RESUMEN

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide; it is the fourth leading cause of death in the world and the third in Brazil. Mutations in the APC, DCC, KRAS and TP53 genes have been associated with the progression of sporadic CRC, occurring at defined pathological stages of the tumor progression and consequently modulating several genes in the corresponding signaling pathways. Therefore, the identification of gene signatures that occur at each stage during the CRC progression is critical and can present an impact on the diagnosis and prognosis of the patient. In this study, our main goal was to determine these signatures, by evaluating the gene expression of paired colorectal adenoma and adenocarcinoma samples to identify novel genetic markers in association to the adenoma-adenocarcinoma stage transition. METHODS: Ten paired adenoma and adenocarcinoma colorectal samples were subjected to microarray gene expression analysis. In addition, mutations in APC, KRAS and TP53 genes were investigated by DNA sequencing in paired samples of adenoma, adenocarcinoma, normal tissue, and peripheral blood from ten patients. RESULTS: Gene expression analysis revealed a signature of 689 differentially expressed genes (DEG) (fold-change> 2, p< 0.05), between the adenoma and adenocarcinoma paired samples analyzed. Gene pathway analysis using the 689 DEG identified important cancer pathways such as remodeling of the extracellular matrix and epithelial-mesenchymal transition. Among these DEG, the ETV4 stood out as one of the most expressed in the adenocarcinoma samples, further confirmed in the adenocarcinoma set of samples from the TCGA database. Subsequent in vitro siRNA assays against ETV4 resulted in the decrease of cell proliferation, colony formation and cell migration in the HT29 and SW480 colorectal cell lines. DNA sequencing analysis revealed KRAS and TP53 gene pathogenic mutations, exclusively in the adenocarcinomas samples. CONCLUSION: Our study identified a set of genes with high potential to be used as biomarkers in CRC, with a special emphasis on the ETV4 gene, which demonstrated involvement in proliferation and migration.

Asunto(s)

Adenocarcinoma/genética , Adenoma/genética , Neoplasias Colorrectales/genética , Genes Relacionados con las Neoplasias , Proteínas de Neoplasias/fisiología , Proteínas Proto-Oncogénicas c-ets/fisiología , Adenocarcinoma/química , Adenocarcinoma/patología , Adenoma/química , Adenoma/patología , Anciano , Biomarcadores de Tumor/genética , Brasil , División Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Transformación Celular Neoplásica/genética , Neoplasias Colorrectales/química , Neoplasias Colorrectales/patología , ADN de Neoplasias/genética , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Ontología de Genes , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-ets/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-ets/genética , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Análisis de Matrices Tisulares , Transcriptoma , Ensayo de Tumor de Célula Madre

RESUMEN

Glioblastoma (GBM) is the most aggressive brain primary malignancy. Toll-like receptor 4 (TLR4) has a dual role in cell fate, promoting cell survival or death depending on the context. Here, we analyzed TLR4 expression in different grades of astrocytoma, and observed increased expression in tumors, mainly in GBM, compared to non-neoplastic brain tissue. TLR4 role was investigated in U87MG, a GBM mesenchymal subtype cell line, upon LPS stimulation. p65 nuclear translocation was observed in late phase, suggesting TLR4-non-canonical pathway activation. In fact, components of ripoptosome and inflammasome cascades were upregulated and they were significantly correlated in GBMs of the TCGA-RNASeq dataset. Moreover, an increased apoptotic rate was observed when the GBM-derived U87MG cells were co-treated with LPS and Temozolomide (TMZ) in comparison to TMZ alone. Increased TLR4 immunostaining was detected in nuclei of U87MG cells 12 h after LPS treatment, concomitant to activation of DNA repair genes. Time-dependent increased RAD51, FEN1 and UNG expression levels were confirmed after LPS stimulation, which may contribute to tumor cell fitness. Moreover, the combined treatment with the RAD51 inhibitor, Amuvatinib in combination with, TMZ after LPS stimulation reduced tumor cell viability more than with each treatment alone. In conclusion, our results suggest that stimulation of TLR4 combined with pharmacological inhibition of the DNA repair pathway may be an alternative treatment for GBM patients.

