RESUMO
DNA sequencing has identified recurrent mutations that drive the aggressiveness of prostate cancers. Surprisingly, the influence of genomic, epigenomic, and transcriptomic dysregulation on the tumor proteome remains poorly understood. We profiled the genomes, epigenomes, transcriptomes, and proteomes of 76 localized, intermediate-risk prostate cancers. We discovered that the genomic subtypes of prostate cancer converge on five proteomic subtypes, with distinct clinical trajectories. ETS fusions, the most common alteration in prostate tumors, affect different genes and pathways in the proteome and transcriptome. Globally, mRNA abundance changes explain only â¼10% of protein abundance variability. As a result, prognostic biomarkers combining genomic or epigenomic features with proteomic ones significantly outperform biomarkers comprised of a single data type.
Assuntos
Neoplasias da Próstata/patologia , Proteogenômica/métodos , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Epigenômica , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Translocação Genética , Sequenciamento Completo do GenomaRESUMO
The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for â¼90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes.
Assuntos
Neoplasias da Próstata/genética , RNA/genética , RNA/metabolismo , Perfilação da Expressão Gênica/métodos , Perfil Genético , Células HEK293 , Humanos , Masculino , MicroRNAs/metabolismo , Próstata/metabolismo , Splicing de RNA/genética , RNA Circular , RNA não Traduzido/genética , Análise de Sequência de RNA/métodos , TranscriptomaRESUMO
Chromosome 20q13.2 is amplified in 20-30% of early-stage breast tumors and is associated with poor prognosis. Detailed mapping of the amplified region using molecular cytogenetics, positional cloning and genomic sequencing culminated in a detailed molecular description of the candidate oncogene ZNF217. ZNF217 proteins resemble Kruppel-like transcription factors, localize predominately to the nucleus and associate with proteins involved in transcriptional repression. The findings that ZNF217 can immortalize human mammary epithelial cells and that its amplification is associated with poor prognosis suggest that it may play roles in both early- and late-stage breast cancer. We present evidence that ZNF217 can attenuate apoptotic signals resulting from telomere dysfunction as well as from doxorubicin-induced DNA damage and that silencing ZNF217 with siRNA restores sensitivity to doxorubicin. Moreover, elevated ZNF217 leads to increased phosphorylation of Akt, whereas inhibition of the phosphatidylinositol 3 kinase pathway and Akt phosphorylation decreases ZNF217 protein levels and increases sensitivity to doxorubicin. These results suggest that ZNF217 may promote neoplastic transformation by increasing cell survival during telomeric crisis and may promote later stages of malignancy by increasing cell survival during chemotherapy.
Assuntos
Apoptose/genética , Neoplasias da Mama/genética , Cromossomos Humanos Par 20/genética , Proteínas de Neoplasias/metabolismo , Telômero/fisiologia , Transativadores/metabolismo , Linhagem Celular Tumoral , Dano ao DNA , Primers do DNA , Doxorrubicina , Tratamento Farmacológico , Inativação Gênica , Humanos , Immunoblotting , Proteínas de Neoplasias/genética , Fosfatidilinositol 3-Quinases/metabolismo , Telômero/genética , Transativadores/genéticaRESUMO
Prostate cancer is the most commonly diagnosed non-cutaneous neoplasm among American males and is the second leading cause of cancer-related death. Prostate specific antigen screening has resulted in earlier disease detection, yet approximately 30% of men will die of metastatic disease. Slow disease progression, an aging population and associated morbidity and mortality underscore the need for improved disease classification and therapies. To address these issues, we analyzed a cohort of patients using array comparative genomic hybridization (aCGH). The cohort comprises 64 patients, half of whom recurred postoperatively. Analysis of the aCGH profiles revealed numerous recurrent genomic copy number aberrations. Specific loss at 8p23.2 was associated with advanced stage disease, and gain at 11q13.1 was found to be predictive of postoperative recurrence independent of stage and grade. Moreover, comparison with an independent set of metastases revealed approximately 40 candidate markers associated with metastatic potential. Copy number aberrations at these loci may define metastatic genotypes.