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BACKGROUND: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. METHODS: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. RESULTS: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. CONCLUSIONS: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.
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Neoplasias Pulmonares , não Fumantes , Fumantes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Feminino , Masculino , Fumantes/estatística & dados numéricos , Pessoa de Meia-Idade , não Fumantes/estatística & dados numéricos , Idoso , Fumar/genética , Fumar/efeitos adversos , Fumar/epidemiologia , Mutação , Genômica/métodos , Adulto , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologiaRESUMO
Colorectal cancer (CRC) is the second leading cause of cancer deaths globally. While ethnic differences in driver gene mutations have been documented, the South American population remains understudied at the genomic level, despite facing a rising burden of CRC. We analyzed tumors of 40 Chilean CRC patients (Chp) using next-generation sequencing and compared them to data from mainly Caucasian cohorts (TCGA and MSK-IMPACT). We identified 388 mutations in 96 out of 135 genes, with TP53 (45%), KRAS (30%), PIK3CA (22.5%), ATM (20%), and POLE (20%) being the most frequently mutated. TSC2 mutations were associated with right colon cancer (44.44% in RCRC vs. 6.45% in LCRC, p-value = 0.016), and overall frequency was higher compared to TCGA (p-value = 1.847 × 10-5) and MSK-IMPACT cohorts (p-value = 3.062 × 10-2). Limited sample size restricts definitive conclusions, but our data suggest potential differences in driver mutations for Chilean patients, being that the RTK-RAS oncogenic pathway is less affected and the PI3K pathway is more altered in Chp compared to TCGA (45% vs. 25.56%, respectively). The prevalence of actionable pathways and driver mutations can guide therapeutic choices, but can also impact treatment effectiveness. Thus, these findings warrant further investigation in larger Chilean cohorts to confirm these initial observations. Understanding population-specific driver mutations can guide the development of precision medicine programs for CRC patients.
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Neoplasias do Colo , Mutação , Proteína 2 do Complexo Esclerose Tuberosa , Humanos , Chile/epidemiologia , Proteína 2 do Complexo Esclerose Tuberosa/genética , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias do Colo/genética , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/patologia , Idoso , Adulto , Sequenciamento de Nucleotídeos em Larga Escala , Idoso de 80 Anos ou mais , Transdução de Sinais/genéticaRESUMO
Dysregulated A>I(G) RNA editing, which is mainly catalyzed by ADAR1 and is a type of post-transcriptional modification, has been linked to cancer. A low response to therapy in breast cancer (BC) is a significant contributor to mortality. However, it remains unclear if there is an association between A>I(G) RNA-edited sites and sensitivity to genotoxic drugs. To address this issue, we employed a stringent bioinformatics approach to identify differentially RNA-edited sites (DESs) associated with low or high sensitivity (FDR 0.1, log2 fold change 2.5) according to the IC50 of PARP inhibitors, anthracyclines, and alkylating agents using WGS/RNA-seq data in BC cell lines. We then validated these findings in patients with basal subtype BC. These DESs are mainly located in non-coding regions, but a lesser proportion in coding regions showed predicted deleterious consequences. Notably, some of these DESs are previously reported as oncogenic variants, and in genes related to DNA damage repair, drug metabolism, gene regulation, the cell cycle, and immune response. In patients with BC, we uncovered DESs predominantly in immune response genes, and a subset with a significant association (log-rank test p < 0.05) between RNA editing level in LSR, SMPDL3B, HTRA4, and LL22NC03-80A10.6 genes, and progression-free survival. Our findings provide a landscape of RNA-edited sites that may be involved in drug response mechanisms, highlighting the value of A>I(G) RNA editing in clinical outcomes for BC.
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Introduction: Uveal melanoma is the most common primary intraocular malignancy in adults, affecting primarily the choroid of the eye. Plaque brachytherapy is the most common procedure for the treatment of small choroidal melanoma, especially in posteriorly located tumors. However, modern radiotherapy techniques, such as CyberKnife or Gamma knife stereotactic radiosurgery (SRS) and proton beam radiotherapy, have shown better results in tumor control and eye retention. Recent studies have indicated that SRS is a promising non-invasive, single-session treatment option, with most studies reporting the best outcomes when using ≥21-22 Gy. However, there is no consistent protocol for managing this pathology using CyberKnife, not only in terms of dose but also fractions. Case Presentations: Here, we report the first case series of patients (n = 4, age range 38-64 years, median age 52.5 years) with choroidal UM in Central America who were treated with CyberKnife SRS (22 Gy in one session). During the follow-up (range 25-29 months, median 27.5 months), a 100% control rate with no systemic metastatic disease has been achieved. We found a statistically significant reduction in the largest basal diameter at 24 months for all tumors. However, visual acuity has progressively decreased in most patients. Notably, two of our patients developed radiation maculopathy, and the other two developed radiation retinopathy after SRS. Conclusions: Our findings suggest that future studies should evaluate the use of different prophylactic therapies to prevent the development of side effects. The clinical management of toxicities presented in our report can serve as a reference in the clinical practice of other centers. Our report supports the growing body of evidence showing that CyberKnife radiosurgery is a safe and effective therapeutic option for the treatment of UM.