Asunto(s)

Neoplasias Encefálicas/metabolismo , Núcleo Celular/metabolismo , Reparación del ADN , ADN de Neoplasias/metabolismo , Glioblastoma/metabolismo , Proteínas de Neoplasias/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Factor de Transcripción ReIA/metabolismo , Transporte Activo de Núcleo Celular , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Núcleo Celular/genética , ADN de Neoplasias/genética , Femenino , Glioblastoma/genética , Humanos , Masculino , Proteínas de Neoplasias/genética , Receptor Toll-Like 4/genética , Factor de Transcripción ReIA/genética

RESUMEN

INTRODUCTION AND OBJECTIVES: Intrahepatic (I-CCA) and extrahepatic (E-CCA) cholangiocarcinoma (CCA) have different growth patterns and risks for tumor metastasis. Inhibition and/or activation of the chemokine receptor CCR subclasses have been reported to alter tumor cell biology in non-CCA cancers. In this study we documented CCR expression profiles in representative human I-CCA and E-CCA cell lines and the in vitro effects of CCR antagonists and agonists on tumor cell biology. MATERIALS AND METHODS: CCR expression profiles were documented by real-time reverse transcription polymerase chain reaction; cell proliferation by WST-1; spheroid formation by sphere dimensions in anchorage-free medium; cell migration by wound healing and invasion by Transwell invasion chambers. RESULTS: All 10 CCR motifs (CCR1-10) were expressed in the I-CCA, HuCCT1 cell line and six (CCR4, 5, 6, 8, 9 and 10) in the E-CCA, KMBC cell line. In HuCCT1 cells, CCR5 expression was most abundant whereas in KMBC cells, CCR6 followed by CCR5 were most abundant. The CCR5 antagonist Maraviroc significantly inhibited cell proliferation, migration and invasion in HuCCT1 cells, and spheroid formation and invasion in KMBC cells. The CCR5 agonist RANTES had no effect on HuCCT1 cells but increased cell proliferation, migration and invasion of KMBC cells. CONCLUSION: These results suggest that CCR expression profiles differ in I-CCA and E-CCA. They also indicate that CCR5 antagonists and agonists have cell-specific effects but in general, CCR5 inactivation inhibits CCA tumor cell aggressiveness. Additional research is required to determine whether CCR5 inactivation is of value in the treatment of CCA in humans.

Asunto(s)

Neoplasias de los Conductos Biliares/genética , Conductos Biliares Extrahepáticos/patología , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/genética , ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica , Receptores CCR5/genética , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Extrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/metabolismo , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Proliferación Celular/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , ADN de Neoplasias/metabolismo , Humanos , Receptores CCR5/biosíntesis , Transducción de Señal

RESUMEN

Human diversity is one of the main pitfalls in the development of robust worldwide biomarkers in oncology. Epigenetic variability across human populations is associated with different genetic backgrounds, as well as variable lifestyles and environmental exposures, each of which should be investigated. To identify potential non-invasive biomarkers of sporadic breast cancer in the Uruguayan population, we studied genome-wide DNA methylation using Illumina methylation arrays in leukocytes of 22 women with sporadic breast cancer and 10 healthy women in a case-control study. We described a panel of 38 differentially methylated CpG positions that was able to cluster breast cancer patients (BCP) and controls, and that also recapitulated methylation differences in 12 primary breast tumors and their matched normal breast tissue. Moving forward, we simplified the detection method to improve its applicability in a clinical setting and used an independent well-characterized cohort of 80 leukocyte DNA samples from BCP and 80 healthy controls to validate methylation results at specific cancer-related genes. Our investigations identified methylation at CYFIP1 as a novel epigenetic biomarker candidate for sporadic breast cancer in the Uruguayan population. These results provide a proof-of-concept for the design of larger studies aimed at validating biomarker panels for the Latin American population.

Asunto(s)

Biomarcadores de Tumor , Neoplasias de la Mama , Metilación de ADN , ADN de Neoplasias , Bases de Datos de Ácidos Nucleicos , Hispánicos o Latinos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/etnología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Estudios de Casos y Controles , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Tasa de Supervivencia , Estados Unidos/epidemiología

RESUMEN

Pigmentation characteristics are well-known risk factors for skin cancer. Polymorphisms in pigmentation genes have been associated with these traits and with the risk of malignancy. However, the functional relationship between genetic variation and disease is still unclear. This study aims to assess whether pigmentation SNPs are associated with pigmentary traits and skin cancer via DNA methylation (DNAm). Using a meta-GWAS of whole-blood DNAm from 36 European cohorts (N = 27,750; the Genetics of DNA Methylation Consortium, GoDMC), we found that 19 out of 27 SNPs in 10 pigmentation genes were associated with 391 DNAm sites across 30 genomic regions. We examined the effect of 25 selected DNAm sites on pigmentation traits, sun exposure phenotypes and skin cancer and on gene expression in whole blood. We uncovered an association of DNAm site cg07402062 with red hair in the Avon Longitudinal Study of Parents and Children (ALSPAC). We also found that the expression of ASIP and CDK10 was associated with hair colour, melanoma and basal cell carcinoma. Our results indicate that DNAm and expression of pigmentation genes may play a role as potential mediators of the relationship between genetic variants, pigmentation phenotypes and skin cancer and thus deserve further scrutiny.

