RESUMEN
The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes, including BAP1. The BAP1 protein, a nuclear deubiquitinase, is inactivated in 15% of clear cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation but not deubiquitination of monoubiquitinated histone 2A lysine 119 (H2AK119ub1). BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10(-5)), [corrected] and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q = 0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
Asunto(s)
Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/patología , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/deficiencia , Ubiquitina Tiolesterasa/genética , Anciano , Carcinoma de Células Renales/metabolismo , Procesos de Crecimiento Celular/fisiología , Células Cultivadas , Proteínas de Unión al ADN , Exoma , Femenino , Expresión Génica/genética , Factor C1 de la Célula Huésped/genética , Factor C1 de la Célula Huésped/metabolismo , Humanos , Neoplasias Renales/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Dominios y Motivos de Interacción de Proteínas , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina Tiolesterasa/metabolismoRESUMEN
All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic.
Asunto(s)
Genes Relacionados con las Neoplasias/genética , Genoma Humano/genética , Mutación/genética , Neoplasias/genética , Adulto , Línea Celular Tumoral , Daño del ADN/genética , Análisis Mutacional de ADN , Reparación del ADN/genética , Dosificación de Gen/genética , Humanos , Pérdida de Heterocigocidad/genética , Masculino , Melanoma/etiología , Melanoma/genética , MicroARNs/genética , Mutagénesis Insercional/genética , Neoplasias/etiología , Polimorfismo de Nucleótido Simple/genética , Medicina de Precisión , Eliminación de Secuencia/genética , Rayos UltravioletaRESUMEN
Transcription factors play a key role in integrating and modulating biological information. In this study, we comprehensively measured the changing abundances of mRNAs over a time course of activation of human peripheral-blood-derived mononuclear cells ("macrophages") with lipopolysaccharide. Global and dynamic analysis of transcription factors in response to a physiological stimulus has yet to be achieved in a human system, and our efforts significantly advanced this goal. We used multiple global high-throughput technologies for measuring mRNA levels, including massively parallel signature sequencing and GeneChip microarrays. We identified 92 of 1,288 known human transcription factors as having significantly measurable changes during our 24-h time course. At least 42 of these changes were previously unidentified in this system. Our data demonstrate that some transcription factors operate in a functional range below 10 transcripts per cell, whereas others operate in a range three orders of magnitude greater. The highly reproducible response of many mRNAs indicates feedback control. A broad range of activation kinetics was observed; thus, combinatorial regulation by small subsets of transcription factors would permit almost any timing input to cis-regulatory elements controlling gene transcription.