RESUMEN
Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring1. However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete2-12. Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery.
Asunto(s)
ADN Tumoral Circulante , Resistencia a Antineoplásicos , Genoma Humano , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Neoplasias de la Próstata , Antagonistas de Receptores Androgénicos/farmacología , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Células Clonales/metabolismo , Células Clonales/patología , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Marcadores Genéticos/genética , Genoma Humano/genética , Genómica/métodos , Humanos , Biopsia Líquida/métodos , Masculino , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Nucleosomas/genética , Nucleosomas/metabolismo , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , ARN Mensajero/análisis , ARN Mensajero/genética , ARN Neoplásico/análisis , ARN Neoplásico/genética , Receptores Androgénicos/metabolismoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.
Asunto(s)
Linaje de la Célula , Metástasis de la Neoplasia/patología , Neoplasias de la Próstata/patología , Andrógenos/deficiencia , Linaje de la Célula/genética , Células Clonales/metabolismo , Células Clonales/patología , Análisis Mutacional de ADN , Progresión de la Enfermedad , Epigénesis Genética , Genes Supresores de Tumor , Humanos , Masculino , Metástasis de la Neoplasia/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Abiraterone acetate plus prednisone and enzalutamide are both used for the treatment of metastatic castration-resistant prostate cancer. We aimed to determine the best sequence in which to use both drugs, as well as their second-line efficacy. METHODS: In this multicentre, randomised, open-label, phase 2, crossover trial done in six cancer centres in British Columbia, Canada, we recruited patients aged 18 years or older with newly-diagnosed metastatic castration-resistant prostate cancer without neuroendocrine differentiation and Eastern Cooperative Oncology Group performance status 2 or less. Patients were randomly assigned (1:1) using a computer-generated random number table to receive either abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily until PSA progression followed by crossover to enzalutamide 160 mg orally once daily (group A), or the opposite sequence (group B). Treatment was not masked to investigators or participants. Primary endpoints were time to second PSA progression and PSA response (≥30% decline from baseline) on second-line therapy, analysed by intention-to-treat in all randomly assigned patients and in patients who crossed over, respectively. The trial is registered with ClinicalTrials.gov, NCT02125357. FINDINGS: Between Oct 21, 2014, and Dec 13, 2016, 202 patients were enrolled and randomly assigned to either group A (n=101) or group B (n=101). At the time of data cutoff, 73 (72%) patients in group A and 75 (74%) patients in group B had crossed over. Time to second PSA progression was longer in group A than in group B (median 19·3 months [95% CI 16·0-30·5] vs 15·2 months [95% CI 11·9-19·8] months; hazard ratio 0·66, 95% CI 0·45-0·97, p=0·036), at a median follow-up of 22·8 months (IQR 10·3-33·4). PSA responses to second-line therapy were seen in 26 (36%) of 73 patients for enzalutamide and three (4%) of 75 for abiraterone (χ2 p<0·0001). The most common grade 3-4 adverse events throughout the trial were hypertension (27 [27%] of 101 patients in group A vs 18 [18%] of 101 patients in group B) and fatigue (six [10%] vs four [4%]). Serious adverse events were reported in 15 (15%) of 101 patients in group A and 20 (20%) of 101 patients in group B. There were no treatment-related deaths. INTERPRETATION: Enzalutamide showed activity as a second-line novel androgen receptor pathway inhibitor, whereas abiraterone acetate did not, leading to a longer time to second PSA progression for the sequence of abiraterone followed by enzalutamide than with the opposite treatment sequence. Our data suggest that using a sequencing strategy of abiraterone acetate followed by enzalutamide provides the greatest clinical benefit. FUNDING: Canadian Cancer Society Research Institute, Prostate Cancer Canada, Movember Foundation, Prostate Cancer Foundation, Terry Fox New Frontiers Program, BC Cancer Foundation, Jane and Aatos Erkko Foundation, Janssen, and Astellas.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/normas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Acetato de Abiraterona/administración & dosificación , Anciano , Anciano de 80 o más Años , Benzamidas , Estudios Cruzados , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Nitrilos , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/análogos & derivados , Prednisona/administración & dosificación , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/patología , Tasa de SupervivenciaRESUMEN