Asunto(s)

Proteína de Señalización Agouti/genética , Carcinoma Basocelular/genética , Quinasas Ciclina-Dependientes/genética , Metilación de ADN , ADN de Neoplasias/genética , Melanoma/genética , Proteínas de Neoplasias/genética , Neoplasias Cutáneas/genética , Pigmentación de la Piel/genética , Proteína de Señalización Agouti/metabolismo , Carcinoma Basocelular/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , ADN de Neoplasias/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Estudios Longitudinales , Melanoma/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Cutáneas/metabolismo

RESUMEN

Tumor DNA has been detected in body fluids of cancer patients. Somatic tumor mutations are being used as biomarkers in body fluids to monitor chemotherapy response as a minimally invasive tool. In this study, we evaluated the potential of tracking somatic mutations in free DNA of plasma and urine collected from Wilms tumor (WT) patients for monitoring treatment response. Wilms tumor is a pediatric renal tumor resulting from cell differentiation errors during nephrogenesis. Its mutational repertoire is not completely defined. Thus, for identifying somatic mutations from tumor tissue DNA, we screened matched tumor/leukocyte DNAs using either a panel containing 16 WT-associated genes or whole-exome sequencing (WES). The identified somatic tumor mutations were tracked in urine and plasma DNA collected before, during and after treatment. At least one somatic mutation was identified in five out of six WT tissue samples analyzed. Somatic mutations were detected in body fluids before treatment in all five patients (three patients in urine, three in plasma, and one in both body fluids). In all patients, a decrease of the variant allele fraction of somatic mutations was observed in body fluids during neoadjuvant chemotherapy. Interestingly, the persistence of somatic mutations in body fluids was in accordance with clinical parameters. For one patient who progressed to death, it persisted in high levels in serial body fluid samples during treatment. For three patients without disease progression, somatic mutations were not consistently detected in samples throughout monitoring. For one patient with bilateral disease, a somatic mutation was detected at low levels with no support of clinical manifestation. Our results demonstrated the potential of tracking somatic mutations in urine and plasma DNA as a minimally invasive tool for monitoring WT patients. Additional investigation is needed to check the clinical value of insistent somatic mutations in body fluids.

Asunto(s)

ADN de Neoplasias/genética , Neoplasias Renales/genética , Mutación , Tumor de Wilms/genética , Alelos , Quimioterapia Adyuvante , Preescolar , ADN de Neoplasias/sangre , ADN de Neoplasias/orina , Femenino , Humanos , Lactante , Neoplasias Renales/sangre , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/orina , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Terapia Neoadyuvante , Secuenciación del Exoma , Tumor de Wilms/sangre , Tumor de Wilms/tratamiento farmacológico , Tumor de Wilms/orina

RESUMEN

Introduction: Breast cancer is a worldwide public health problem; between 5% and 10% of the cases present familial aggregation explained by genes of high risk such as BRCA1 and BRCA2. The founding origin of the deletion BRCA1 3450del4 in Colombia has been previously reported. Objective: To carry out in six families from Tolima and Huila departments a descriptive analysis of the presence of the BRCA1 3450del4 mutation associated with breast cancer and familial aggregation. Materials and methods: We conducted a descriptive and cross-sectional study of six index cases with breast cancer positive for BRCA1 3450del4 that fulfilled three of the criteria established by Jalkh, et al. The genealogical trees were made using the information of the interview data (GenoPro™, version 2016). The mutation was typified in healthy and affected relatives who agreed to participate. Results: Thirty of the 78 individuals selected by convenience in the six families presented the mutation BRCA1 3450del4 six of whom developed breast cancer, one, ovarian cancer, one ovarian and breast cancer, and one prostate cancer; 21 did not present any type of neoplasm at the time of the study. Of the 30 individuals carrying the pathogenic variant, six were men, 24 were women, and 13 of these were under 30. Conclusions: In this study of families with the deletion BRCA1 3450del4 in Tolima and Huila we confirmed its association with familial aggregation of breast cancer.

