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1.
Cancer Discov ; 6(3): 300-15, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26732095

RESUMEN

UNLABELLED: We have identified previously undiscovered BRAF in-frame deletions near the αC-helix region of the kinase domain in pancreatic, lung, ovarian, and thyroid cancers. These deletions are mutually exclusive with KRAS mutations and occur in 4.21% of KRAS wild-type pancreatic cancer. siRNA knockdown in cells harboring BRAF deletions showed that the MAPK activity and cell growth are BRAF dependent. Structurally, the BRAF deletions are predicted to shorten the ß3/αC-helix loop and hinder its flexibility by locking the helix in the active αC-helix-in conformation that favors dimer formation. Expression of L485-P490-deleted BRAF is able to transform NIH/3T3 cells in a BRAF dimer-dependent manner. BRAF homodimer is confirmed to be the dominant RAF dimer by proximity ligation assays in BRAF deletion cells, which are resistant to the BRAF inhibitor vemurafenib and sensitive to LY3009120, a RAF dimer inhibitor. In tumor models with BRAF deletions, LY3009120 has shown tumor growth regression, whereas vemurafenib is inactive. SIGNIFICANCE: This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells. LY3009120 is active against these cells and represents a potential treatment option for patients with cancer with these BRAF deletions, or other atypical BRAF mutations where BRAF functions as a dimer.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Eliminación de Gen , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Multimerización de Proteína , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Pirimidinas/farmacología , Animales , Antineoplásicos/química , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Modelos Animales de Enfermedad , Expresión Génica Ectópica , Expresión Génica , Humanos , Sistema de Señalización de MAP Quinasas , Ratones , Modelos Moleculares , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas/genética , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/química , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Nat Med ; 21(5): 449-56, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25894828

RESUMEN

Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Neoplasias Gástricas/genética , Anciano , Estudios de Cohortes , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Femenino , Dosificación de Gen , Perfilación de la Expresión Génica , Helicobacter pylori/genética , Humanos , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Análisis de Componente Principal , Pronóstico , Modelos de Riesgos Proporcionales , Recurrencia , Neoplasias Gástricas/terapia , Análisis de Matrices Tisulares , Investigación Biomédica Traslacional , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genética
3.
Nat Commun ; 5: 5477, 2014 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-25407104

RESUMEN

Gastric cancer (GC) is the second most common cause of cancer-related deaths. It is known to be a heterogeneous disease with several molecular and histological subtypes. Here we perform whole-genome sequencing of 49 GCs with diffuse (N=31) and intestinal (N=18) histological subtypes and identify three mutational signatures, impacting TpT, CpG and TpCp[A/T] nucleotides. The diffuse-type GCs show significantly lower clonality and smaller numbers of somatic and structural variants compared with intestinal subtype. We further divide the diffuse subtype into one with infrequent genetic changes/low clonality and another with relatively higher clonality and mutations impacting TpT dinucleotide. Notably, we discover frequent and exclusive mutations in Ephrins and SLIT/ROBO signalling pathway genes. Overall, this study delivers new insights into the mutational heterogeneity underlying distinct histologic subtypes of GC that could have important implications for future research in the diagnosis and treatment of GC.


Asunto(s)
Adenocarcinoma/genética , Neoplasias Gástricas/genética , Adulto , Anciano , Femenino , Heterogeneidad Genética , Genómica , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN , Adulto Joven
4.
Lipids ; 46(6): 513-20, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21312067

RESUMEN

Triglyceride (TAG) absorption involves its initial hydrolysis to fatty acids and monoacylglycerol (MAG), which are resynthesized back to diacylglycerol (DAG) and TAG within enterocytes. The resynthesis of DAG is facilitated by fatty acyl-CoA dependent monoacylglycerol acyltransferases (MGATs). Three MGAT enzymes have been isolated in humans and the expression of MGAT2 and MGAT3 in the intestines suggests their functional role in the TAG absorption. In this paper, we report that the Mogat3 gene appears to be a pseudogene in mice while it is a functional gene in rats. Examination of the mouse genomic Mogat3 sequence revealed multiple changes that would result in a translational stop codon or frameshifts. The rat Mogat3 gene, however, is predicted to encode a functional enzyme of 362 amino acids. Expression of rat MGAT3 in human embryonic kidney 293 (HEK293) cells led to the formation of a 36-kDa protein that displayed significant MGAT but not DGAT activity. Tissue expression analysis of rat MGAT3 by real-time PCR analysis indicated that rat MGAT3 has a high level of expression in intestines and pancreas. Our results thus provide the molecular basis to understand the relative functional role of MGAT2 and MGAT3 and also for future exploration of MGAT3 function in animal models.


Asunto(s)
Aciltransferasas/química , Aciltransferasas/genética , Seudogenes/genética , Aciltransferasas/clasificación , Animales , Línea Celular , Humanos , Ratones , Ratas , Análisis de Secuencia de ADN
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