Small-cell prostate carcinoma (SCPC) is an aggressive malignancy that is managed similarly to small-cell lung cancer. SCPC can evolve from prostate adenocarcinoma in response to androgen deprivation therapy, but, in rare cases, is present at initial cancer diagnosis. The molecular aetiology of de novo SCPC is incompletely understood, owing to the scarcity of tumour tissue and the short life-expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017. Ten patients had pure SCPC pathology, and the remainder had some admixed adenocarcinoma foci, but all were treated with first-line platinum-based chemotherapy. The median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing and mRNA profiling on formalin-fixed paraffin-embedded archival tumour tissue. We observed frequent biallelic deletion and/or mutation of the tumour suppressor genes TP53, RB1, and PTEN, similarly to what was found in treatment-related SCPC. Indeed, at the RNA level, pure de novo SCPC closely resembled treatment-related SCPC. However, five patients had biallelic loss of DNA repair genes, including BRCA1, BRCA2, ATM, and MSH2/6, potentially underlying the high genomic instability of this rare disease variant. Two patients with pure de novo SCPC harboured ETS gene rearrangements involving androgen-driven promoters, consistent with the evolution of de novo SCPC from an androgen-driven ancestor. Overall, our results reveal a highly aggressive molecular landscape that underlies this unusual pathological variant, and suggest opportunities for targeted therapy strategies in a disease with few treatment options. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Carcinoma de Células Pequeñas/genética , Reparación del ADN , Genes Supresores de Tumor , Inestabilidad Genómica , Neoplasias Complejas y Mixtas/genética , Neoplasias de la Próstata/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/mortalidad , Carcinoma de Células Pequeñas/patología , Cisplatino/uso terapéutico , Bases de Datos Factuales , Etopósido/farmacología , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Complejas y Mixtas/tratamiento farmacológico , Neoplasias Complejas y Mixtas/mortalidad , Neoplasias Complejas y Mixtas/patología , Fenotipo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: A significant subset of prostate cancer (PC) patients with a castration-resistant form of the disease (CRPC) show primary resistance to androgen receptor (AR)-targeting drugs developed against CRPC. As one explanation could be the expression of constitutively active androgen receptor splice variants (AR-Vs), our current objectives were to study AR-Vs and other AR aberrations to better understand the emergence of CRPC. METHODS: We analysed specimens from different stages of prostate cancer by next-generation sequencing and immunohistochemistry. RESULTS: AR mutations and copy number variations were detected only in CRPC specimens. Genomic structural rearrangements of AR were observed in 5/30 metastatic CRPC patients, but they were not associated with expression of previously known AR-Vs. The predominant AR-Vs detected were AR-V3, AR-V7 and AR-V9, with the expression levels being significantly higher in CRPC cases compared to prostatectomy samples. Out of 25 CRPC metastases that expressed any AR variant, 17 cases harboured expression of all three of these AR-Vs. AR-V7 protein expression was highly heterogeneous and higher in CRPC compared to hormone-naïve tumours. CONCLUSIONS: AR-V3, AR-V7 and AR-V9 are co-expressed in CRPC metastases highlighting the fact that inhibiting AR function via regions common to all AR-Vs is likely to provide additional benefit to patients with CRPC.
Asunto(s)
Hiperplasia Prostática/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Isoformas de Proteínas/genética , Receptores Androgénicos/genética , Andrógenos/genética , Línea Celular Tumoral , Variaciones en el Número de Copia de ADN/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Metástasis de la Neoplasia , Próstata/metabolismo , Próstata/patología , Hiperplasia Prostática/patología , Hiperplasia Prostática/cirugía , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/cirugía , Empalme del ARN/genética , Secuenciación del Exoma , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: Somatic alterations, including loss of heterozygosity, can affect the expression of oncogenes and tumor suppressor genes. Whole genome sequencing enables detailed characterization of such aberrations. However, due to the limitations of current high throughput sequencing technologies, this task remains challenging. Hence, accurate and reliable detection of such events is crucial for the identification of cancer-related alterations. RESULTS: We introduce a new tool called Segmentum for determining somatic copy numbers using whole genome sequencing from paired tumor/normal samples. In our approach, read depth and B-allele fraction signals are smoothed, and double sliding windows are used to detect breakpoints, which makes our approach fast and straightforward. Because the breakpoint detection is performed simultaneously at different scales, it allows accurate detection as suggested by the evaluation results from simulated and real data. We applied Segmentum to paired tumor/normal whole genome sequencing samples from 38 patients with low-grade glioma from the TCGA dataset and were able to confirm the recurrence of copy-neutral loss of heterozygosity in chromosome 17p in low-grade astrocytoma characterized by IDH1/2 mutation and lack of 1p/19q co-deletion, which was previously reported using SNP array data. CONCLUSIONS: Segmentum is an accurate, user-friendly tool for somatic copy number analysis of tumor samples. We demonstrate that this tool is suitable for the analysis of large cohorts, such as the TCGA dataset.