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Introducción. El cáncer de mama es un problema mundial de salud pública; entre el 5 y el 10 % de los casos presentan agregación familiar, lo que se explicaría por la presencia de mutaciones en genes de alto riesgo como el BRCA1 y el BRCA2. El origen fundador de la deleción BRCA1 3450del4 en Colombia ya fue reportado. Objetivo. Hacer un análisis descriptivo de seis familias del del Tolima y del Huila con la deleción BRCA1 3450del4 de la asociación de la mutación germinal, con el cáncer de mama y la agregación familiar. Materiales y métodos. Se hizo un estudio descriptivo y transversal de seis casos índice con cáncer de mama positivos para BRCA1 3450del4, que cumplían tres de los criterios establecidos por Jalkh, et al. A partir de la información de las entrevistas, se realizaron los árboles genealógicos (GenoPro™, versión 2016). Se tipificó la mutación en familiares sanos y afectados que aceptaron participar. Resultados. De los 78 individuos seleccionados por conveniencia en las seis familias, 30 presentaron la mutación BRCA1 3450del4; de ellos, seis tenían cáncer de mama, uno, cáncer de ovario, uno, cáncer de mama y ovario, y otro, cáncer de próstata; 21 no presentaban neoplasias. De los 30 individuos portadores de la variante patogénica, seis eran hombres y 24 mujeres, 13 de ellas menores de 30 años. Conclusiones. En este estudio se confirmó la asociación de la deleción BRCA1 3450del4 con el cáncer de mama de agregación familiar.

Asunto(s)

Proteína BRCA1/genética , Neoplasias de la Mama/genética , Genes BRCA1 , Eliminación de Secuencia , Adulto , Neoplasias de la Mama/epidemiología , Ciudades , Colombia/epidemiología , Estudios Transversales , ADN de Neoplasias/genética , Salud de la Familia , Femenino , Mutación de Línea Germinal , Humanos , Masculino , Neoplasias Ováricas/genética , Linaje , Neoplasias de la Próstata/genética , Adulto Joven

RESUMEN

Importance: Comprehensive understanding of the genomic and gene-expression differences between retinoblastoma tumors from patients with bilateral disease may help to characterize risk and optimize treatment according to individual tumor characteristics. Objective: To compare the genomic features between each eye and a specimen from an orbital relapse in patients with bilateral retinoblastoma. Design, Setting, and Participants: In this case, 2 patients with retinoblastoma underwent upfront bilateral enucleation. Tumor samples were subjected to genomic and gene-expression analysis. Primary cell cultures were established from both of the tumors of 1 patient and were used for gene-expression studies. Main Outcomes and Measures: Whole-exome sequencing was performed on an Illumina platform for fresh tumor samples and DNA arrays (CytoScan or OncoScan) were used for paraffin-embedded samples and cell lines. Gene-expression analysis was performed using Agilent microarrays. Germinal and somatic alterations, copy number alterations, and differential gene expression were assessed. Results: After initial bilateral enucleation, patient 1 showed massive choroidal and laminar optic nerve infiltration, while patient 2 showed choroidal and laminar optic nerve invasion. Patient 1 developed left-eye orbital recurrence and bone marrow metastasis less than 1 year after enucleation. Both ocular tumors showed gains on 1q and 6p but presented other distinct genomic alterations, including an additional gain in 2p harboring the N-myc proto-oncogene (MYCN) in the left tumor and orbital recurrence. Similar copy number alterations between the orbital recurrence and the left eye supported the origin of the relapse, with an additional 11q loss only detected in the orbital relapse. Specimens from patient 2 showed common copy number gains and losses, but further evolution rendered a 2p gain spanning MYCN in the left tumor. For this patient, microarray expression analysis showed differential expression of the MYCN and the forkhead box protein G1 (FOXG1) gene pathways between the left and right tumors. Conclusions and Relevance: Differential genomic and gene expression features were observed between tumors in 2 patients with bilateral disease, confirming intereye heterogeneity that might be considered if targeted therapies are used in such patients. Chromosomal alteration profile supported the origin of the orbital recurrence from the homolateral eye in 1 patient. Loss in chromosome 11q may have been associated with extraocular relapse in this patient.

