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‣ KRAS gene mutations in Noonan syndrome familial cases cluster in the vicinity of the switch II region of the G-domain: Report of another family with metopic craniosynostosis

Brasil, Amanda S.; Malaquias, Alexsandra C.; Kim, Chong A.; Krieger, Jose Eduardo; Jorge, Alexander A. L.; Pereira, Alexandre C.; Bertola, Debora R.
Fonte: WILEY-BLACKWELL; MALDEN Publicador: WILEY-BLACKWELL; MALDEN
Tipo: Artigo de Revista Científica
Português
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Noonan syndrome (NS) and Noonan-related disorders [cardio-facio-cutaneous (CFC), Costello, Noonan syndrome with multiple lentigines (NS-ML), and neurofibromatosis-Noonan syndromes (NFNS)] are a group of developmental disorders caused by mutations in genes of the RAS/MAPK pathway. Mutations in the KRAS gene account for only a small proportion of affected Noonan and CFC syndrome patients that present an intermediate phenotype between these two syndromes, with more frequent and severe intellectual disability in NS and less ectodermal involvement in CFC syndrome, as well as atypical clinical findings such as craniosynostosis. Recently, the first familial case with a novel KRAS mutation was described. We report on a second vertical transmission (a mother and two siblings) with a novel mutation (p.M72L), in which the proband has trigonocephaly and the affected mother and sister, prominent ectodermal involvement. Metopic suture involvement has not been described before, expanding the main different cranial sutures which can be affected in NS and KRAS gene mutations. The gene alteration found in the studied family is in close proximity to the one reported in the other familial case (close to the switch II region of the G-domain), suggesting that this specific region of the gene could have less severe effects on intellectual ability than the other KRAS gene mutations found in NS patients and be less likely to hamper reproductive fitness. (c) 2012 Wiley Periodicals...

‣ Investigação das quinases Aurora A e Aurora B como potenciais alvos terapêuticos no câncer de pulmão induzido pelo oncogene KRAS; Investigation of Aurora A and Aurora B kinases as potential targets in KRAS-induced lung cancer

Santos, Edmilson Ozorio dos
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 27/11/2013 Português
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As alterações genéticas mais frequentes em tumores de pulmão são mutações pontuais que ativam o oncogene KRAS. Apesar destas mutações estarem ligadas à oncogênese de forma causal, diferentes abordagens para inibir as proteínas RAS diretamente fracassaram na clínica. Portanto, para que melhores alvos terapêuticos para o câncer de pulmão se tornem disponíveis, será necessário identificar as vias sinalizadoras ativadas pela proteína KRAS, que são críticas para a oncogênese. O objetivo deste projeto foi identificar novos alvos terapêuticos na oncogênese pulmonar induzida pela KRAS. Este projeto se baseou na seguinte hipótese: (1) a KRAS oncogênica leva à ativação das quinases mitóticas Aurora A e/ou B e (2) que as quinases Aurora A e/ou B são alvos terapêuticos relevantes no câncer de pulmão induzido pelo oncogene KRAS. Esta hipótese foi formulada com base em estudos anteriores mostrando que a quinase Aurora A fosforila diretamente componentes das vias efetoras de RAS, e que a Aurora A e Aurora B cooperam com a RAS oncogênica na transformação maligna. Para testar esta hipótese, nós inicialmente determinamos se a forma oncogênica da KRAS induz a expressão das quinases Aurora A e B. Para tanto, nós usamos 3 modelos celulares: (1) uma linhagem primária epitelial pulmonar imortalizada e seu par isogênico transformado pela KRAS oncogênica; (2) células tumorais pulmonares H1703 manipuladas geneticamente para expressar a forma oncogênica da KRAS de forma induzível; e (3) células de adenocarcinoma pulmonar portadoras de mutações oncogênicas em KRAS H358 e A549 manipuladas geneticamente para expressar short hairpin RNAs (shRNAs) para KRAS de forma induzível. Em todos os casos...

‣ Identificação de micrornas diferencialmente expressos em células pulmonares e pancreáticas transformadas pelo oncogene KRAS; Identification of microRNAs regulated by oncogenic KRAS in lung and pancreatic cancer

Aoki, Mateus Nóbrega
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 04/07/2014 Português
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As neoplasias induzidas pela forma oncogênica da KRAS são doenças muito comuns, para as quais não existem terapias efetivas. Uma inibição direta da KRAS falhou em ensaios clínicos e esforços intensos tem sido feitos para identificar alvos de KRAS importantes para a oncogênese. Uma via promissora regulada por KRAS, que tem sido pouco explora a é a via dos microRNAs (miRNAs). Nossa meta foi identificar miRNAs regulados pela KRAS em células pulmonares e pancreáticas, que possam contribuir para o fenótipo oncogênico. Para alcançar esta meta nós usamos duas abordagens: (1) Nós investigamos o miRNA 486-5p como um alvo de KRAS em câncer de pâncreas e de pulmão. A expressão deste miRNA havia sido correlacionada positivamente com a presença de mutações em KRAS em pacientes portadores de câncer de cólon; (2) Nós usamos uma plataforma de microarranjo para identificar miRNAs diferencialmente expressos entre células humanas primárias imortalizadas pulmonares ou pancreáticas e suas linhagens isogênicas transformadas por KRAS. Na primeira abordagem, conseguimos mostrar que a expressão do miRNA 486-5p está correlacionada ao status de KRAS em células primárias pulmonares, mas não em células primárias pancreáticas. Além disso...

‣ KRAS insertions in colorectal cancer: What do we know about unusual KRAS mutations?

Macedo, Mariana Petaccia de; Cernaglia Aureliano de Lima, Luiz Guilherme; Ferreira de Souza Begnami, Maria Dirlei; Melo, Fernanda Machado de; Brot Andrade, Louise D.; Garcia Lisboa, Bianca Cristina; Soares, Luisa Martelli; Soares, Fernando Augusto; Carrar
Fonte: Elsevier B.V. Publicador: Elsevier B.V.
Tipo: Artigo de Revista Científica Formato: 257-260
Português
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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Processo FAPESP: 11/08510-2; Introduction: KRAS mutations are negative predictors of the response to anti-EGFR therapy in colorectal carcinomas (CRCs). Point mutations in codons 12,13, and 61 are the most common KRAS mutations in CRC There are few reports on insertions in KRAS, and little is known about its ability to activate the RAS pathway. The scarcity of data regarding insertion frequencies and nucleotide additions in KRAS impedes the management of patients with such mutations. We present data on KRAS insertions in CRC and discuss a case.Materials and methods: Pyrosequencing and Sanger sequencing were performed to identify KRAS and BRAF mutations in paraffin-embedded samples of CRC Expression of mismatch repair proteins was examined by immunohistochemistry.Results: We detected a GGT insertion between codons 12 and 13 (c.36_37insGGT;p.G12_G13insG) in a CRC patient. We found that insertions in KRAS is very rare in CRC and that the most frequent type of insertion is c36_37insGGT.Conclusions: KRAS gene insertions represent a diagnostic and clinical challenge due to the difficult and unusual pyrosequencing findings and the lack of information regarding its clinical impact. (C) 2014 Elsevier Inc. All rights reserved.

‣ Epidermal growth factor receptor and KRAS mutations in Brazilian lung cancer patients

Bacchi,Carlos E.; Ciol,Heloísa; Queiroga,Eduardo M.; Benine,Lucimara C.; Silva,Luciana H.; Ojopi,Elida B.
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2012 Português
Relevância na Pesquisa
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OBJECTIVE: Epidermal growth factor receptor is involved in the pathogenesis of non-small cell lung cancer and has recently emerged as an important target for molecular therapeutics. The KRAS oncogene also plays an important role in the development of lung cancer. The aim of this study was to evaluate the frequency of epidermal growth factor receptor and KRAS mutations in a population of Brazilian patients with non-small cell lung cancer. METHODS: A total of 207 specimens from Brazilian patients with non-small cell lung cancer were analyzed for activating epidermal growth factor receptor and KRAS somatic mutations, and their associations with clinicopathological characteristics (including age, gender, ethnicity, smoking habits, and histological subtype) were examined. RESULTS: We identified 63 cases (30.4%) with epidermal growth factor receptor mutations and 30 cases (14.6%) with KRAS mutations. The most frequent epidermal growth factor receptor mutation we detected was a deletion in exon 19 (60.3%, 38 patients), followed by an L858R amino acid substitution in exon 21 (27%, 17 patients). The most common types of KRAS mutations were found in codon 12. There were no significant differences in epidermal growth factor receptor or KRAS mutations by gender or primary versus metastatic lung cancer. There was a higher prevalence of KRAS mutations in the non-Asian patients. Epidermal growth factor receptor mutations were more prevalent in adenocarcinomas than in non-adenocarcinoma histological types. Being a non-smoker was significantly associated with the prevalence of epidermal growth factor receptor mutations...

‣ Atorvastatin overcomes gefitinib resistance in KRAS mutant human non-small cell lung carcinoma cells

Chen, J; Bi, H; Hou, J; Zhang, X; Zhang, C; Yue, L; Wen, X; Liu, D; Shi, H; Yuan, J; Liu, J; Liu, B
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Português
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The exact influence of statins on gefitinib resistance in human non-small cell lung cancer (NSCLC) cells with KRAS mutation alone or KRAS/PIK3CA and KRAS/PTEN comutations remains unclear. This work found that transfection of mutant KRAS plasmids significantly suppressed the gefitinib cytotoxicity in Calu3 cells (wild-type KRAS). Gefitinib disrupted the Kras/PI3K and Kras/Raf complexes in Calu3 cells, whereas not in Calu3 KRAS mutant cells. These trends were corresponding to the expression of pAKT and pERK in gefitinib treatment. Atorvastatin (1 μM) plus gefitinib treatment inhibited proliferation, promoted cell apoptosis, and reduced the AKT activity in KRAS mutant NSCLC cells compared with gefitinib alone. Atorvastatin (5 μM) further enhanced the gefitinib cytotoxicity through concomitant inhibition of AKT and ERK activity. Atorvastatin could interrupt Kras/PI3K and Kras/Raf complexes, leading to suppression of AKT and ERK activity. Similar results were also obtained in comutant KRAS/PTEN or KRAS/PIK3CA NSCLC cells. Furthermore, mevalonate administration reversed the effects of atorvastatin on the Kras/Raf and Kras/PI3K complexes, as well as AKT and ERK activity in both A549 and Calu1 cells. The in vivo results were similar to those obtained in vitro. Therefore...

‣ MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells

Kharbanda, Akriti; Rajabi, Hasan; Jin, Caining; Alam, Maroof; Wong, Kwok-Kin; Kufe, Donald
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Português
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Non-small cell lung cancers (NSCLCs) that harbor an oncogenic KRAS mutation are often associated with resistance to targeted therapies. The MUC1-C transmembrane protein is aberrantly overexpressed in NSCLCs and confers a poor outcome; however, the functional role for MUC1-C in mutant KRAS NSCLC cells has remained unclear. The present studies demonstrate that silencing MUC1-C in A549/KRAS(G12S) and H460/KRAS(Q61H) NSCLC cells is associated with downregulation of AKT signaling and inhibition of growth. Overexpression of a MUC1-C(CQC→AQA) mutant, which inhibits MUC1-C homodimerization and function, suppressed both AKT and MEK activation. Moreover, treatment with GO-203, an inhibitor of MUC1-C homodimerization, blocked AKT and MEK signaling and decreased cell survival. The results further demonstrate that targeting MUC1-C suppresses expression of the ZEB1 transcriptional repressor by an AKT-mediated mechanism, and in turn induces miR-200c. In concert with these effects on the ZEB1/miR-200c regulatory loop, targeting MUC1-C was associated with reversal of the epithelial-mesenchymal transition (EMT) and inhibition of self-renewal capacity. Loss of MUC1-C function also attenuated KRAS independence and inhibited growth of KRAS mutant NSCLC cells as tumors in mice. These findings support a model in which targeting MUC1-C inhibits mutant KRAS signaling in NSCLC cells and thereby reverses the EMT phenotype and decreases self-renewal.

‣ Panitumumab in the management of patients with KRAS wild-type metastatic colorectal cancer

Hocking, C.M.; Price, T.J.
Fonte: SAGE Publications Publicador: SAGE Publications
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
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The past 15 years has seen a marked increase in available therapeutic options for patients with metastatic colorectal cancer resulting in improvements in median survival from 12 to 24 months. One of these new options is panitumumab, which is a fully humanized monoclonal antibody that binds to the epidermal growth factor receptor of tumor cells and inhibits downstream cell signaling with antitumor effects of inhibition of tumor growth, induction of apoptosis and inhibition of angiogenesis. Large randomized clinical trials have demonstrated significant improvements in tumor response rates and progression-free survival when panitumumab is combined with chemotherapy and as monotherapy in chemorefractory metastatic colorectal cancer. Clinical benefit with panitumumab is limited to patients with nonmutated KRAS tumors. Rash is a common toxicity of panitumumab treatment but can potentially be ameliorated with the use of prophylactic strategies. The role of panitumumab in the overall treatment of metastatic colorectal cancer is evolving and future clinical trials will focus on improved patient selection through use of novel predictive biomarkers, and the optimal timing of treatment.; Christopher M. Hocking and Timothy J. Price

‣ Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

Rosty, C.; Young, J.P.; Walsh, M.D.; Clendenning, M.; Walters, R.J.; Pearson, S.; Pavluk, E.; Nagler, B.; Pakenas, D.; Jass, J.R.; Jenkins, M.A.; Win, A.K.; Southey, M.C.; Parry, S.; Hopper, J.L.; Giles, G.G.; Williamson, E.; English, D.R.; Buchanan, D.D.
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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KRAS-mutated carcinomas comprise 35-40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O(6)-methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wild-type carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; P<0.001), demonstrated mucinous differentiation (46 vs 31%; P=0.001) and were associated with different MSI status (P<0.001) and with MGMT methylation (47 vs 21%; P=0.001). Compared with tumors demonstrating neither BRAF nor KRAS mutation, KRAS-mutated carcinomas showed more frequent location in the proximal colon (41 vs 27%; P=0.001), mucinous differentiation (46 vs 25%; P<0.001), presence of a contiguous polyp (38 vs 22%; P<0.001)...

‣ Kalhous, The Anatomy of a Duchy (Pawe?? Kras)

Pawe?? Kras
Fonte: The Medieval Review Publicador: The Medieval Review
Tipo: Revisão
Português
Relevância na Pesquisa
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Pawe?? Kras, John Paul II Catholic University of Lublin, palks@kul.lublin.pl

‣ Detección de mutaciones en el gen KRAS como screening rutinario para la elección del tratamiento óptimo en el cáncer colorrectal

Garzón Otero, Eztizen
Fonte: Universidade de Cantabria Publicador: Universidade de Cantabria
Tipo: Dissertação de Mestrado
Português
Relevância na Pesquisa
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Los objetivos de este proyecto son valorar la posible eficacia de realizar como screening rutinario el análisis de las mutaciones en el gen KRAS, ya que cuando este gen se encuentra mutado disminuye notablemente la eficacia de los tratamientos con anticuerpos monoclonales y puesto que es una prueba sencilla y barata, mejoraría las tasas de supervivencia en los pacientes afectados de CCR ya que permitiría que estos pacientes recibiesen un tratamiento más particular y personalizado adaptado a sus circunstancias.; Máster en Biología Molecular y Biomedicina

‣ Investigating dependencies of RAS mutant lung cancer cells

Lima, Nádia Sofia de Carvalho
Fonte: Universidade de Lisboa Publicador: Universidade de Lisboa
Tipo: Dissertação de Mestrado
Publicado em //2015 Português
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Tese de mestrado em Bioquímica Médica, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2015; O cancro do pulmão é uma das principais causas de morte no mundo. Só em 2012 na Europa cerca de 388.000 mortes foram registadas. Apesar da existência de algumas drogas eficazes para o tratamento do cancro do pulmão, o reaparecimento da doença é frequente após o tratamento. A aquisição de mutações pontuais que causam resistência e aparecimento de vias de sinalização alternativas e compensatórias é a principal causa. Apesar da conhecida associação do cancro do pulmão com o tabagismo, outros fatores de risco são conhecidos. Entre os principais, conta-se a história familiar. Alterações genéticas incluem na maioria dos casos mutações nos genes p53, Bcl2, Rb, FHIT e p16INK. Perda de heterozigotia, mudanças em telomerases e a ativação constitutiva do oncogene KRAS são também evidentes fatores de risco. Dentro do vasto painel de mutações para KRAS, pode contar-se como mais comum a G12D, responsável pelo desenvolvimento do subtipo cancro do pulmão de células não-pequenas (NSCLC), um dos mais agressivos. A proteína RAS é codificada pelo gene KRAS. Pertence à família das GTPases e tem como função molecular a ativação e desativação por fosforilação de GDP a GTP e vice-versa. Está envolvida numa longa cascata de transdução do sinal responsável pela proliferação e sobrevivência celular. As mutações em KRAS têm portanto um papel fundamental no aparecimento e desenvolvimento do cancro. A sua ativação constitutiva leva à continua estimulação das vias de sinalização a jusante promovendo a constante proliferação e sobrevivência...

‣ Carcinogenic Ability of Schistosoma Haematobium Possibly through Oncogenic Mutation of KRAS Gene

Botelho, Mónica C.; Veiga, Isabel; Oliveira, Paula A.; Lopes, Carlos; Teixeira, Manuel; Costa, José M Correia da; Machado, José C.
Fonte: IBIMA Publishing Publicador: IBIMA Publishing
Tipo: Artigo de Revista Científica
Publicado em 28/04/2013 Português
Relevância na Pesquisa
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Schistosoma haematobium is a parasitic flatworm that infects millions of people, mostly in the developing world, and is associated with high incidence of bladder cancer, although why is not clear. Previously, we have used CD-1 mice to show that Schistosoma haematobium total antigen (Sh) has a carcinogenic ability. Sh intravesically instillation induced the development of several urothelial lesions, namely nodular hyperplasia and dysplasia (LGIUN—Low Grade Intra-Urothelial Neoplasia) after 40 weeks of treatment. These results suggested that Sh induce urothelium malignization. Bladder carcinoma frequently harbours gene mutations that constitutively activate the receptor tyrosine kinase-Ras pathway for this reason we studied activating mutations in KRAS gene. Twenty percent of the bladders with dysplasia presented a KRAS mutation in codon 12 of exon 2. We concluded from these results that the parasite extract of S. haematobium has carcinogenic ability possibly through oncogenic mutation of KRAS gene.

‣ Targeting `Undruggable' Cancer Proteins with Irreversible Small Molecule Inhibitors: Her3 and KRas

Xie, Ting
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
Português
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With the lighting speed revolution of technologies in chemistry and biology, increasing number of proteins which eluded scientists' efforts to block them before and were labeled as `undruggable', were successfully targeted with small molecule inhibitors. During the past five years, I have been working on figuring out the path to inhibit two elusive cancer targets: Her3 and KRas.; Chemistry and Chemical Biology

‣ Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model

Álamo, Patricia; Gallardo Alcañiz, Alberto; Di Nicolantonio, Federica; Pavón Ribas, Miguel Ángel; Casanova, Isolda; Trias Folch, Manuel; Mangues i Bafalluy, Ma. Antònia; Lopez-Pousa, Antonio; Villaverde Corrales, Antonio; Vázquez Gómez, Esther; Bar
Fonte: Universidade Autônoma de Barcelona Publicador: Universidade Autônoma de Barcelona
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/submittedVersion Formato: application/pdf
Publicado em //2015 Português
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Although all KRas (protein that in humans is encoded by the KRas gene) point mutants are considered to have a similar prognostic capacity, their transformation and tumorigenic capacities vary widely. We compared the metastatic efficiency of KRas G12V (Kirsten rat sarcoma viral oncogene homolog with valine mutation at codon 12) and KRas G13D (Kirsten rat sarcoma viral oncogene homolog with aspartic mutation at codon 13) oncogenes in an orthotopic colorectal cancer (CRC) model. Following subcutaneous preconditioning, recombinant clones of the SW48 CRC cell line [Kras wild-type (Kras WT)] expressing the KRas G12V or KRas G13D allele were microinjected in the mouse cecum. The percentage of animals developing lymph node metastasis was higher in KRas G12V than in KRas G13D mice. Microscopic, macroscopic, and visible lymphatic foci were 1.5- to 3.0-fold larger in KRas G12V than in KRas G13D mice (P < 0.05). In the lung, only microfoci were developed in both groups. KRas G12V primary tumors had lower apoptosis (7.0 ± 1.2 vs. 7.4 ± 1.0 per field, P = 0.02), higher tumor budding at the invasion front (1.2 ± 0.2 vs. 0.6 ± 0.1, P = 0.04), and a higher percentage of C-X-C chemokine receptor type 4 (CXCR4)-overexpressing intravasated tumor emboli (49.8 ± 9.4% vs. 12.8 ± 4.4%...

‣ Epidermal growth factor receptor and KRAS mutations in Brazilian lung cancer patients

Bacchi, Carlos E.; Ciol, Heloísa; Queiroga, Eduardo M.; Benine, Lucimara C.; Silva, Luciana H.; Ojopi, Elida B.
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; Formato: application/pdf
Publicado em 01/01/2012 Português
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OBJECTIVE: Epidermal growth factor receptor is involved in the pathogenesis of non-small cell lung cancer and has recently emerged as an important target for molecular therapeutics. The KRAS oncogene also plays an important role in the development of lung cancer. The aim of this study was to evaluate the frequency of epidermal growth factor receptor and KRAS mutations in a population of Brazilian patients with non-small cell lung cancer. METHODS: A total of 207 specimens from Brazilian patients with non-small cell lung cancer were analyzed for activating epidermal growth factor receptor and KRAS somatic mutations, and their associations with clinicopathological characteristics (including age, gender, ethnicity, smoking habits, and histological subtype) were examined. RESULTS: We identified 63 cases (30.4%) with epidermal growth factor receptor mutations and 30 cases (14.6%) with KRAS mutations. The most frequent epidermal growth factor receptor mutation we detected was a deletion in exon 19 (60.3%, 38 patients), followed by an L858R amino acid substitution in exon 21 (27%, 17 patients). The most common types of KRAS mutations were found in codon 12. There were no significant differences in epidermal growth factor receptor or KRAS mutations by gender or primary versus metastatic lung cancer. There was a higher prevalence of KRAS mutations in the non-Asian patients. Epidermal growth factor receptor mutations were more prevalent in adenocarcinomas than in non-adenocarcinoma histological types. Being a non-smoker was significantly associated with the prevalence of epidermal growth factor receptor mutations...

‣ Evaluation of Altered Kras Codon Bias and NOS Inhibition During Lung Tumorigenesis

Pershing, Nicole L.
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2014 Português
Relevância na Pesquisa
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The small GTPases HRAS, NRAS and KRAS are mutated in approximately one-third of all human cancers, rendering the proteins constitutively active and oncogenic. Lung cancer is the leading cause of cancer deaths worldwide, and more than 20% of human lung cancers harbor mutations in RAS, with 98% of those occurring in the KRAS isoform. While there have been many advances in the understanding of KRAS–driven lung tumorigenesis, it remains a therapeutic challenge. To further this understanding and assess novel approaches for treatment, I have investigated two aspects of Kras–driven tumorigenesis in the lung:

(I) Despite nearly identical protein sequences, the three RAS proto-oncogenes exhibit divergent codon usage. Of the three isoforms, KRAS contains the most rare codons resulting in lower levels of KRAS protein expression relative to HRAS and NRAS. To determine the consequences of rare codon bias during de novo tumorigenesis, we created a knock-in Krasex3op mouse in which synonymous mutations in exon 3 converted codons from rare to common. These mice had reduced tumor burden and fewer oncogenic mutations in the Krasex3op allele following carcinogen exposure. The reduction in tumorigenesis appeared to be a product of rare codons affecting both the oncogenic and non–oncogenic alleles. Converting rare codons to common codons yielded a more potent oncogenic allele that promoted growth arrest and enhanced tumor suppression by the non-oncogenic allele. Thus...

‣ Oncogenic KRAS Expression and Signaling

Lampson, Benjamin Logan
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2012 Português
Relevância na Pesquisa
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RAS is a small GTPase that helps to convert extracellular cues into intracellular actions. It is the most commonly mutated oncogene and is found in an active mutant form in 90% of pancreatic cancers. Therefore, study of how this protein is made and then how this protein signals in the cell could provide the foundation for novel approaches to treat RAS-driven malignancies.

First I demonstrate that the level of protein expressed from the gene KRAS, but not the highly homologous gene HRAS, is limited in mammalian cells by an abundance of underrepresented (rare) codons in the encoding mRNA. KRAS mRNA from both ectopic plasmids as well as from the endogenous cellular gene is subject to slowed translation due to these rare codons within its coding sequence. This has consequences for tumorigenesis, as replacement of the rare codons with commonly used codons accelerates RAS driven tumor growth. This may extend beyond HRAS and KRAS, as many other homologous gene pairs show a high divergence in codon usage and protein expression, suggesting that this could be a wider phenomenon used by mammalian cells to regulate protein levels.

Second, I demonstrate that RAS driven tumors partially depend on eNOS for growth. Using genetically engineered mouse models that recapitulate the spontaneous development of pancreatic cancer...

‣ Mutación del gen KRAS en el cáncer de colon y recto

Roa,Iván; Sánchez,Tamara; Majlis,Alejandro; Schalper,Kurt
Fonte: Sociedad Médica de Santiago Publicador: Sociedad Médica de Santiago
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/09/2013 Português
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Background: KRAS oncogene is involved in colorectal carcinogenesis in 22 to 45% of cases. Aim: To determine the frequency, types and distribution of KRAS mutations in colorectal cancer. Material and Methods: KRAS mutations studies were carried out in primary tumors and metastases of colo-rectal cancer from 56 women aged 60 ± 14 years and 53 men aged 61 ± 11 years. Formalin fixed and paraffin embedded tissue samples were evaluated using RFLP (Restriction Fragment Length Polymorphism) and direct sequencing. Results: Primary tumors were located in the colon and rectum in 82 (75.2%) and 24 cases (20%), respectively. In three cases the extraction site of the tumor sample was unknown. In 46 cases (42.2%) KRAS mutations were demonstrated. The main point mutations were located in codon 12 (80.4%), G12D (39.1%), G12V (24.2%), G12S (6.5%), G12A (4.3%); G12C (4.3%), G12R (2.1%) and 19.6% at codon 13 (G13D). No differences were demonstrated in the frequency and distribution of mutations by gender, age, primary versus metastatic tumors or tumor location. Conclusions: In this series, 42% of colorectal cancer tissue samples had KRAS mutations. Their frequency and distribution are similar to those reported in the literature, except for G12C mutation.

‣ Prevalencia y características de mutaciones somáticas del gen KRAS en pacientes chilenos con cáncer colorrectal

Hurtado,Claudia; Encina,Gonzalo; Wielandt,Ana María; Zárate,Alejandro José; Castro,Magdalena; Carrillo,Katya; Kronberg,Udo; López-Köstner,Francisco
Fonte: Sociedad Médica de Santiago Publicador: Sociedad Médica de Santiago
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/11/2014 Português
Relevância na Pesquisa
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Background: The molecular testing of KRAS mutation status in metastatic colorectal cancer patients is mandatory to identify patients eligible for anti-epidermal growth factor receptor monoclonal antibody therapy. Aim: To report the frequency of KRAS gene mutations in Chilean patients with colorectal cancer (CRC). Material and Methods: A cohort of 262 Chilean patients with CRC aged 26 to 90 years (53% males), was studied. KRAS mutation status was analyzed by real-time polymerase chain reaction and correlated with clinicopathological data. Results: Ninety-eight patients (37%) were positive for KRAS mutations. G12D was the most common mutation with a frequency of 36.7%, followed by G12V (25.5%), G13D (17.3%), G12A (7.1%), G12C (6.1%), G12S (5.1%) and G12R (2%). The frequency of the mutation in left, right colon and rectal tumors was 37.8, 32.6 and 44.9%, respectively. Among tumors with mutations, 86.7% were well or moderately differentiated tumors and the rest were poorly differentiated. No significant associations between KRAS gene mutations and other clinicopathological features of the tumor were observed. Conclusions: The frequencies of KRAS mutations reported in this study are similar to frequencies reported for European and North-American populations...