a dominant role in carcinogenesis. In colon cancers, KRAS mutations are common and clearly contribute to malignant progression. The frequency of NRAS mutations and their relationship to clinical, pathologic, and molecular features remains uncertain. We developed and validated a Pyroseqencing assay to detect NRAS mutations at codons 12, 13 and 61. Utilizing a collection of 225 colorectal cancers from two prospective cohort studies, we examined the relationship between NRAS mutations, clinical outcome, and other molecular features, including mutation of KRAS, BRAF, and PIK3CA, microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP). Finally, we examined whether NRAS mutation was associated with patient survival or prognosis. NRAS mutations were detected in 5 (2.2%) of the 225 colorectal cancers and tended to occur in left-sided cancers arising in women, but did not appear to be associated with any of the molecular features that were examined.

Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis

Wilson, Todd M.; Maric, Irina; Simakova, Olga; Bai, Yun; Ching Chan, Eunice; Olivares, Nicolas; Carter, Melody; Maric, Dragan; Robyn, Jamie; Metcalfe, Dean D.
Fonte: Ferrata Storti Foundation Publicador: Ferrata Storti Foundation
Tipo: Artigo de Revista Científica
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Cooperating genetic events are likely to contribute to the phenotypic diversity of KIT-D816V systemic mastocytosis. In this study, 44 patients with KIT-D816V systemic mastocytosis were evaluated for coexisting NRAS, KRAS, HRAS or MRAS mutations. Activating NRAS mutations were identified in 2 of 8 patients with advanced disease. NRAS mutations were not found in patients with indolent systemic mastocytosis. To better understand the clonal evolution of mastocytosis, we evaluated the cell compartments impacted by the NRAS and KIT mutations. Clonal mast cells harbored both mutations. KIT-D816V was not detected in bone marrow CD34+ progenitors, whereas the NRAS mutation was present. These findings suggest that NRAS mutations may have the potential to precede KIT-D816V in clonal development. Unlike other mature lineages, mast cell survival is dependent on KIT and the presence of these two activating mutations may have a greater impact on the expansion of this cell compartment and in resultant disease severity. (Clinicaltrials.gov identifier: NCT00044122, NCT00001756)

Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose- and cell type-dependent manner

Wang, Jinyong; Liu, Yangang; Li, Zeyang; Wang, Zhongde; Tan, Li Xuan; Ryu, Myung-Jeom; Meline, Benjamin; Du, Juan; Young, Ken H.; Ranheim, Erik; Chang, Qiang; Zhang, Jing
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 14/07/2011 Português
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Both monoallelic and biallelic oncogenic NRAS mutations are identified in human leukemias, suggesting a dose-dependent role of oncogenic NRAS in leukemogenesis. Here, we use a hypomorphic oncogenic Nras allele and a normal oncogenic Nras allele (Nras G12Dhypo and Nras G12D, respectively) to create a gene dose gradient ranging from 25% to 200% of endogenous Nras G12D/+. Mice expressing Nras G12Dhypo/G12Dhypo develop normally and are tumor-free, whereas early embryonic expression of Nras G12D/+ is lethal. Somatic expression of Nras G12D/G12D but not Nras G12D/+ leads to hyperactivation of ERK, excessive proliferation of myeloid progenitors, and consequently an acute myeloproliferative disease. Using a bone marrow transplant model, we previously showed that ∼ 95% of animals receiving Nras G12D/+ bone marrow cells develop chronic myelomonocytic leukemia (CMML), while ∼ 8% of recipients develop acute T-cell lymphoblastic leukemia/lymphoma [TALL] (TALL-het). Here we demonstrate that 100% of recipients transplanted with Nras G12D/G12D bone marrow cells develop TALL (TALL-homo). Although both TALL-het and -homo tumors acquire Notch1 mutations and are sensitive to a γ-secretase inhibitor, endogenous Nras G12D/+ signaling promotes TALL through distinct genetic mechanism(s) from Nras G12D/G12D. Our data indicate that the tumor transformation potential of endogenous oncogenic Nras is both dose- and cell type-dependent.