Asunto(s)

Regulación Neoplásica de la Expresión Génica/genética , Heterogeneidad Genética , Genómica , Neoplasias de la Retina/genética , Retinoblastoma/genética , Transcriptoma , Línea Celular Tumoral , Variaciones en el Número de Copia de ADN , ADN de Neoplasias/genética , Enucleación del Ojo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Pérdida de Heterocigocidad , Polimorfismo de Nucleótido Simple , Proto-Oncogenes Mas , Neoplasias de la Retina/patología , Retinoblastoma/patología , Secuenciación del Exoma

RESUMEN

Mechanisms of viral oncogenesis are diverse and include the off-target activity of enzymes expressed by the infected cells, which evolved to target viral genomes for controlling their infection. Among these enzymes, the single-strand DNA editing capability of APOBECs represent a well-conserved viral infection response that can also cause untoward mutations in the host DNA. Here we show, after evaluating somatic single-nucleotide variations and transcriptome data in 240 gastric cancer samples, a positive correlation between APOBEC3s mRNA-expression and the APOBEC-mutation signature, both increased in EBV+ tumors. The correlation was reinforced by the observation of APOBEC mutations preferentially occurring in the genomic loci of the most active transcripts. This EBV infection and APOBEC3 mutation-signature axis were confirmed in a validation cohort of 112 gastric cancer patients. Our findings suggest that APOBEC3 upregulation in EBV+ cancer may boost the mutation load, providing further clues to the mechanisms of EBV-induced gastric carcinogenesis. After further validation, this EBV-APOBEC axis may prove to be a secondary driving force in the mutational evolution of EBV+ gastric tumors, whose consequences in terms of prognosis and treatment implications should be vetted.

Asunto(s)

Citidina Desaminasa/genética , ADN de Neoplasias/genética , Herpesvirus Humano 4/patogenicidad , Neoplasias Gástricas/virología , Desaminasas APOBEC , Carcinogénesis , Genes Virales , Herpesvirus Humano 4/genética , Humanos , Mutación , Neoplasias Gástricas/patología

RESUMEN

HPV73 is classified as possibly oncogenic. It is neither routinely evaluated in HPV screening, nor covered by any of the prophylactic vaccines. We sought to investigate the carcinogenic characteristics of HPV73. Molecular studies were performed on eight cervix cancer biopsy specimens containing HPV73 from a cross-sectional cancer cohort of 590 women referred to the National Cancer Institute in Rio de Janeiro, Brazil. Transcriptional activity of HPV73 was evaluated by detection of spliced transcripts of E6/E6* and E1^E4 in cDNA created from RNA isolated from fresh tissue. Disruption of viral E1 and E2 genes in the tumor DNA was assessed by overlapping PCR amplification. Evaluation of viral integration was performed using a customized capture panel and next-generation sequencing, and an in-house bioinformatic pipeline. HPV73 E6/E6* transcripts were found in 7/7 specimens with available RNA, and three also had HPV73 E1^E4 transcripts. Disruption of E1 and E2 genes was observed in 4/8 specimens. Integration of HPV73 sequences into the cancer cell genomes was identified in all cervix cancer tissues. These results provide evidence that HPV73 is an oncogenic virus that can cause invasive cervix cancer. With current molecular screening and HPV vaccination, not all cervix cancers will be prevented.

Asunto(s)

Infecciones por Papillomavirus/complicaciones , Neoplasias del Cuello Uterino/etiología , Neoplasias del Cuello Uterino/virología , Adulto , Anciano , Brasil , Estudios Transversales , ADN de Neoplasias/genética , Femenino , Humanos , Persona de Mediana Edad , Proteínas Oncogénicas Virales/genética , Papillomaviridae/genética , Reacción en Cadena de la Polimerasa/métodos , ARN Viral/genética , Integración Viral/genética

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is one of the most frequent cancers. Genetic mutations in CRC already described can be detected in feces. Microarray methods in feces can represent a new diagnostic tool for CRC and significant improvement at public health. AIM: to analyze stool DNA by human DNA quantify and microarray methods as alternatives to CRC screening. METHOD: Three methods were analyzed in stool samples: Human DNA Quantify, RanplexCRC and KRAS/BRAF/PIK3CA (KBP) Arrays. RESULTS: KBP array mutations were presented in 60.7% of CRC patients and RanplexCRC Array mutations in 61.1% of CRC patients. Sensitivity and specificity for human DNA quantification was 66% and 82% respectively. Fecal KBP Array had 35% sensitivity and 96% specificity and RanplexCRC Array method had 78% sensitivity and 100% specificity. CONCLUSION: Microarray methods showed promise as potential biomarkers for CRC screening; however, these methods had to be optimized to improve accuracy and applicability by clinical routine.

