RESUMEN
Epigenetic modifications, such as DNA methylation, is widely studied in cancer. DNA methylation patterns have been shown to distinguish between benign and malignant tumors in various cancers, including prostate cancer. It may also contribute to oncogenesis, as it is frequently associated with downregulation of tumor suppressor genes. Aberrant patterns of DNA methylation, in particular the CpG island hypermethylator phenotype (CIMP), have shown associative evidence with distinct clinical features and outcomes, such as aggressive subtypes, higher Gleason score, prostate-specific antigen (PSA), and overall tumor stage, overall worse prognosis, as well as reduced survival. In prostate cancer, hypermethylation of specific genes is significantly different between tumor and normal tissues. Methylation patterns could distinguish between aggressive subtypes of prostate cancer, including neuroendocrine prostate cancer (NEPC) and castration resistant prostate adenocarcinoma. Further, DNA methylation is detectable in cell-free DNA (cfDNA) and is reflective of clinical outcome, making it a potential biomarker for prostate cancer. This review summarizes recent advances in understanding DNA methylation alterations in cancers with the focus on prostate cancer. We discuss the advanced methodology used for evaluating DNA methylation changes and the molecular regulators behind these changes. We also explore the clinical potential of DNA methylation as prostate cancer biomarkers and its potential for developing targeted treatment of CIMP subtype of prostate cancer.
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Metastatic prostate cancer remains a major clinical challenge and metastatic lesions are highly heterogeneous and difficult to biopsy. Liquid biopsy provides opportunities to gain insights into the underlying biology. Here, using the highly sensitive enrichment-based sequencing technology, we provide analysis of 60 and 175 plasma DNA methylomes from patients with localized and metastatic prostate cancer, respectively. We show that the cell-free DNA methylome can capture variations beyond the tumor. A global hypermethylation in metastatic samples is observed, coupled with hypomethylation in the pericentromeric regions. Hypermethylation at the promoter of a glucocorticoid receptor gene NR3C1 is associated with a decreased immune signature. The cell-free DNA methylome is reflective of clinical outcomes and can distinguish different disease types with 0.989 prediction accuracy. Finally, we show the ability of predicting copy number alterations from the data, providing opportunities for joint genetic and epigenetic analysis on limited biological samples.
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Ácidos Nucleicos Libres de Células , Neoplasias de la Próstata , Masculino , Humanos , Epigenoma , Ácidos Nucleicos Libres de Células/genética , Neoplasias de la Próstata/patología , Próstata/patología , Metilación de ADN/genéticaRESUMEN
Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease. SIGNIFICANCE: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.
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5-Metilcitosina , Neoplasias de la Próstata , Masculino , Humanos , Próstata , BiopsiaRESUMEN
Genomic sequencing of thousands of tumors has revealed many genes associated with specific types of cancer. Similarly, large scale CRISPR functional genomics efforts have mapped genes required for cancer cell proliferation or survival in hundreds of cell lines. Despite this, for specific disease subtypes, such as metastatic prostate cancer, there are likely a number of undiscovered tumor specific driver genes that may represent potential drug targets. To identify such genetic dependencies, we performed genome-scale CRISPRi screens in metastatic prostate cancer models. We then created a pipeline in which we integrated pan-cancer functional genomics data with our metastatic prostate cancer functional and clinical genomics data to identify genes that can drive aggressive prostate cancer phenotypes. Our integrative analysis of these data reveals known prostate cancer specific driver genes, such as AR and HOXB13, as well as a number of top hits that are poorly characterized. In this study we highlight the strength of an integrated clinical and functional genomics pipeline and focus on two top hit genes, KIF4A and WDR62. We demonstrate that both KIF4A and WDR62 drive aggressive prostate cancer phenotypes in vitro and in vivo in multiple models, irrespective of AR-status, and are also associated with poor patient outcome.
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Proteínas de Ciclo Celular/genética , Cinesinas/genética , Proteínas del Tejido Nervioso/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Animales , Sistemas CRISPR-Cas , Ciclo Celular/fisiología , Proteínas de Ciclo Celular/metabolismo , Movimiento Celular/fisiología , Células Cultivadas , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Cinesinas/metabolismo , Masculino , Ratones Endogámicos NOD , Ratones SCID , Metástasis de la Neoplasia , Estadificación de Neoplasias , Proteínas del Tejido Nervioso/metabolismo , Neoplasias de la Próstata/metabolismo , Tasa de SupervivenciaRESUMEN
Prostate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of 260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.
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Sistemas CRISPR-Cas , Metilación de ADN , Edición Génica/métodos , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Neoplasias de la Próstata/genética , Animales , Factor de Unión a CCCTC/genética , Factor de Unión a CCCTC/metabolismo , Carcinogénesis/genética , Línea Celular Tumoral , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-myc/genética , Sitios de Carácter Cuantitativo/genética , Elementos Reguladores de la Transcripción/genética , Factores de RiesgoRESUMEN
Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.
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Metilación de ADN/genética , Neoplasias de la Próstata/genética , Anciano , Anciano de 80 o más Años , Carcinogénesis/genética , Epigenómica/métodos , Regulación Neoplásica de la Expresión Génica/genética , Genoma/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Estudios Prospectivos , Análisis de Secuencia de ADN/métodos , Secuenciación del Exoma/métodos , Secuenciación Completa del Genoma/métodosRESUMEN
The transcriptome of prostate cancer is highly heterogeneous, with noncoding transcripts being essential players. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are two unique classes of noncoding RNA drawing increasing attention. Biologically, they have intriguing properties with important regulatory functions. Clinically, they present as promising biomarkers and therapeutic targets. Recent advancements in technologies have opened up new directions for noncoding RNA research, which include RNA-protein interaction, RNA secondary structure, and spatial transcriptomics. Furthermore, recent work has also evaluated the clinical applications of these noncoding RNAs in noninvasive liquid biopsy and RNA-based therapies. In this review, we summarize recent findings on lncRNAs and circRNAs in prostate cancer, discuss their clinical utilities, and highlight these exciting areas of research.
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Biomarcadores de Tumor , Predisposición Genética a la Enfermedad , Neoplasias de la Próstata/genética , ARN Largo no Codificante/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Neoplasias de la Próstata/metabolismo , ARN Circular/genética , ARN Largo no Codificante/química , Proteínas de Unión al ARN/metabolismo , Relación Estructura-ActividadRESUMEN
Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479-90. ©2017 AACR.