Association of Activated c-Met with NRAS-Mutated Human Melanomas: A Possible Avenue for Targeting

Chattopadhyay, Chandrani; Ellerhorst, Julie A.; Ekmekcioglu, Suhendan; Greene, Victoria R.; Davies, Michael A.; Grimm, Elizabeth A.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Cutaneous melanomas can be divided into three mutually exclusive genetic subsets: tumors with mutated BRAF, tumors with mutated NRAS, and tumors wild type at both loci (wt/wt). Targeted therapy for melanoma has been advancing with agents directed to mutated BRAF, accounting for 50% of melanoma patients. The c-Met pathway is known to play a role in melanoma tumorigenesis and preliminary data from our laboratory suggested that this pathway is preferentially activated in NRAS-mutated tumors. The objective of this study was to test the hypothesis that melanomas carrying the mutated NRAS genotype are uniquely sensitively to c-Met inhibition, thus providing rationale for therapeutic targeting of c-Met in this patient cohort. Using primary human melanomas with known BRAF/NRAS genotypes, we observed greater immunostaining for phosphorylated (activated) c-Met in NRAS-mutated and wt/wt tumors, compared to BRAF-mutated tumors. NRAS-mutated and wt/wt cell lines also demonstrated more robust c-Met activation in response to hepatocyte growth factor (HGF). Knock-down of mutated N-Ras, but not wild type N-Ras, by RNA interference resulted in decreased c-Met phosphorylation. Compared to BRAF mutants, NRAS-mutated melanoma cells were more sensitive to pharmacologic c-Met inhibition in terms of c-Met activation...

NRAS Mutations in Noonan Syndrome

Denayer, E.; Peeters, H.; Sevenants, L.; Derbent, M.; Fryns, J.P.; Legius, E.
Fonte: S. Karger AG Publicador: S. Karger AG
Tipo: Artigo de Revista Científica
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Noonan syndrome is a genetically heterogeneous disorder caused by mutations in PTPN11, SOS1, RAF1 and less frequently in KRAS, NRAS or SHOC2. Here, we performed mutation analysis of NRAS and SHOC2 in 115 PTPN11, SOS1, RAF1, and KRAS mutation-negative individuals. No SHOC2 mutations were found, but we identified 3 NRAS mutations in 3 probands. One NRAS mutation was novel. The phenotype associated with germline NRAS mutations is variable. Our results confirm that a small proportion of Noonan syndrome patients carry germline NRAS mutations.

Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo

Posch, Christian; Moslehi, Homayoun; Feeney, Luzviminda; Green, Gary A.; Ebaee, Anoosheh; Feichtenschlager, Valentin; Chong, Kim; Peng, Lily; Dimon, Michelle T.; Phillips, Thomas; Daud, Adil I.; McCalmont, Timothy H.; LeBoit, Philip E.; Ortiz-Urda, Susana
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15–25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR1,2 inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR1,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR1,2 inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR1,2 inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways...

Inhibition of melanoma development in the Nras(Q61K)::Ink4a−/− mouse model by the small molecule BI-69A11

Feng, Yongmei; Lau, Eric; Scortegagna, Marzia; Ruller, Chelsea; De, Surya K; Barile, Elisa; Krajewski, Stan; Blanc, Pedro Aza; Williams, Roy; Pinkerton, Anthony B.; Jackson, Michael; Chin, Lynda; Pellecchia, Maurizio; Bosenberg, Marcus; Ronai, Ze’ev A.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Despite advances in developing specific inhibitors to BRAF mutant melanomas, to date there are no effective therapies for tumors bearing NRAS mutations, present in approximately 15–20% of human melanomas. Here, we extend earlier studies, demonstrating that the small molecule BI-69A11 inhibits the growth of melanoma cell lines in vitro and in vivo. Gene expression microarray analysis of BI-69A11-responsive melanoma cells revealed the induction of interferon- and cell death-related genes that were associated with responsiveness to BI-69A11. Strikingly, the administration of BI-69A11 inhibited melanoma development in genetically modified mice bearing an inducible form of activated Nras and a deletion of the Ink4a gene (Nras(Q61K)::Ink4a−/−). Biweekly administration of BI-69A11 starting at 10 weeks or as late as 24 weeks after the induction of mutant Nras expression inhibited melanoma development (100% and 36%, respectively). BI-69A11 treatment did not inhibit the development of histiocytic sarcomas, which comprise about 50% of the tumors in this model. Immunofluorescent staining analyses of CD45 revealed increased levels of immune cell infiltration in BI-69A11–treated tumors. Gene expression profiling of BI-69A11-resistant Nras(Q61K)::Ink4a−/− tumors revealed the upregulation of functional gene networks associated with the cytoskeleton...