Asunto(s)

Pólipos del Colon/genética , Neoplasias Colorrectales/genética , ADN de Neoplasias/genética , Heces/química , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Anciano , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Pólipos del Colon/diagnóstico , Colonoscopía , Neoplasias Colorrectales/diagnóstico , ADN de Neoplasias/análisis , Detección Precoz del Cáncer/métodos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico

RESUMEN

PURPOSE: Despite considerable evidence that supports the NF-kB role in the immune system and lymphomagenesis, it is unclear whether specific NF-kB dimers control a particular set of genes that account for their biological functions. Our previous work showed that Hodgkin Lymphoma (HL) is unique, among germinal center (GC)-derived lymphomas, with respect to its dependency on Rel-B to survive. In contrast, diffuse large B-Cell lymphoma (DLBCL) including both Activated B-Cell-Like and Germinal Center B-Cell-Like, requires cREL and Rel-A to survive and it is not affected by Rel-B depletion. These findings highlighted the activity of specific NF-kB subunits in different GC-derived lymphomas. METHODS: Sequenced chromatin immunoprecipitated DNA fragments (ChIP-Seq) analysis revealed an extensive NF-kB DNA-binding network in DLBCL and HL. The ChIP-Seq data was merged with microarray analysis following the Rel-A, Rel-B or cRel knockdown to determine effectively regulated genes. RESULTS: Downstream target analysis showed enrichment for cell cycle control, among other signatures. Rel-B and cRel controlled different genes within the same signature in HL and DLBCL, respectively. BCL2 was exclusively controlled by Rel-B in HL. Both mRNA and protein levels decreased following Rel-B depletion meanwhile there was no change upon cRel knock-down. BCL2 exogenous expression partially rescued the death induced by decreased Rel-B in HL cells. CONCLUSION: The Rel-B hierarchical network defined HL and the cRel hierarchical network characterized DLBCL. Each Rel member performs specific functions in distinct GC-derived lymphomas. This result should be considered for the development of targeted therapies that are aimed to selectively inhibit individual NF-kB dimers.

Asunto(s)

ADN de Neoplasias/metabolismo , Enfermedad de Hodgkin/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , FN-kappa B/metabolismo , Apoptosis/genética , Linfocitos B/metabolismo , Linfocitos B/patología , Línea Celular Tumoral , ADN de Neoplasias/genética , Perfilación de la Expresión Génica , Células HEK293 , Enfermedad de Hodgkin/genética , Humanos , Linfoma de Células B Grandes Difuso/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-rel/genética , Proteínas Proto-Oncogénicas c-rel/metabolismo , Transducción de Señal , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Factor de Transcripción ReIB/genética , Factor de Transcripción ReIB/metabolismo , Transcripción Genética

RESUMEN

This review aims to present the genetic, clinical and diagnostic aspects of Lynch syndrome, as well as providing the most relevant information about genetic counseling in these patients and the current recommendations for their surveillance.

Asunto(s)

Neoplasias Colorrectales Hereditarias sin Poliposis , Algoritmos , Biomarcadores de Tumor , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/historia , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Reparación de la Incompatibilidad de ADN/genética , ADN de Neoplasias/genética , Diagnóstico Diferencial , Endoscopía Gastrointestinal , Genes Relacionados con las Neoplasias , Estudios de Asociación Genética , Asesoramiento Genético , Heterogeneidad Genética , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Inestabilidad de Microsatélites , Modelos Genéticos , Síndromes Neoplásicos Hereditarios/diagnóstico , Penetrancia , Riesgo , Medición de Riesgo

RESUMEN

Esta revisión tiene como objetivo dar a conocer los aspectos genéticos, clínicos y diagnósticos del síndrome de Lynch, además de brindar la información más relevante acerca de la asesoría genética en estos pacientes y las recomendaciones actuales para su seguimiento.

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This review aims to present the genetic, clinical and diagnostic aspects of Lynch syndrome, as well as providing the most relevant information about genetic counseling in these patients and the current recommendations for their surveillance.

Asunto(s)

Historia del Siglo XIX , Historia del Siglo XX , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis , Algoritmos , Síndromes Neoplásicos Hereditarios/diagnóstico , ADN de Neoplasias/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/historia , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Biomarcadores de Tumor , Riesgo , Endoscopía Gastrointestinal , Medición de Riesgo , Heterogeneidad Genética , Penetrancia , Diagnóstico Diferencial , Genes Relacionados con las Neoplasias , Inestabilidad de Microsatélites , Reparación de la Incompatibilidad de ADN/genética , Estudios de Asociación Genética , Asesoramiento Genético , Modelos Genéticos

RESUMEN

Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including IDH1, IDH2, HUWE1, KLHL6, and PTPN11 Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure. Patients with more driver gene abnormalities are associated with worse outcomes, as are identified mechanisms of genomic instability. Oncogenic dependencies were identified between mutations in driver genes, common regions of copy number change, and primary translocation and hyperdiploidy events. These dependencies included associations with t(4;14) and mutations in FGFR3, DIS3, and PRKD2; t(11;14) with mutations in CCND1 and IRF4; t(14;16) with mutations in MAF, BRAF, DIS3, and ATM; and hyperdiploidy with gain 11q, mutations in FAM46C, and MYC rearrangements. These associations indicate that the genomic landscape of myeloma is predetermined by the primary events upon which further dependencies are built, giving rise to a nonrandom accumulation of genetic hits. Understanding these dependencies may elucidate potential evolutionary patterns and lead to better treatment regimens.