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Introducción: La epidemiología de las fracturas maxilofaciales varía en dependencia de los estilos de vida, el nivel cultural y el estatus socioeconómico en diferentes zonas geográficas. Objetivo: Caracterizar epidemiológica y terapéuticamente a los pacientes con fracturas maxilofaciales, atendidos en un hospital universitario cubano durante la pandemia de COVID-19. Métodos: Se realizó un estudio observacional, descriptivo y transversal a los pacientes atendidos en el Servicio de Cirugía Maxilofacial del Hospital General Universitario "Carlos Manuel de Céspedes" de Bayamo, provincia Granma, durante el 1 de enero y el 31 de diciembre de 2020. Se estudiaron variables epidemiológicas y terapéuticas. Resultados: Se incluyeron 85 pacientes con 220 fracturas. Los hombres fueron los más afectados (n = 74; 87,06 %) y la proporción hombre/mujer resultó de 6,73:1. El grupo etario de 41-60 años (n = 40; 47,06 %) sobresalió. En el 38,89 % de los casos el trauma se relacionó con violencia interpersonal. Cincuenta y cuatro pacientes (63,52 %) tuvieron fracturas del complejo cigomático. El ángulo mandibular constituyó la localización anatómica más afectada. Las fracturas mandibulares se trataron fundamentalmente mediante reducción cerrada. Conclusiones: El perfil epidemiológico de las fracturas maxilofaciales se destacó en los pacientes adultos masculinos debido, principalmente, a la violencia interpersonal. Las fracturas complejas del tercio medio facial se trataron por método abierto. La distribución temporal de los casos mostró el impacto de la COVID-19 en la epidemiología de estos traumas.
Introduction: The epidemiology of maxillofacial fractures varies according to lifestyles, cultural level and socioeconomic status in different geographical areas. Objective: To characterize epidemiologically and therapeutically the patients with maxillofacial fractures treated in a Cuban university hospital during the COVID-19 pandemic. Methods: An observational, descriptive and cross-sectional study was carried out on patients attended at the Maxillofacial Surgery Service of the General University Hospital "Carlos Manuel de Céspedes" of Bayamo, Granma province, between January 1 and December 31, 2020. Epidemiological and therapeutic variables were studied. Results: 85 patients with 220 fractures were included. Men were the most affected (n = 74; 87.06 %) and the male/female ratio was 6.73:1. The age group 41-60 years (n = 40; 47.06 %) stood out. In 38.89 % of the cases the trauma was related to interpersonal violence. Fifty-four patients (63.52 %) had fractures of the zygomatic complex. The mandibular angle was the most damaged anatomical location. Fractures were treated primarily by closed reduction. Conclusions: The epidemiological profile of maxillofacial fractures was prominent in adult male patients mainly due to interpersonal violence. Complex fractures of the midfacial third were treated by open method. The temporal distribution of the cases showed the impact of COVID-19 on the epidemiology of these traumas.
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In cancer cells, the long non-coding RNA (lncRNA) MALAT1 has arisen as a key partner for the Polycomb Repressive Complex 2 (PRC2), an epigenetic modifier. However, it is unknown whether this partnership occurs genome-wide at the chromatin level, as most of the studies focus on single genes that are usually repressed. Due to the genomic binding properties of both macromolecules, we wondered whether there are binding sites shared by PRC2 and MALAT1. Using public genome-binding datasets for PRC2 and MALAT1 derived from independent ChIP- and CHART-seq experiments performed with the breast cancer cell line MCF7, we searched for regions containing PRC2 and MALAT1 overlapping peaks. Peak calls for each molecule were performed using MACS2 and then overlapping peaks were identified by bedtools intersect. Using this approach, we identified 1293 genomic sites where PRC2 and MALAT1 concur. Interestingly, 54.75% of those sites are within gene promoter regions (<3000 bases from the TSS). These analyses were also linked with the transcription profiles of MCF7 cells, obtained from public RNA-seq data. Hence, it is suggested that MALAT1 and PRC2 can concomitantly bind to promoters of actively-transcribed genes in MCF7 cells. Gene ontology analyses revealed an enrichment of genes related to categories including cancer malignancy and epigenetic regulation. Thus, by re-visiting occupancy and transcriptomic data, we identified a key gene subset controlled by the collaboration of MALAT1 and PRC2.