Asunto(s)
Astrocitoma/genética , Variaciones en el Número de Copia de ADN , Glioma/genética , Pérdida de Heterocigocidad , Programas Informáticos , Astrocitoma/patología , Deleción Cromosómica , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 17 , Simulación por Computador , Estudio de Asociación del Genoma Completo , Glioma/patología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Isocitrato Deshidrogenasa/genética , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Fibroblast growth factor receptors (FGFRs) are well-known proto-oncogenes in several human malignancies and are currently therapeutically targeted in clinical trials. Among glioma subtypes, activating FGFR1 alterations have been observed in a subpopulation of pilocytic astrocytomas while FGFR3 fusions occur in IDH wild-type diffuse gliomas, resulting in high FGFR3 protein expression. The purpose of this study was to associate FGFR1 and FGFR3 protein levels with clinical features and genetic alterations in ependymoma and pilocytic astrocytoma. METHODS: FGFR1 and FGFR3 expression levels were detected in ependymoma and pilocytic astrocytoma tissues using immunohistochemistry. Selected cases were further analyzed using targeted sequencing. RESULTS: Expression of both FGFR1 and FGFR3 varied within all tumor types. In ependymomas, increased FGFR3 or FGFR1 expression was associated with high tumor grade, cerebral location, young patient age, and poor prognosis. Moderate-to-strong expression of FGFR1 and/or FGFR3 was observed in 76% of cerebral ependymomas. Cases with moderate-to-strong expression of both proteins had poor clinical prognosis. In pilocytic astrocytomas, moderate-to-strong FGFR3 expression was detected predominantly in non-pediatric patients. Targeted sequencing of 12 tumors found no protein-altering mutations or fusions in FGFR1 or FGFR3. CONCLUSIONS: Elevated FGFR3 and FGFR1 protein expression is common in aggressive ependymomas but likely not driven by genetic alterations. Further studies are warranted to evaluate whether ependymoma patients with high FGFR3 and/or FGFR1 expression could benefit from treatment with FGFR inhibitor based therapeutic approaches currently under evaluation in clinical trials.
Asunto(s)
Astrocitoma/genética , Ependimoma/genética , Glioma/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Adolescente , Factores de Edad , Anciano , Astrocitoma/epidemiología , Astrocitoma/patología , Niño , Preescolar , Ependimoma/epidemiología , Ependimoma/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Glioma/patología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Pronóstico , Transducción de Señal , Adulto JovenRESUMEN
BACKGROUND: Recently, there has been increasing attention on the role of microRNAs (miRNAs) in cancer development. Several expression profiling studies have provided evidence of aberrant expression of miRNAs in prostate cancer and have highlighted the potential use of specific miRNA expression signatures as prognostic or predictive markers. Here we report an expression analysis of miR-1247-5p, miR-1249, miR-1269a, miR-1271-5p, miR-1290, miR-1291, and miR-1299. METHODS: qRT-PCR was performed to validate the differential expression of miRNAs in clinical samples, and the effect of miR-1247-5p was studied in prostate cancer cell lines transiently transfected with a miR-1247-5p mimic. The expression of miR-1247-5p's putative target MYCBP2 was evaluated by qRT-PCR and Western blotting, and the interaction of the miRNA with the target gene was assessed using a luciferase assay. RESULTS: We found a significant up-regulation of miR-1247-5p in castration-resistant prostate cancer (CRPC) samples compared to non-malignant prostate. The expression of miR-1247-5p was subsequently studied in prostate cancer (PC) cell lines where an up-regulation of miR-1247-5p was observed in the androgen-independent PC-3 model. Target prediction analysis for miR-1247-5p performed online revealed that MYCBP2 (myc-binding protein 2) was a high-scoring potential target. Functional studies in vitro performed using PC-3 and LNCaP models confirmed the down-regulation of MYCBP2 at the mRNA and protein levels, and a luciferase assay showed interaction between the miRNA and target gene. CONCLUSION: miR-1247-5p is overexpressed in CRPC and targets MYCBP2.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Regulación Neoplásica de la Expresión Génica , MicroARNs/biosíntesis , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Anciano , Línea Celular Tumoral , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata Resistentes a la Castración/patología , ARN Mensajero/biosíntesis , Ubiquitina-Proteína Ligasas/antagonistas & inhibidoresRESUMEN