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/genética , Mutagénesis , Oncogenes , Células Clonales , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Conjuntos de Datos como Asunto , Dosificación de Gen , Estudio de Asociación del Genoma Completo , Inestabilidad Genómica , Genómica , Humanos , Pérdida de Heterocigocidad , Mieloma Múltiple/patología , Mutación , Pronóstico , Translocación Genética , Resultado del Tratamiento , Secuenciación del Exoma

RESUMEN

High-risk Human Papillomavirus (HR-HPV) is the causative agent of different human cancers. A persistent HR-HPV infection alters several cellular processes involved in cell proliferation, apoptosis, immune evasion, genomic instability and transformation. Cumulative evidence from past studies indicates that HR-HPV proteins are associated with oxidative stress (OS) and has been proposed as a risk factor for cancer development. Reactive oxygen and nitrogen species (RONS) regulate a plethora of processes inducing cellular proliferation, differentiation and death. Oxidative stress (OS) is generated when an imbalance in the redox state occurs due to deregulation of the oxidant and antioxidant systems, which, in turn, promotes the damage of DNA, proteins and lipids, allowing the accumulation of mutations and genome instability. OS has been associated with the establishment and development of different cancers, and it has recently been proposed as a co-factor in cervical cancer development. This review is focused on evidence regarding the association of OS with HR-HPV proteins, and the interplay of the viral proteins with different elements of the antioxidant and DNA damage response (DDR) systems, emphasizing the processes that might be required for the viral life cycle and viral DNA integration into the host genome, which is a key element in the carcinogenic process induced by HR-HPV.

Asunto(s)

Transformación Celular Neoplásica/genética , ADN de Neoplasias/genética , Papillomaviridae/patogenicidad , Infecciones por Papillomavirus/genética , Neoplasias del Cuello Uterino/genética , Proteínas Virales/genética , Muerte Celular , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Daño del ADN , ADN de Neoplasias/química , ADN de Neoplasias/metabolismo , Femenino , Inestabilidad Genómica , Interacciones Huésped-Patógeno , Humanos , Oxidación-Reducción , Estrés Oxidativo , Papillomaviridae/genética , Papillomaviridae/metabolismo , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Proteínas Virales/metabolismo

RESUMEN

Next generation sequencing (NGS) has become an informative tool to guide cancer treatment and conduce a personalized approach in oncology. The biopsy collected for pathologic analysis is usually stored as formalin-fixed paraffin-embedded (FFPE) blocks and then availed for molecular diagnostic, resulting in DNA molecules that are invariably fragmented and chemically modified. In an attempt to improve NGS based diagnostics in oncology we developed a straightforward DNA integrity assessment assay based on qPCR, defining clear parameters to whether NGS sequencing results is accurate or when it should be analyzed with caution. We performed DNA extraction from 12 tumor samples from diverse tissues and accessed DNA integrity by straightforward qPCR assays. In order to perform a cancer panel NGS sequencing, DNA library preparation was performed using RNA capture baits. Reads were aligned to the reference human genome and mutation calls were further validated by Sanger sequencing. Results obtained by the DNA integrity assays correlated to the efficiency of the pre-capture library preparation in up to 0.94 (Pearson's test). Moreover, sequencing results showed that poor integrity DNA leads to high rates of false positive mutation calls, specially C:G>T:A and C:G>A:T. Poor quality FFPE DNA samples are prone to generating false positive mutation calls. These are especially perilous in cases in which subclonal populations are expected, such as in advance disease, since it could lead clinicians to erroneous conclusions and equivocated conduct.