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Introducción: Las fracturas nasales son las más comunes de la región maxilofacial. Sin embargo, la literatura cubana sobre el tema es escasa y desactualizada, por lo que surgió la motivación para realizar esta investigación. Objetivo: Caracterizar clínica y epidemiológicamente los pacientes con fractura nasal atendidos en un hospital universitario cubano. Métodos: Se realizó un estudio observacional, descriptivo y transversal en pacientes atendidos en el Servicio de Cirugía Maxilofacial del Hospital General Universitario "Carlos Manuel de Céspedes" de Bayamo, provincia Granma, Cuba, en el período comprendido entre el 1 de enero y el 31 de diciembre del 2020. Se estudiaron variables clínicas, epidemiológicas y terapéuticas. Resultados: Se incluyeron 99 pacientes, de los cuales 74 (74,75 por ciento) fueron masculinos. En el 44,44 por ciento de los casos las edades estuvieron comprendidas entre los 21 y 40 años. Cincuenta pacientes (50,51 por ciento) tuvieron fracturas producto de la violencia interpersonal. Noventa y siete pacientes (97,98 por ciento) presentaron epistaxis. Cincuenta y nueve pacientes (59,60 por ciento) recibieron reducción cerrada asociada con taponamiento nasal y fijación externa con yeso. Conclusiones: Predominó el sexo masculino y el grupo de edades de 21 a 40 años. La principal etiología fue la violencia interpersonal. En la mayoría de los casos la epistaxis estuvo presente. Prevalecieron las fracturas cerradas, así como las que tuvieron el dorso desviado lateralmente(AU)
Introduction: Nasal fractures are the most common fractures of the maxillofacial region. However, Cuban literature on the subject is scarce and outdated, so the motivation for this research arose. Objective: To characterize patients with nasal fractures treated in a Cuban university hospital in a clinical and epidemiological manner. Methods: An observational, descriptive and cross-sectional study was carried out in patients treated at the Maxillofacial Surgery Service of the University General Hospital. "Carlos Manuel de Céspedes" of Bayamo, Granma province, Cuba, from January 1 to December 31, 2020. Clinical, epidemiological and therapeutic variables were studied. Results: 99 patients were included, of whom 74 (74.75 percent) were male. In 44.44 percent of the cases the ages were between 21 and 40 years. Fifty patients (50.51 percent) had fractures resulting from interpersonal violence. Ninety-seven patients (97.98 percent) presented epistaxis. Fifty-nine patients (59.60 percent) received closed reduction associated with nasal packing and external fixation with plaster cast. Conclusions: Male gender and age group 21 to 40 years predominated. The main etiology was interpersonal violence. Epistaxis was present in most cases. Closed fractures prevailed, as well as those with laterally deviated dorsum(AU)
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Humanos , Masculino , Adulto , Osso Nasal/lesões , Literatura de Revisão como Assunto , Epidemiologia Descritiva , Estudos Observacionais como AssuntoRESUMO
Introduction: COVID-19 pandemic has had a significant impact on people's behavior. Aim: To evaluate the impact of the COVID-19 on the epidemiology of maxillofacial fractures surgically treated in a Cuban university hospital. Methods: This research involved a 4-year descriptive, comparative, retrospective and cross-sectional study. Patients surgically treated between March 1 and December 31, 2020 (COVID-19 period) were compared with those who had undergone surgery between the same date in the years 2017-2019 (non-pandemic period). Age, sex, residence, year, month, alcohol consumption at the time of trauma, etiology, fractures types, and number of fractures per patient were recorded. Results: A decline in patients with maxillofacial fractures in 2020 (n=25) was observed when compared to equivalent periods in the three previous years (2017: n=37; 2018: n=31; 2019: n=41), respectively, with an annual average reduction of 31.19 percent. Interpersonal violence was found to be the paramount etiological factor for maxillofacial fractures during the comparison periods (2017-2019); however, road traffic accident prevailed in the 2020 (n=12; 48 percent). There was a small increase in the number of alcohol-related fractures (56 percent in 2020 vs 46.34 percent, 41.94 percent, and 51.35 percent in 2019, 2018, and 2017, respectively). Conclusion: COVID-19 impacted on the epidemiology maxillofacial fractures surgically treated in this Cuban university hospital (AU)