The emergence of fibroblast growth factor receptor (FGFR) family fusions across diverse cancers has brought attention to FGFR-derived cancer therapies. The discovery of the first recurrent FGFR fusion in glioblastoma was followed by discoveries of FGFR fusions in bladder, lung, breast, thyroid, oral, and prostate cancers. Drug targeting of FGFR fusions has shown promising results and should soon be translating into clinical trials. FGFR fusions form as a result of various mechanisms predominantly deletion for FGFR1, translocation for FGFR2, and tandem duplication for FGFR3. The ability to exploit the unique targetability of FGFR fusions proves that FGFR-derived therapies could have a promising future in cancer therapeutics. Drug targeting of fusion genes has proven to be an extremely effective therapeutic approach for cancers such as the recurrent BCRABL1 fusion in chronic myeloid leukaemia. The recent discovery of recurrent FGFR family fusions in several cancer types has brought to attention the unique therapeutic potential for FGFR-positive patients. Understanding the diverse mechanisms of FGFR fusion formation and their oncogenic potential will shed light on the impact of FGFR-derived therapy in the future.
Asunto(s)
Glioblastoma/terapia , Neoplasias/terapia , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Transducción de Señal , Genómica , Glioblastoma/genética , Humanos , Mutación , Neoplasias/genética , Fusión de Oncogenes , Fenotipo , Estructura Terciaria de Proteína , Translocación GenéticaRESUMEN
Insulin-like growth factor-binding protein 2 (IGFBP2) is increasingly recognized as a glioma oncogene, emerging as a target for therapeutic intervention. In this study, we used an integrative approach to characterizing the IGFBP2 network, combining transcriptional profiling of human glioma with validation in glial cells and the replication-competent ASLV long terminal repeat with a splice acceptor/tv-a glioma mouse system. We demonstrated that IGFBP2 expression is closely linked to genes in the integrin and integrin-linked kinase (ILK) pathways and that these genes are associated with prognosis. We further showed that IGFBP2 activates integrin ß1 and downstream invasion pathways, requires ILK to induce cell motility, and activates NF-κB. Most significantly, the IGFBP2/integrin/ILK/NF-κB network functions as a physiologically active signaling pathway in vivo by driving glioma progression; interfering with any point in the pathway markedly inhibits progression. The results of this study reveal a signaling pathway that is both targetable and highly relevant to improving the survival of glioma patients.
Asunto(s)
Neoplasias Encefálicas/patología , Terapia Genética , Vectores Genéticos/uso terapéutico , Glioblastoma/patología , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/fisiología , Integrina beta1/fisiología , FN-kappa B/fisiología , Proteínas de Neoplasias/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Animales , Astrocitoma/genética , Astrocitoma/metabolismo , Proteínas Aviares/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Genes Sintéticos , Genes sis , Vectores Genéticos/administración & dosificación , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/toxicidad , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/toxicidad , Proteínas de Filamentos Intermediarios/genética , Estimación de Kaplan-Meier , Ratones , Ratones Transgénicos , Inhibidor NF-kappaB alfa , Invasividad Neoplásica , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteínas del Tejido Nervioso/genética , Nestina , Oligodendroglioma/genética , Oligodendroglioma/metabolismo , Pronóstico , Proteínas Serina-Treonina Quinasas/toxicidad , Receptores Virales/genética , Retroviridae , Transducción de Señal/fisiologíaRESUMEN
Altered expression of oncogenic and tumour-suppressing microRNAs (miRNAs) is widely associated with tumourigenesis. However, the regulatory mechanisms underlying these alterations are poorly understood. We sought to shed light on the deregulation of miRNA biogenesis promoting the aberrant miRNA expression profiles identified in these tumours. Using sequencing technology to perform both whole-transcriptome and small RNA sequencing of glioma patient samples, we examined precursor and mature miRNAs to directly evaluate the miRNA maturation process, and examined expression profiles for genes involved in the major steps of miRNA biogenesis. We found that ratios of mature to precursor forms of a large number of miRNAs increased with the progression from normal brain to low-grade and then to high-grade gliomas. The expression levels of genes involved in each of the three major steps of miRNA biogenesis (nuclear processing, nucleo-cytoplasmic transport, and cytoplasmic processing) were systematically altered in glioma tissues. Survival analysis of an independent data set demonstrated that the alteration of genes involved in miRNA maturation correlates with survival in glioma patients. Direct quantification of miRNA maturation with deep sequencing demonstrated that deregulation of the miRNA biogenesis pathway is a hallmark for glioma genesis and progression.
