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1.
Cell ; 174(3): 758-769.e9, 2018 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-30033370

RESUMEN

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.


Asunto(s)
Variación Estructural del Genoma/genética , Neoplasias de la Próstata/genética , Anciano , Anciano de 80 o más Años , Proteína BRCA2/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Variaciones en el Número de Copia de ADN , Exoma , Perfilación de la Expresión Génica/métodos , Genómica/métodos , Humanos , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Secuencias Repetidas en Tándem/genética , Proteína p53 Supresora de Tumor/metabolismo , Secuenciación Completa del Genoma/métodos
3.
Bioinformatics ; 31(22): 3673-5, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26163694

RESUMEN

UNLABELLED: Mutational signatures are patterns in the occurrence of somatic single-nucleotide variants that can reflect underlying mutational processes. The SomaticSignatures package provides flexible, interoperable and easy-to-use tools that identify such signatures in cancer sequencing data. It facilitates large-scale, cross-dataset estimation of mutational signatures, implements existing methods for pattern decomposition, supports extension through user-defined approaches and integrates with existing Bioconductor workflows. AVAILABILITY AND IMPLEMENTATION: The R package SomaticSignatures is available as part of the Bioconductor project. Its documentation provides additional details on the methods and demonstrates applications to biological datasets. CONTACT: julian.gehring@embl.de, whuber@embl.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Programas Informáticos , Genoma Humano , Humanos , Neoplasias/genética
4.
Nat Genet ; 47(1): 13-21, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25401301

RESUMEN

To further understand the molecular distinctions between kidney cancer subtypes, we analyzed exome, transcriptome and copy number alteration data from 167 primary human tumors that included renal oncocytomas and non-clear cell renal cell carcinomas (nccRCCs), consisting of papillary (pRCC), chromophobe (chRCC) and translocation (tRCC) subtypes. We identified ten significantly mutated genes in pRCC, including MET, NF2, SLC5A3, PNKD and CPQ. MET mutations occurred in 15% (10/65) of pRCC samples and included previously unreported recurrent activating mutations. In chRCC, we found TP53, PTEN, FAAH2, PDHB, PDXDC1 and ZNF765 to be significantly mutated. Gene expression analysis identified a five-gene set that enabled the molecular classification of chRCC, renal oncocytoma and pRCC. Using RNA sequencing, we identified previously unreported gene fusions, including ACTG1-MITF fusion. Ectopic expression of the ACTG1-MITF fusion led to cellular transformation and induced the expression of downstream target genes. Finally, we observed upregulation of the anti-apoptotic factor BIRC7 in MiTF-high RCC tumors, suggesting a potential therapeutic role for BIRC7 inhibitors.


Asunto(s)
Carcinoma de Células Renales/clasificación , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/genética , Mutación , Adenoma Oxifílico/clasificación , Adenoma Oxifílico/genética , Adenoma Oxifílico/patología , Secuencia de Aminoácidos , Secuencia de Bases , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , ADN de Neoplasias , Dosificación de Gen , Inestabilidad Genómica , Humanos , Neoplasias Renales/clasificación , Neoplasias Renales/patología , Datos de Secuencia Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiología , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/fisiología , Polimorfismo de Nucleótido Simple , Conformación Proteica , Proteínas Proto-Oncogénicas c-met/química , Proteínas Proto-Oncogénicas c-met/genética , Translocación Genética
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