Introducción: La pandemia de la COVID-19 ha tenido un impacto significativo en el comportamiento de la población. Objetivo: Evaluar el impacto de la COVID-19 en la epidemiología de las fracturas maxilofaciales tratadas quirúrgicamente en un hospital universitario cubano. Métodos: Esta investigación consistió en un estudio descriptivo, comparativo, retrospectivo y transversal de 4 años de duración. Se compararon los pacientes intervenidos quirúrgicamente entre el 1 de marzo y el 31 de diciembre de 2020 (periodo COVID-19) con los intervenidos entre la misma fecha en los años 2017-2019 (periodo no pandémico). Se registraron edad, sexo, residencia, año, mes, consumo de alcohol en el momento del traumatismo, etiología, tipos de fracturas y número de fracturas por paciente. Resultados: Se observó un descenso de pacientes con fracturas maxilofaciales en 2020 (n=25) en comparación con periodos equivalentes de los tres años anteriores (2017: n=37; 2018: n=31; 2019: n=41), respectivamente, con una reducción media anual del 31,19 poe ciento. Se observó que la violencia interpersonal fue el factor etiológico primordial de las fracturas maxilofaciales durante los periodos de comparación (2017-2019); sin embargo, el accidente de tráfico prevaleció en el 2020 (n=12; 48 por ciento). Hubo un pequeño aumento en el número de fracturas relacionadas con el alcohol (56 por ciento en 2020 frente a 46,34 por ciento, 41,94 por ciento y 51,35 por ciento en 2019, 2018 y 2017, respectivamente). Conclusiones: La COVID-19 impactó en la epidemiología de fracturas maxilofaciales atendidas quirúrgicamente en este hospital universitario cubano (AU)
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Humanos , Ossos Faciais/cirurgia , Fraturas Maxilares/cirurgia , Fraturas Maxilares/epidemiologia , Violência , Estudo Comparativo , Acidentes de Trânsito , Epidemiologia Descritiva , Estudos Transversais , Estudos Retrospectivos , Impactos da Poluição na Saúde , COVID-19/epidemiologiaRESUMO
RESUMEN La fractura nasal es la más frecuente entre las fracturas de los huesos faciales, pudiendo generar alteraciones estéticas importantes y a su vez determinar cambios en la funcionalidad, tratarlas de forma inmediata evita complicaciones al paciente. Con el objetivo de caracterizar las fracturas nasales atendidas en el servicio de urgencias de cirugía maxilofacial del hospital "Carlos Manuel de Céspedes" se realizó un estudio observacional descriptivo que incluyó todos los pacientes (105) que fueron atendidos ambulatoriamente con diagnóstico de fractura nasal reciente en el servicio de urgencias en el período de enero 2018 a diciembre del 2019. Las variables estudiadas fueron edad, sexo, procedencia, factores etiológicos, signos clínicos, clasificación según desplazamiento, exposición del foco de fractura y dirección del trauma. Se confeccionó una planilla de recolección de datos. Se emplearon números enteros, porcentajes y tablas estadísticas. Se siguieron los principios éticos para la investigación en humanos. La población más afectada se encontró entre los 20 y 29 años de edad, de procedencia urbana y del sexo masculino. Se encontró asociación entre el sexo y los factores etiológicos, predominando las agresiones físicas en hombres y las caídas casuales en mujeres. El principal signo clínico presente en los pacientes fue la epistaxis. Las fracturas nasales desplazadas, con desviaciones laterales y cerradas predominaron en ambos sexos.
ABSTRACT The nasal fracture is the most frequent among the fractures of the facial bones, being able to generate important aesthetic alterations and in turn determine changes in functionality, treating them immediately avoids complications for the patient. In order to characterize the nasal fractures treated in the maxillofacial surgery emergency service of the "Carlos Manuel de Céspedes" hospital, a descriptive observational study was carried out that included all the patients (105) who were seen outpatiently with a diagnosis of recent nasal fracture in the emergency department in the period from January 2018 to December 2019. The variables studied were age, sex, origin, etiological factors, clinical signs, classification according to displacement, exposure of the fracture site and direction of the trauma. A data collection sheet was prepared. Whole numbers, percentages and statistical tables were used. Ethical principles for human research were followed. The most affected population was between 20 and 29 years of age, of urban origin and male. An association was found between sex and etiological factors, predominantly physical aggression in men and accidental falls in women. The main clinical sign present in the patients was epistaxis. Displaced nasal fractures with lateral and closed deviations predominated in both sexes.
RESUMO A fratura nasal é a mais frequente entre as fraturas dos ossos faciais, sendo capaz de gerar alterações estéticas importantes e, por sua vez, determinar alterações na funcionalidade, tratando-as imediatamente evita complicações para o paciente. Com o objetivo de caracterizar as fraturas nasais atendidas no pronto-socorro de cirurgia maxilofacial do hospital Carlos Manuel de Céspedes, foi realizado um estudo observacional descritivo que incluiu todos os pacientes (105) que foram atendidos ambulatorialmente com diagnóstico de fratura nasal recente no pronto-socorro no período de janeiro de 2018 a dezembro de 2019. As variáveis estudadas foram idade, sexo, origem, fatores etiológicos, sinais clínicos, classificação segundo deslocamento, exposição do foco da fratura e direção do trauma. Um formulário de coleta de dados foi preparado. Foram utilizados números completos, percentuais e tabelas estatísticas. Foram seguidos princípios éticos para a pesquisa humana. A população mais afetada foi entre 20 e 29 anos, de origem urbana e do sexo masculino. Foi encontrada associação entre sexo e fatores etiológicos, com aagressão física predominante em homens e quedas casuais nas mulheres. O principal sinal clínico presente nos pacientes foi a epistaxe. Fraturas nasais deslocadas, com desvios laterais e fechados predominaram em ambos os sexos.