Asunto(s)

ADN de Neoplasias/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Oncología Médica/métodos , Neoplasias/diagnóstico , Humanos , Mutación , Neoplasias/genética , Neoplasias/patología , Adhesión en Parafina

RESUMEN

Aberrant DNA methylation is a hallmark of many cancers. Currently, there are four intrinsic molecular subtypes in breast cancer (BC): Luminal A, B, Her2-positive, and triple negative (TNBC). Recently, The Cancer Genome Atlas (TCGA) project has revealed that Luminal subtypes have higher levels of genome-wide methylation that may be a result of Estrogen/Estrogen receptor α (E2/ERα) signaling pathway activation. In this study, we analyze promoter CpG-island (CGIs) of the Reprimo (RPRM) gene in breast cancers (n = 77), cell lines (n = 38), and normal breast tissue (n = 10) using a MBDCap-seq database. Then, a validation cohort (n = 26) was used to confirm the results found in the MBDCap-seq platform. A differential methylation pattern was found between BC and cell lines compared to normal breast tissue. In BC, a higher DNA methylation was observed in tissues that were ERα-positive than in ERα-negative ones; more precisely, subtypes Luminal A compared to TNBC. Also, significant reverse correlation was observed between DNA methylation and RPRM mRNA expression in BC. Our data suggest that ERα expression in BC may affect the DNA methylation of CGIs in the RPRM gene. This approach suggests that DNA methylation status in CGIs of some tumor suppressor genes could be driven by E2 availability, subsequently inducing the activation of the ERα pathway.

Asunto(s)

Neoplasias de la Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Islas de CpG , Metilación de ADN , ADN de Neoplasias/metabolismo , Genes Supresores de Tumor , Glicoproteínas/metabolismo , Adulto , Anciano , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteínas de Ciclo Celular/genética , ADN de Neoplasias/genética , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Glicoproteínas/genética , Humanos , Persona de Mediana Edad

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is an heterogeneous disease. Three carcinogenic pathways determine its molecular profile: microsatellite instability (MSI), chromosomal instability (CIN) and CpG island methylator phenotype (CIMP). Based on the new molecular classification, four consensus CRC molecular subtypes (CMS) are established, which are related to clinical, pathological and biological characteristics of the tumor. AIM: To classify Chilean patients with sporadic CRC according to the new consensus molecular subtypes of carcinogenic pathways. MATERIAL AND METHODS: Prospective analytical study of 53 patients with a mean age of 70 years (55% males) with CRC, operated at a private clinic, without neoadjuvant treatment. From normal and tumor tissue DNA of each patient, CIN, MSI and CIMP were analyzed. Combining these variables, tumors were classified as CMS1/MSI-immune, CMS2/canonical, CMS3/metabolic and CMS4/mesenchymal. RESULTS: CMS1 tumors (19%) were located in the right colon, were in early stages, had MMR complex deficiencies and 67% had an activating mutation of the BRAF oncogene. CMS2 tumors (31%) were located in the left colon, had moderate differentiation, absence of vascular invasion, lymphatic and mucin. CMS3 tumors (29%) were also left-sided, with absence of vascular and lymphatic invasion, and 29% had an activating mutation of the KRAS oncogene. CMS4 tumors (21%) showed advanced stages and presence of metastases. CONCLUSIONS: This new molecular classification contributes to understanding the heterogeneity of tumors. It is possible to differentiate molecular subgroups of a single pathological diagnosis of adenocarcinoma, opening the door to personalized medicine.

Asunto(s)

Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Metilación de ADN/genética , ADN de Neoplasias/genética , Inestabilidad de Microsatélites , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Chile , Neoplasias Colorrectales/patología , Consenso , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Estudios Prospectivos

RESUMEN

BACKGROUND: Mutations previously considered drivers of malignant neoplasms also occur in benign tumors. From the biological perspective, the study of malignant and benign neoplasms is equally relevant. The study of rare tumors contributes to the understanding of the more common ones, as both could share the same hallmark genetic drivers. The identification of driver mutations in benign tumors is facilitated by the fact that they harbor quiet genomes. Pathogenic mutations have being described in benign epithelial odontogenic tumors, such as ameloblastomas and adenomatoid odontogenic tumors. However, the molecular pathogenesis of odontogenic myxoma (OM), a benign aggressive ectomesenchymal tumor, is still poorly characterized, precluding the development of personalized therapy. Aiming to find druggable genetic mutations, we investigated in OM mutations in 50 genes commonly mutated in cancer. METHODS: We used targeted next-generation sequencing to interrogate over 2,800 COSMIC mutations in OM. RESULTS: Missense single nucleotide variants were detected in KDR, TP53, PIK3CA, KIT, JAK3; however, these did not include pathogenic mutations. CONCLUSION: These aggressive tumors do not harbor pathogenic mutations in genes commonly mutated in human cancers or if they do, these mutations probably occur in a low proportion of cases.

Asunto(s)

ADN de Neoplasias/genética , Genes Supresores de Tumor , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Mixoma/genética , Tumores Odontogénicos/genética , Oncogenes/genética , Análisis de Secuencia de ADN , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven