Cytoplasmic-membrane egfr predicts expanded ras mutation status in colorectal carcinomas? / Egfr membrano-citoplasmático prediz mutação ras expandida no carcinoma colorretal?

ABSTRACT Background: Inhibitors of the epidermal growth factor (EGFR) represent an effective therapeutic option for patients with metastatic colorectal carcinoma, free of activating mutations in KRAS and NRAS. However, the research of mutations is of high cost and scarcely accessible. The expression of the EGFR by immunohistochemistry predicting the mutation status of the expanded RAS (KRAS and NRAS), may allow treatment by a diagnostic method less costly and more accessible. Aim: Investigate the correlation between the clinical-pathological data, the cytoplasmic-membrane expression of the EGFR and the mutational status of the expanded RAS. Method: A total of 139 patients with colorectal carcinoma from the archives of Instituto Goiano de Oncologia e Hematologia were evaluated. Results: Mutation of the expanded RAS was detected in 78 (56.1%) cases. The EGFR expression was stratified in 23 (16.5%) "positive", 49 (35.2%) "negative" and 67 (48.2%) "uncertain". No significant correlation was found between the mutational status of the RAS and the EGFR expression in comparison to age, gender, location, histological type, histological grade and stage. From 23 "positive" cases, 21 (91.3%) showed wild-type RAS gene, and 49 "negative", 41 (83.7%) presented mutation, resulting in a strong association between EGFR "positive", "negative" groups and the mutational status of the RAS (p<0.001), with 86.1% of accuracy. Conclusions: The cytoplasmic-membrane analysis of the EGFR expression stratified into "positive", "negative" and "uncertain" predicts mutational status of the RAS in 51.7% of the cases (p<0.001), with 86.1% of accuracy.

RESUMO Racional: Inibidores do fator de crescimento epidermal (EGFR) representam opção de terapia efetiva para o câncer colorrectal metastático, na ausência de ativação de mutações KRAS e NRAS. Entretanto, a pesquisa de mutações é cara e pouco acessível. A expressão de EGFR por imuno-histoquímica predizendo o status mutacional do RAS expandido (KRAS e NRAS) poderia permitir o tratamento por método diagnóstico menos caro e mais acessível. Objetivo: Investigar a correlação entre os dados clinicopatológicos, a expressão de EGFR na membrana citoplasmática e o status mutacional do RAS expandido. Método: Estudo retrospectivo de acurácia envolvendo 139 pacientes com carcinoma colorretal. Resultado: A mutação do RAS expandido foi detectada em 78 (56,1%) casos. A expressão de EGFR foi estratificada em 23 (16,5%) casos "positivos", 49 (35,2%) casos "negativos" e 67 (48,2%) "duvidosos". Não houve correlação significante entre o status mutacional do RAS e a expressão de EGFR em relação a idade, gênero, local do tumor, tipo histológico, grau histológico e estádio clínico. Em 23 casos "positivos", 21 (91,3%) mostraram gene RAS tipo selvagem, e em 49 "negativos", 41 (83,7%) apresentaram mutação, resultando em forte associação entre grupos EGFR "positivo" ou "negativo" e o status mutacional do RAS (p<0.001), com 86,1% de acurácia. Conclusão: A análise da expressão de EGFR na membrana citoplasmática estratificada em "positivo", "negativo" e "duvidoso" prediz o status mutacional do RAS em 51,7% dos casos (p<0.001), com 86,1% de acurácia.

Complete screening of exons 2, 3, and 4 of kras and nras genes reveals a higher number of clinically relevant mutations than food and drug administration quantitative polymerase chain reaction-based commercial kits

Abstract Background: The presence of clinically relevant mutations in KRAS and NRAS genes determines the response of anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer (mCRC). The only quantitative polymerase chain reaction (qPCR)-based diagnostic tests approved by the Food and Drug Administration (FDA) screen merely for mutations in codons 12 and 13 of KRAS. Objective: The objective of the study was to study the frequency of clinically relevant mutations in KRAS and NRAS genes that are not included in FDA-approved qPCR tests. Methods: Formalin-fixed paraffin-embedded tumor specimens from 1113 mCRC Mexican patients from different health institutions across the country were analyzed by Sanger sequencing for KRAS mutations in exons 2, 3, and 4. Furthermore, 83 were analyzed in exons 2, 3, and 4 of NRAS. Results: From the specimens tested for KRAS, 33.69% harbored a mutation. From these, 71.77% were in codon 12 and 27.69% in codon 13 (both located in exon 2). Codons 59 (exon 3) and 146 (exon 4) accounted for the remaining 0.54%. From the 83 specimens, in which NRAS was analyzed, three mutations were found in codon 12 (3.61%). Approximately 6% of RAS mutated specimens would have been falsely reported as RAS wild type if an FDA-approved qPCR diagnostic test had been used. Conclusions: While these kits based on qPCR can be very practical and highly sensitive, their mutation coverage ignores mutations from poorly genetically characterized populations.

Use of a High-Throughput Genotyping Platform (OncoMap) for RAS Mutational Analysis to Predict Cetuximab Efficacy in Patients with Metastatic Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Cetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS exon 2. Resistance to cetuximab is mediated by activating less frequent mutations in the RAS genes beyond KRAS exon 2. We performed extended RAS Mutational analysis using a high-throughput genotyping platform (OncoMap) and evaluated extended RAS analysis for predicting cetuximab efficacy in patients harboring wild-type KRAS exon 2 tumors following Sanger sequencing. MATERIALS AND METHODS: Extended RAS analysis was performed on 227 wild-type KRAS exon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0. Targeted genes included exon 2, exon 3, and exon 4, both in KRAS and NRAS, and included BRAF exon 15. We assessed efficacy by the new RAS mutation status. RESULTS: The OncoMap detected 57 additional mutations (25.1%): 25 (11%) in KRAS exon 2 and 32 (14.1%) beyond KRAS exon 2. Survival differences were observed after dividing patients into the wild-type RAS group (n=170) and mutant RAS group (n=57) using OncoMap. Progression-free survival was 4.8 months versus 1.8 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.32 to 0.61), and overall survival was 11.9 months versus 8.4 months (HR, 0.65; 95% CI, 0.47 to 0.88). CONCLUSION: Sanger sequencing is not sufficient for selecting candidates for cetuximab treatment. High-throughput extended RAS genotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment.

Síndrome cardio-facio-cutáneo: reporte de caso / Cardio-facio-cutaneous syndrome: a case report

Resumen: el síndrome cardio-facio-cutáneo es una entidad clínica y genéticamente heterogénea, perteneciente a un grupo de síndromes conocidos como RASopatías.Este trastorno es de baja prevalencia, con alrededor de 200 a 300 casos en el mundo, e incluye entre sus manifestaciones clínicas rasgos faciales dismórficos, defectos cardíacos y alteraciones cutáneas. Los hallazgos fenotípicos del síndrome cardio-facio-cutáneo que se comparten con otros síndromes y la ausencia de criteriosdiagnósticos o signos patognomónicos lo convierten en un reto diagnóstico. En este manuscrito se presenta un caso confirmado de síndrome cardio-facio-cutáneo por estudios de genética molecular en una paciente de siete años de edad, mediante el cual se exponen las principales características de esta condición.

Abstract: The cardio-facio-cutaneous syndrome is a clinically and genetically heterogeneous disorder, belonging to a group of syndromes known as RASopathies. This condition has a low prevalence, with around of 200 to 300 cases in the world, and includes dysmorphic facial features, heart defects, and skin abnormalities among its clinical manifestations. The phenotypic findings of cardio-facio-cutane1ous syndrome that are shares with other syndromes and the absence of diagnostic criteria or pathognomonic signs make it a diagnostic challenge. Here its present a confirmed case of cardio-facio-cutaneous syndrome by molecular genetic studies in one seven years old patient, through which are exposed the main characteristics of this condition.

A study on the amplification, rearrangement and deletion of ras-oncogenes in gastric cancerous and juxtacancerous tissues / 第三军医大学学报

The amplification,rearrangement and deletion of c-Ha-ras,K-ras and N-ras were studied in 33 cases of gastric cancerous and juxtacancerous tissues.It was found that the amplification rearangement,and deletion of c-Ha-ras were shown in 25.8% (8/33) of cases and the ampli-cation of K-ras in 3.8% (1/26).No such changes was found for N-ras.