Multiple Congenital Melanocytic Nevi and Neurocutaneous Melanosis Are Caused by Postzygotic Mutations in Codon 61 of NRAS

Kinsler, Veronica A; Thomas, Anna C; Ishida, Miho; Bulstrode, Neil W; Loughlin, Sam; Hing, Sandra; Chalker, Jane; McKenzie, Kathryn; Abu-Amero, Sayeda; Slater, Olga; Chanudet, Estelle; Palmer, Rodger; Morrogh, Deborah; Stanier, Philip; Healy, Eugene; Sebi
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Congenital melanocytic nevi (CMN) can be associated with neurological abnormalities and an increased risk of melanoma. Mutations in NRAS, BRAF, and Tp53 have been described in individual CMN samples; however, their role in the pathogenesis of multiple CMN within the same subject and development of associated features has not been clear. We hypothesized that a single postzygotic mutation in NRAS could be responsible for multiple CMN in the same individual, as well as for melanocytic and nonmelanocytic central nervous system (CNS) lesions. From 15 patients, 55 samples with multiple CMN were sequenced after site-directed mutagenesis and enzymatic digestion of the wild-type allele. Oncogenic missense mutations in codon 61 of NRAS were found in affected neurological and cutaneous tissues of 12 out of 15 patients, but were absent from unaffected tissues and blood, consistent with NRAS mutation mosaicism. In 10 patients, the mutation was consistently c.181C>A, p.Q61K, and in 2 patients c.182A>G, p.Q61R. All 11 non-melanocytic and melanocytic CNS samples from 5 patients were mutation positive, despite NRAS rarely being reported as mutated in CNS tumors. Loss of heterozygosity was associated with the onset of melanoma in two cases, implying a multistep progression to malignancy. These results suggest that single postzygotic NRAS mutations are responsible for multiple CMN and associated neurological lesions in the majority of cases.

Inhibition of Wee1, AKT and CDK4 underlies the efficacy of the HSP90 inhibitor XL888 in an in vivo model of NRAS mutant melanoma

Haarberg, H. Eirik; Paraiso, Kim H. T.; Wood, Elizabeth; Rebecca, Vito W.; Sondak, Vernon K.; Koomen, John M.; Smalley, Keiran S. M.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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The HSP90 inhibitor XL888 is effective at reversing BRAF inhibitor resistance in melanoma, including that mediated through acquired NRAS mutations. The present study has investigated the mechanism of action of XL888 in NRAS mutant melanoma. Treatment of NRAS mutant melanoma cell lines with XL888 led to an inhibition of growth, G2/M phase cell cycle arrest and the inhibition of cell survival in 3D spheroid and colony formation assays. In vitro, HSP90 inhibition led to the degradation of ARAF, CRAF, Wee1, Chk1 and cdc2 and was associated with decreased MAPK, AKT, mTOR and JNK signaling. Apoptosis induction was associated with increased BIM expression and a decrease in the expression of the pro-survival protein Mcl-1. The critical role of increased BIM and decreased Mcl-1 expression in the survival of NRAS mutant melanoma cell lines was demonstrated through siRNA knockdown and overexpression studies. In an animal xenograft model of NRAS mutant melanoma, XL888 treatment led to reduced tumor growth and apoptosis induction. Important differences in the pattern of client degradation were noted between the in vivo and in vitro studies. In vivo, XL888 treatment led to degradation of CDK4 and Wee1 and the inhibition of AKT/S6 signaling with little or no effect observed upon ARAF...

Bevacizumab-Based Treatment in Colorectal Cancer with a NRAS Q61K Mutation

Janku, Filip; Wheler, Jennifer J.; Hong, David S.; Kurzrock, Razelle
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Despite development of new therapies, metastatic colorectal cancer (mCRC) largely remains an incurable disease. Approximately 2–6% of colorectal cancers harbor NRAS mutations. The anti-VEGF antibody bevacizumab is a backbone of most therapeutic regimens; however, biomarkers predicting its activity are not known. We report two cases of mCRC with a Q61K NRAS mutation that had a favorable response to bevacizumab and the histone deacetylase inhibitor valproic acid. In contrast, none of 10 patients with wild-type NRAS or unknown NRAS status and mutated KRAS (NRAS and KRAS mutations are mutually exclusive) responded to the same regimen. These results suggest that NRAS mutation merits further investigation as a potential biomarker predicting the efficacy of bevacizumab-based treatment.