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RESUMEN Introducción: La región de la cabeza y el cuello es una de las áreas más complejas del cuerpo y el carcinoma epidermoide es la neoplasia maligna más frecuente en esta localización. Objetivo: Caracterizar, desde el punto de vista clínico, epidemiológico y terapéutico, los pacientes con carcinoma epidermoide de cavidad bucal. Métodos: Estudio observacional, descriptivo y transversal en pacientes tratados en un servicio de cirugía maxilofacial entre el 1 de enero de 2018 y el 31 de diciembre de 2020. Se analizaron variables clínicas, epidemiológicas y terapéuticas. La información se obtuvo mediante la entrevista y el examen clínico. Como medidas de resumen se utilizaron frecuencias absolutas y porcentajes. Resultados: Se estudiaron 29 pacientes, con predominio del sexo masculino (69,0 %). La edad media fue de 60,3 años (rango entre 41 y 80 años). La lengua fue la región anatómica más afectada (34,5 %) y la úlcera hundida o infiltrante la variante clínica de mayor presentación (27,6 %). El 48,3 % de las neoplasias fueron diferenciadas histológicamente. El 65,5 % de los diagnósticos se realizó en estadios avanzados de la enfermedad (etapas III y IV). Los tratamientos más utilizados fueron la cirugía (31,0 %) y la combinación de quimioterapia más radioterapia (27,6 %). Conclusión: Predominan los pacientes masculinos, las lesiones linguales, de aspecto ulcerado y diferenciadas histológicamente. La modalidad terapéutica más utilizada fue la cirugía.
ABSTRACT Introduction: Head and neck region is one of the more complex areas of the body and the squamous cell carcinoma is the most frequent malignant neoplasm in this location. Objective: To characterize, from a clinic, epidemiologic and therapeutic point of view, patients with squamous cell carcinoma of the oral cavity. Methods: Observational, descriptive and cross-sectional study with patients treated in maxillofacial surgery service between January 1, 2018 and December 31, 2020. Clinic, epidemiologic and therapeutic variables were analyzed. The information was obtained through interview and clinical examination. Absolute frequencies and percentages were used as summary measures. Results: Twenty-nine (29) patients, with a predominance of males (69.0 %), were studied. Mean age was 12 years (range between 41 and 80 years). The tongue was the most affected anatomical region (34.5 %) and the sunken or infiltrating ulcer was the most common clinical variant (27.6 %); 48.3 % of the neoplasms were differentiated histologically. 65.5 % of the diagnoses were made in advanced stages of the disease (stages III and IV). The most used treatments were surgery (31.0 %) and the combination of chemotherapy plus radiotherapy (27.6 %). Conclusion: Male patients, lingual lesions, ulcerated appearance and histologically differentiated predominated. The most used therapeutic modality was surgery.
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About 4% to 7% of the non-small-cell lung cancer patients have anaplastic lymphoma kinase (ALK) rearrangements, and specific targeted therapies improve patients' outcomes significantly. ALK gene fusions are detected by immunohistochemistry or fluorescent in situ hybridization as gold standards in South America. Next-generation sequencing-based assays are a reliable alternative, able to perform simultaneous detection of multiple events from a single sample. We analyzed 4240 non-small-cell lung cancer samples collected in 37 hospitals from Chile, Brazil, and Peru, where ALK rearrangements were determined as part of their standard of care (SofC) using either immunohistochemistry or fluorescent in situ hybridization. A subset of 1450 samples was sequenced with the Oncomine Focus Assay (OFA), and the concordance with the SofC tests was measured. An orthogonal analysis was performed using a real-time quantitative PCR echinoderm microtubule-associated protein-like 4-ALK fusion detection kit. ALK fusion prevalence is similar for Chile (3.67%; N = 2142), Brazil (4.05%; N = 1013), and Peru (4.59%; N = 675). Although a comparison between OFA and SofC assays showed similar sensitivity, OFA had significantly higher specificity and higher positive predictive value, which opens new opportunities for a more specific determination of ALK gene rearrangements.
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Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Fusão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Proteínas de Fusão Oncogênica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Chile/epidemiologia , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente/métodos , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Peru/epidemiologia , Estudos Prospectivos , Estudos Retrospectivos , Padrão de Cuidado , Adulto JovemRESUMO
AIMS: Breast cancer is one of the leading causes of woman deaths worldwide, being a major public health problem. It has been reported that the expression of the RNA-editing enzyme Adenosine Deaminase Acting on RNAs 1 (ADAR1) is upregulated in breast cancer, predicting poor prognosis in patients. A few reports in literature examine ADAR1 and long non-coding RNAs (lncRNAs) interplay in cancer and suggest key roles in cancer-related pathways. This study aimed to investigate whether ADAR1 could alter the expression levels of lncRNAs and explore how those changes are related to breast cancer biology. MAIN METHODS: ADAR1 overexpression and knockdown studies were performed in breast cancer cell lines to analyze the effects over lncRNAs expression. Guilt-by-Association correlation analysis of the TCGA-BRCA cohort was performed to predict the function of the lncRNA LINC00944. KEY FINDINGS: Here, we show that LINC00944 is responsive to ADAR1 up- and downregulation in breast cancer cells. We found that LINC00944 expression has a strong relationship with immune signaling pathways. Further assessment of the TCGA-BRCA cohort showed that LINC00944 expression was positively correlated to tumor-infiltrating T lymphocytes and pro-apoptotic markers. Moreover, we found that LINC00944 expression was correlated to the age at diagnosis, tumor size, and estrogen and progesterone receptor expression. Finally, we show that low expression of LINC00944 is correlated to poor prognosis in breast cancer patients. SIGNIFICANCE: Our study provides further evidence of the effect of ADAR1 over lncRNA expression levels, and on the participation of LINC00944 in breast cancer, suggesting to further investigate its potential role as prognostic biomarker.
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Adenosina Desaminase/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Adenosina Desaminase/metabolismo , Adulto , Apoptose/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Mutação com Ganho de Função , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Prognóstico , Proteínas de Ligação a RNA/metabolismoRESUMO
Introducción: La dupla Cyberknife y bisturí de rayos gamma (Infini) que se describe es la primera en Latinoamérica. Ambas máquinas han mostrado ser los mejores equipos para radiocirugía intracraneal. Se describe la experiencia inicial de Cyberknife en Centroamérica y su incorporación a un programa existente de bisturí de rayos gamma por vía de análisis comparativos dosimétricos. Material y método: En el año 2019 se realizaron planes comparativos y se trataron 180 pacientes con radiocirugía intracraneal con ambos sistemas tanto en patología tumoral, como vascular y funcional. Resultados: En el análisis dosimétrico comparativo en el gradiente de dosis de Infini mostró ser superior a Cyberknife en todos los casos. Para una esfera utilizando el colimador de 4 mm en Infini y de 5 mm en Cyberknife utilizando un plan isocéntrico con el -Trigeminal Path- el gradiente de dosis para Infini fue de 1.5 y para Cyberknife de 1.66. Para los casos de patología el gradiente de dosis media para Infini fue de 3 mm y para Cyberknife de 3.8 mm. Dando un puntaje de gradiente de dosis (Gradient Score Index) si Infini fuese de 100, Cyberknife obtuvo 87.3. Cyberknife mostró mejor conformalidad y cobertura (97% versus 96%) para todos los targets. Entre enero 2019 y enero 2020 se realizaron 180 radiocirugías, 60 con Cyberknife y 120 con Infini, 60 pacientes recibieron 146 sesiones con Cyberknife, radiocirugía fraccionada 39 (65%) y 21 (35%) en sesión única. Las dosis medias en tumores en dosis única fue 15 Gy (12.5 a 25 Gy) y en radiocirugía fraccionada 21 Gy (18 y 35). Ningún paciente ha experimentado toxicidad mayor a grado dos. Conclusiones: El bisturí de rayos gamma rotatorio reveló superioridad en gradiente de dosis con relación al Cyberknife. En su primer año Cyberknife ha mostrado ser una herramienta segura en el tratamiento de patología intracraneal. Más seguimiento clínico y radiológico es necesario para verificar su efectividad comparativa
Introduction: The match between Cyberknife and Infini here described in this article is the first in Latinamerica. Both machines have proven to be the best for intracranial radiosurgery, we describe our initial experience with Cyberknife in Central America and how it was incorporated in an existing gamma ray program by ways of dosimetry comparisons. Methods: During 2019 comparative plans were made and a total of 180 patients received intracranial radiosurgery with both technologies, patients were treated for tumors, vascular anomalies, and functional pathology. Results: Basic dosimetry analysis regarding dose gradient the Infini proved superior to Cyberknife in all plans. For a sphere using the 4 mm collimator in Infini and the 5 mm in Cyberknife along with an isocentric plan using the -Trigeminal Path- dose gradient was 1.5 for Infini and 1.66 for Cyberknife. For the pathology cases Infini was 3 mm and for Cyberknife 3.8 mm on mean. Giving a Gradient Score Index (GSI) if Infini would be 100, Cyberknife would be 87.3. Cyberknife showed better conformality and coverage for all pathology targets (97% versus 96%). From January 2019 to January 2020, 180 intracranial radiosurgeries were done, 60 with Cyberknife and 120 with Infini, 60 patients received 146 sessions with Cyberknife, fractionated scheme 39 (65%) and 21 (35%) single dose. The median dose for tumors was 15 Gy (12.5 a 25 Gy) for single session and 21 Gy (18 y 35) for fractionated scheme. No patient experienced a higher toxicity tan grade two. Conclusions: In its first year Cyberknife has shown to be safe in treating intracranial pathology. Infini had a better dose gradient than Cyberknife. Longer clinical and radiological follow-up is needed to verify its comparative effectiveness.
Assuntos
Humanos , Radiocirurgia , Cérebro , Metástase Neoplásica , Neoplasias , NeurocirurgiaRESUMO
RNA editing has emerged as a novel mechanism in cancer progression. The double stranded RNA-specific adenosine deaminase (ADAR) modifies the expression of an important proportion of genes involved in cell cycle control, DNA damage response (DDR) and transcriptional processing, suggesting an important role of ADAR in transcriptome regulation. Despite the phenotypic implications of ADAR deregulation in several cancer models, the role of ADAR on DDR and proliferation in breast cancer has not been fully addressed. Here, we show that ADAR expression correlates significantly with clinical outcomes and DDR, cell cycle and proliferation mRNAs of previously reported edited transcripts in breast cancer patients. ADAR's knock-down in a breast cancer cell line produces stability changes of mRNAs involved in DDR and DNA replication. Breast cancer cells with reduced levels of ADAR show a decreased viability and an increase in apoptosis, displaying a significant decrease of their DDR activation, compared to control cells. These results suggest that ADAR plays an important role in breast cancer progression through the regulation of mRNA stability and expression of those genes involved in proliferation and DDR impacting the viability of breast cancer cells.
Assuntos
Adenosina Desaminase/metabolismo , Neoplasias da Mama/metabolismo , Ciclo Celular/fisiologia , Dano ao DNA/fisiologia , Edição de RNA , Proteínas de Ligação a RNA/metabolismo , Transcriptoma , Adenosina Desaminase/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Humanos , Células MCF-7 , Estabilidade de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genéticaRESUMO
BACKGROUND: Current South American populations trace their origins mainly to three continental ancestries, i.e. European, Amerindian and African. Individual variation in relative proportions of each of these ancestries may be confounded with socio-economic factors due to population stratification. Therefore, ancestry is a potential confounder variable that should be considered in epidemiologic studies and in public health plans. However, there are few studies that have assessed the ancestry of the current admixed Chilean population. This is partly due to the high cost of genome-scale technologies commonly used to estimate ancestry. In this study we have designed a small panel of SNPs to accurately assess ancestry in the largest sampling to date of the Chilean mestizo population (n = 3349) from eight cities. Our panel is also able to distinguish between the two main Amerindian components of Chileans: Aymara from the north and Mapuche from the south. RESULTS: A panel of 150 ancestry-informative markers (AIMs) of SNP type was selected to maximize ancestry informativeness and genome coverage. Of these, 147 were successfully genotyped by KASPar assays in 2843 samples, with an average missing rate of 0.012, and a 0.95 concordance with microarray data. The ancestries estimated with the panel of AIMs had relative high correlations (0.88 for European, 0.91 for Amerindian, 0.70 for Aymara, and 0.68 for Mapuche components) with those obtained with AXIOM LAT1 array. The country's average ancestry was 0.53 ± 0.14 European, 0.04 ± 0.04 African, and 0.42 ± 0.14 Amerindian, disaggregated into 0.18 ± 0.15 Aymara and 0.25 ± 0.13 Mapuche. However, Mapuche ancestry was highest in the south (40.03%) and Aymara in the north (35.61%) as expected from the historical location of these ethnic groups. We make our results available through an online app and demonstrate how it can be used to adjust for ancestry when testing association between incidence of a disease and nongenetic risk factors. CONCLUSIONS: We have conducted the most extensive sampling, across many different cities, of current Chilean population. Ancestry varied significantly by latitude and human development. The panel of AIMs is available to the community for estimating ancestry at low cost in Chileans and other populations with similar ancestry.
Assuntos
Etnicidade/genética , Genética Populacional/organização & administração , Indígenas Sul-Americanos/genética , Polimorfismo de Nucleotídeo Único/genética , Grupos Populacionais/genética , Chile , Feminino , Frequência do Gene/genética , Marcadores Genéticos/genética , Genótipo , Técnicas de Genotipagem , Humanos , Masculino , Filogeografia , SalivaRESUMO
BACKGROUND: Current South American populations trace their origins mainly to three continental ancestries, i.e. European, Amerindian and African. Individual variation in relative proportions of each of these ancestries may be confounded with socio-economic factors due to population stratification. Therefore, ancestry is a potential confounder variable that should be considered in epidemiologic studies and in public health plans. However, there are few studies that have assessed the ancestry of the current admixed Chilean population. This is partly due to the high cost of genome-scale technologies commonly used to estimate ancestry. In this study we have designed a small panel of SNPs to accurately assess ancestry in the largest sampling to date of the Chilean mestizo population (n = 3349) from eight cities. Our panel is also able to distinguish between the two main Amerindian components of Chileans: Aymara from the north and Mapuche from the south. RESULTS: A panel of 150 ancestry-informative markers (AIMs) of SNP type was selected to maximize ancestry informativeness and genome coverage. Of these, 147 were successfully genotyped by KASPar assays in 2843 samples, with an average missing rate of 0.012, and a 0.95 concordance with microarray data. The ancestries estimated with the panel of AIMs had relative high correlations (0.88 for European, 0.91 for Amerindian, 0.70 for Aymara, and 0.68 for Mapuche components) with those obtained with AXIOM LAT1 array. The country's average ancestry was 0.53 ± 0.14 European, 0.04 ± 0.04 African, and 0.42 ± 0.14 Amerindian, disaggregated into 0.18 ± 0.15 Aymara and 0.25 ± 0.13 Mapuche. However, Mapuche ancestry was highest in the south (40.03%) and Aymara in the north (35.61%) as expected from the historical location of these ethnic groups. We make our results available through an online app and demonstrate how it can be used to adjust for ancestry when testing association between incidence of a disease and nongenetic risk factors. CONCLUSIONS: We have conducted the most extensive sampling, across many different cities, of current Chilean population. Ancestry varied significantly by latitude and human development. The panel of AIMs is available to the community for estimating ancestry at low cost in Chileans and other populations with similar ancestry.
Assuntos
Humanos , Masculino , Feminino , Etnicidade/genética , Indígenas Sul-Americanos/genética , Polimorfismo de Nucleotídeo Único/genética , Grupos Populacionais/genética , Genética Populacional/organização & administração , Saliva , Marcadores Genéticos/genética , Chile , Filogeografia , Técnicas de Genotipagem , Frequência do Gene/genética , GenótipoRESUMO
BACKGROUND: Whole transcriptome RNA variant analyses have shown that adenosine deaminases acting on RNA (ADAR) enzymes modify a large proportion of cellular RNAs, contributing to transcriptome diversity and cancer evolution. Despite the advances in the understanding of ADAR function in breast cancer, ADAR RNA editing functional consequences are not fully addressed. RESULTS: We characterized A to G(I) mRNA editing in 81 breast cell lines, showing increased editing at 3'UTR and exonic regions in breast cancer cells compared to immortalized non-malignant cell lines. In addition, tumors from the BRCA TCGA cohort show a 24% increase in editing over normal breast samples when looking at 571 well-characterized UTRs targeted by ADAR1. Basal-like subtype breast cancer patients with high level of ADAR1 mRNA expression shows a worse clinical outcome and increased editing in their 3'UTRs. Interestingly, editing was particularly increased in the 3'UTRs of ATM, GINS4 and POLH transcripts in tumors, which correlated with their mRNA expression. We confirmed the role of ADAR1 in this regulation using a shRNA in a breast cancer cell line (ZR-75-1). CONCLUSIONS: Altogether, these results revealed a significant association between the mRNA editing in genes related to cancer-relevant pathways and clinical outcomes, suggesting an important role of ADAR1 expression and function in breast cancer.
Assuntos
Regiões 3' não Traduzidas/genética , Adenosina Desaminase/genética , Neoplasias da Mama/genética , Edição de RNA/genética , Estabilidade de RNA/genética , Proteínas de Ligação a RNA/genética , Adenosina Desaminase/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estabilidade de RNA/fisiologia , Proteínas de Ligação a RNA/metabolismoRESUMO
Patagonia was the last region of the Americas reached by humans who entered the continent from Siberia â¼15,000-20,000 y ago. Despite recent genomic approaches to reconstruct the continental evolutionary history, regional characterization of ancient and modern genomes remains understudied. Exploring the genomic diversity within Patagonia is not just a valuable strategy to gain a better understanding of the history and diversification of human populations in the southernmost tip of the Americas, but it would also improve the representation of Native American diversity in global databases of human variation. Here, we present genome data from four modern populations from Central Southern Chile and Patagonia (n = 61) and four ancient maritime individuals from Patagonia (â¼1,000 y old). Both the modern and ancient individuals studied in this work have a greater genetic affinity with other modern Native Americans than to any non-American population, showing within South America a clear structure between major geographical regions. Native Patagonian Kawéskar and Yámana showed the highest genetic affinity with the ancient individuals, indicating genetic continuity in the region during the past 1,000 y before present, together with an important agreement between the ethnic affiliation and historical distribution of both groups. Lastly, the ancient maritime individuals were genetically equidistant to a â¼200-y-old terrestrial hunter-gatherer from Tierra del Fuego, which supports a model with an initial separation of a common ancestral group to both maritime populations from a terrestrial population, with a later diversification of the maritime groups.
Assuntos
Variação Genética , Genoma Humano , Indígenas Sul-Americanos/genética , Chile , Feminino , História Antiga , Humanos , Indígenas Sul-Americanos/história , MasculinoRESUMO
BACKGROUND: Whole transcriptome RNA variant analyses have shown that adenosine deaminases acting on RNA ( ADAR ) enzymes modify a large proportion of cellular RNAs, contributing to transcriptome diversity and cancer evolution. Despite the advances in the understanding of ADAR function in breast cancer, ADAR RNA editing functional consequences are not fully addressed. RESULTS: We characterized A to G(I) mRNA editing in 81 breast cell lines, showing increased editing at 3'UTR and exonic regions in breast cancer cells compared to immortalized non-malignant cell lines. In addition, tumors from the BRCA TCGA cohort show a 24% increase in editing over normal breast samples when looking at 571 well-characterized UTRs targeted by ADAR1. Basal-like subtype breast cancer patients with high level of ADAR1 mRNA expression shows a worse clinical outcome and increased editing in their 3'UTRs. Interestingly, editing was particularly increased in the 3'UTRs of ATM, GINS4 and POLH transcripts in tumors, which correlated with their mRNA expression. We confirmed the role of ADAR1 in this regulation using a shRNA in a breast cancer cell line (ZR-75-1). CONCLUSIONS: Altogether, these results revealed a significant association between the mRNA editing in genes related to cancer-relevant pathways and clinical outcomes, suggesting an important role of ADAR1 expression and function in breast cancer.