GAB2 induces tumor angiogenesis in NRAS-driven melanoma

Yang, Ying; Wu, Julia; Demir, Ahu; Castillo-Martin, Mireia; Melamed, Rachel D.; Zhang, Gao; Fukunaga-Kanabis, Mizuho; Perez-Lorenzo, Rolando; Zheng, Bin; Silvers, David N.; Brunner, Georg; Wang, Shuang; Rabadan, Raul; Cordon-Cardo, Carlos; Celebi, Julide
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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GAB2 is a scaffold protein with diverse upstream and downstream effectors. MAPK and PI3K signaling pathways are known effectors of GAB2. It is amplified and overexpressed in a variety of human tumors including melanoma. Here we show a previously undescribed role for GAB2 in NRAS-driven melanoma. Specifically, we found that GAB2 is co-expressed with mutant NRAS in melanoma cell lines and tumor samples and its expression correlated with metastatic potential. Co-expression of GAB2WT and NRASG12D in melanocytes and in melanoma cells increased anchorage independent growth by providing GAB2-expressing cells a survival advantage through upregulation of BCL-2 family of anti-apoptotic factors. Of note, collaboration of GAB2 with mutant NRAS enhanced tumorigenesis in vivo and led to an increased vessel density with strong CD34 and VEGFR2 activity. We found that GAB2 facilitiated an angiogenic switch by upregulating HIF-1α and VEGF levels. This angiogenic response was significantly suppressed with the MEK inhibitor PD325901. These data suggest that GAB2-mediated signaling cascades collaborate with NRAS-driven downstream activation for conferring an aggressive phenotype in melanoma. Second, we show that GAB2/NRAS signaling axis is non-linear and non-redundant in melanocytes and melanoma...

Low BRAF and NRAS expression levels are associated with clinical benefit from DTIC therapy and prognosis in metastatic melanoma

Birkeland, Einar; Busch, Christian; Berge, Elisabet Ognedal; Geisler, Jürgen; Jönsson, Göran; Lillehaug, Johan Richard; Knappskog, Stian; Lønning, Per Eystein
Fonte: Springer Netherlands Publicador: Springer Netherlands
Tipo: Artigo de Revista Científica
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Metastatic melanoma is characterized by a poor response to chemotherapy. Furthermore, there is a lack of established predictive and prognostic markers. In this single institution study, we correlated mutation status and expression levels of BRAF and NRAS to dacarbazine (DTIC) treatment response as well as progression-free and overall survival in a cohort of 85 patients diagnosed with advanced melanoma. Neither BRAF nor NRAS mutation status correlated to treatment response. However, patients with tumors harboring NRAS mutations had a shorter overall survival (p < 0.001) compared to patients with tumors wild-type for NRAS. Patients having a clinical benefit (objective response or stable disease at 3 months) on DTIC therapy had lower BRAF and NRAS expression levels compared to patients progressing on therapy (p = 0.037 and 0.003, respectively). For BRAF expression, this association was stronger among patients with tumors wild-type for BRAF (p = 0.005). Further, low BRAF as well as NRAS expression levels were associated with a longer progression-free survival in the total population (p = 0.004 and <0.001, respectively). Contrasting low NRAS expression levels, which were associated with improved overall survival in the total population (p = 0.01)...

Effectors of Epidermal Growth Factor Receptor Pathway: The Genetic Profiling of KRAS, BRAF, PIK3CA, NRAS Mutations in Colorectal Cancer Characteristics and Personalized Medicine

Shen, Yinchen; Wang, Jianfei; Han, Xiaohong; Yang, Hongying; Wang, Shuai; Lin, Dongmei; Shi, Yuankai
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 10/12/2013 Português
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Mutations in KRAS oncogene are recognized biomarkers that predict lack of response to anti- epidermal growth factor receptor (EGFR) antibody therapies. However, some patients with KRAS wild-type tumors still do not respond, so other downstream mutations in BRAF, PIK3CA and NRAS should be investigated. Herein we used direct sequencing to analyze mutation status for 676 patients in KRAS (codons 12, 13 and 61), BRAF (exon 11 and exon 15), PIK3CA (exon 9 and exon 20) and NRAS (codons12, 13 and 61). Clinicopathological characteristics associations were analyzed together with overall survival (OS) of metastatic colorectal cancer patients (mCRC). We found 35.9% (242/674) tumors harbored a KRAS mutation, 6.96% (47/675) harbored a BRAF mutation, 9.9% (62/625) harbored a PIK3CA mutation and 4.19% (26/621) harbored a NRAS mutation. KRAS mutation coexisted with BRAF, PIK3CA and NRAS mutation, PIK3CA exon9 mutation appeared more frequently in KRAS mutant tumors (P = 0.027) while NRAS mutation almost existed in KRAS wild-types (P<0.001). Female patients and older group harbored a higher KRAS mutation (P = 0.018 and P = 0.031, respectively); BRAF (V600E) mutation showed a higher frequency in colon cancer and poor differentiation tumors (P = 0.020 and P = 0.030...

Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes

Pedersen, Malin; Küsters-Vandevelde, Heidi V.N.; Viros, Amaya; Groenen, Patricia J.T.A.; Sanchez-Laorden, Berta; Gilhuis, Jacobus H.; van Engen- van Grunsven, Ilse A.; Renier, Willy; Schieving, Jolanda; Niculescu-Duvaz, Ion; Springer, Caroline J.; Küste
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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NRAS mutations are common in human melanoma. To produce a mouse model of NRAS-driven melanoma, we expressed oncogenic NRAS (NRASG12D) in mouse melanocytes. When NRASG12D was expressed in the melanocytes of developing embryos, it induced melanocyte proliferation and congenital melanocytic lesions reminiscent of human blue nevi, but did not induce cutaneous melanoma. Unexpectedly however, it did induce early onset primary melanoma of the central nervous system (CNS). The tumors were rapidly proliferating and caused neurological symptoms, rapid health deterioration and death. NRAS is not a common driver oncogene of primary melanoma of the CNS in adults, but we report two cases of primary melanoma of the CNS in children, both of which carried oncogenic mutations in NRAS. We conclude that acquisition of somatic mutations in NRAS in CNS melanocytes is a predisposing risk factor to primary melanoma of the CNS in children and present a mouse model of this disease.

Impact of NRAS Mutations on the Diagnosis of Follicular Neoplasm of the Thyroid

Bae, Ja-Seong; Choi, Seung Kyu; Jeon, Sora; Kim, Yourha; Lee, Sohee; Lee, Youn Soo; Jung, Chan Kwon
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
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Background. Most patients with a preoperative diagnosis of thyroid follicular neoplasm (FN) undergo diagnostic surgery to determine whether the nodule is benign or malignant. Point mutations at NRAS codon 61 are the most common mutations observed in FN. However, the clinical significance of NRAS mutation remains unclear. Methods. From 2012 to 2013, 123 consecutive patients undergoing thyroidectomy for FN were evaluated prospectively. Molecular analyses for NRAS codon 61 were performed with pyrosequencing. Results. The overall malignancy rate in FN was 48.8% (60/123). Of 123 FNs, 33 (26.8%) were positive for the NRAS mutation. The sensitivity, specificity, positive predictive value, and negative predictive value of a NRAS mutation-positive FN specimen to predict malignancy were 37%, 83%, 67%, and 58%, respectively. Patients with a NRAS-positive FN had a higher malignancy rate in additional thyroid nodules beyond the FN than patients with a NRAS-negative FN. The overall malignancy rate of patients with a NRAS-positive FN was significantly higher than that of patients with a NRAS-negative FN (79% versus 52%; P = 0.008). Conclusions. Determining NRAS mutation status in FN helps to improve the accuracy of thyroid cancer diagnosis and to predict cancer risk in accompanying thyroid nodules.

Determinación de mutaciones del gen NRAS en pacientes con cáncer colorrectal

Pardo Llama, Mikel
Fonte: Universidade de Cantabria Publicador: Universidade de Cantabria
Tipo: Dissertação de Mestrado
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El objetivo de este trabajo es identificar las mutaciones del gen NRAS en el ADN procedente de muestras de tejido de pacientes con cáncer colorrectal para verificar su relación con el mismo y con la respuesta a los tratamientos para esta patología.; Máster en Biología Molecular y Biomedicina