Asunto(s)
Neoplasias Encefálicas/genética , Glioma/genética , MicroARNs/biosíntesis , Análisis de Secuencia de ARN/métodos , Transcriptoma , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Glioblastoma/genética , Glioblastoma/patología , Glioma/mortalidad , Glioma/patología , Humanos , Tasa de Supervivencia , Texas/epidemiologíaRESUMEN
Epithelial ovarian cancer (EOC) is one of the leading causes of cancer-related death in women worldwide, and is characterized by a high rate of recurrence after surgery and chemotherapy. We sought to implement a circulating tumor DNA (ctDNA)-based blood test for more accurate post-operative surveillance of this disease. We analyzed 264 plasma samples collected between June 2016 and September 2021 from 63 EOC patients using tumor-guided plasma cell-free DNA analysis to detect residual disease after treatment. Assay specificity was verified using cross-patient analysis of 1,195 control samples. ctDNA was detected in 51 of 55 (93%) samples at diagnosis, and 18 of 18 (100%) samples at progression. Positive ctDNA in the last on-treatment sample was associated with rapid progression (median 1.02 versus 3.38 yr, HR = 5.63, P < 0.001) and reduced overall survival (median 2.31 versus NR yr, HR = 8.22, P < 0.001) in patients with high-grade serous cancer. In the case of 12 patients, ctDNA assays detected progression earlier than standard surveillance, with a median lead time of 5.9 mo. To approach the physical limits of ctDNA detection, five patients were analyzed using ultra-sensitive assays interrogating 479-1,856 tumor mutations, capable of tracking ctDNA fractions down to 0.0004%. Our results demonstrate that ctDNA assays achieve high sensitivity and specificity in detecting post-operative residual disease in EOC.
Asunto(s)
ADN Tumoral Circulante , Neoplasias Ováricas , Humanos , Femenino , ADN Tumoral Circulante/genética , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/genética , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genéticaRESUMEN
BACKGROUND: The phase 3 CALGB 90203 (Alliance) trial evaluated neoadjuvant chemohormonal therapy for high-risk localized prostate cancer before radical prostatectomy. We dissected the molecular features of post-treated tumors with long-term clinical outcomes to explore mechanisms of response and resistance to chemohormonal therapy. METHODS: We evaluated 471 radical prostatectomy tumors, including 294 samples from 166 patients treated with 6 cycles of docetaxel plus androgen deprivation therapy before radical prostatectomy and 177 samples from 97 patients in the control arm (radical prostatectomy alone). Targeted DNA sequencing and RNA expression of tumor foci and adjacent noncancer regions were analyzed in conjunction with pathologic changes and clinical outcomes. RESULTS: Tumor fraction estimated from DNA sequencing was significantly lower in post-treated tumor tissues after chemohormonal therapy compared with controls. Higher tumor fraction after chemohormonal therapy was associated with aggressive pathologic features and poor outcomes, including prostate-specific antigen-progression-free survival. SPOP alterations were infrequently detected after chemohormonal therapy, while TP53 alterations were enriched and associated with shorter overall survival. Residual tumor fraction after chemohormonal therapy was linked to higher expression of androgen receptor-regulated genes, cell cycle genes, and neuroendocrine genes, suggesting persistent populations of active prostate cancer cells. Supervised clustering of post-treated high-tumor-fraction tissues identified a group of patients with elevated cell cycle-related gene expression and poor clinical outcomes. CONCLUSIONS: Distinct recurrent prostate cancer genomic and transcriptomic features are observed after exposure to docetaxel and androgen deprivation therapy. Tumor fraction assessed by DNA sequencing quantifies pathologic response and could be a useful trial endpoint or prognostic biomarker. TP53 alterations and high cell cycle transcriptomic activity are linked to aggressive residual disease, despite potent chemohormonal therapy.
Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/cirugía , Terapia Neoadyuvante , Docetaxel , Antagonistas de Andrógenos/uso terapéutico , Andrógenos/uso terapéutico , Resultado del Tratamiento , Recurrencia Local de Neoplasia/cirugía , Antígeno Prostático Específico , Prostatectomía , Proteínas Nucleares , Proteínas RepresorasRESUMEN
De novo metastatic prostate cancer is highly aggressive, but the paucity of routinely collected tissue has hindered genomic stratification and precision oncology. Here, we leveraged a rare study of surgical intervention in 43 de novo metastatic prostate cancers to assess somatic genotypes across 607 synchronous primary and metastatic tissue regions plus circulating tumor DNA. Intra-prostate heterogeneity was pervasive and impacted clinically relevant genes, resulting in discordant genotypes between select primary restricted regions and synchronous metastases. Additional complexity was driven by polyclonal metastatic seeding from phylogenetically related primary populations. When simulating clinical practice relying on a single tissue region, genomic heterogeneity plus variable tumor fraction across samples caused inaccurate genotyping of dominant disease; however, pooling extracted DNA from multiple biopsy cores before sequencing can rescue misassigned somatic genotypes. Our results define the relationship between synchronous treatment-sensitive primary and metastatic lesions in men with de novo metastatic prostate cancer and provide a framework for implementing genomics-guided patient management.
Asunto(s)
Medicina de Precisión , Neoplasias de la Próstata , Masculino , Humanos , Genotipo , Neoplasias de la Próstata/genética , Próstata/patología , BiopsiaRESUMEN
No consensus strategies exist for prognosticating metastatic castration-resistant prostate cancer (mCRPC). Circulating tumor DNA fraction (ctDNA%) is increasingly reported by commercial and laboratory tests but its utility for risk stratification is unclear. Here, we intersect ctDNA%, treatment outcomes, and clinical characteristics across 738 plasma samples from 491 male mCRPC patients from two randomized multicentre phase II trials and a prospective province-wide blood biobanking program. ctDNA% correlates with serum and radiographic metrics of disease burden and is highest in patients with liver metastases. ctDNA% strongly predicts overall survival, progression-free survival, and treatment response independent of therapeutic context and outperformed established prognostic clinical factors. Recognizing that ctDNA-based biomarker genotyping is limited by low ctDNA% in some patients, we leverage the relationship between clinical prognostic factors and ctDNA% to develop a clinically-interpretable machine-learning tool that predicts whether a patient has sufficient ctDNA% for informative ctDNA genotyping (available online: https://www.ctDNA.org ). Our results affirm ctDNA% as an actionable tool for patient risk stratification and provide a practical framework for optimized biomarker testing.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Pronóstico , Estudios Prospectivos , Bancos de Muestras Biológicas , Biomarcadores de Tumor/genética , Biopsia Líquida , MutaciónRESUMEN
PURPOSE: Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naïve metastatic castration-resistant prostate cancer (mCRPC), but rapid resistance is common. Early identification of resistance will improve management strategies. We investigated whether changes in circulating tumor DNA (ctDNA) fraction during ARPI treatment are linked with mCRPC clinical outcomes. EXPERIMENTAL DESIGN: Plasma cell-free DNA was collected from 81 patients with mCRPC at baseline and after 4 weeks of first-line ARPI treatment during two prospective multicenter observational studies (NCT02426333; NCT02471469). ctDNA fraction was calculated from somatic mutations in targeted sequencing and genome copy-number profiles. Samples were classified into detected versus undetected ctDNA. Outcome measurements were progression-free survival (PFS) and overall survival (OS). Nondurable treatment response was defined as PFS ≤6 months. RESULTS: ctDNA was detected in 48/81 (59%) baseline and 29/81 (36%) 4-week samples. ctDNA fraction for samples with detected ctDNA was lower at 4 weeks versus baseline (median 5.0% versus 14.5%, P = 0.017). PFS and OS were shortest for patients with persistent ctDNA at 4 weeks (univariate HR, 4.79; 95% CI, 2.62-8.77 and univariate HR, 5.49; 95% CI, 2.76-10.91, respectively), independent of clinical prognostic factors. For patients exhibiting change from detected to undetected ctDNA by 4 weeks, there was no significant PFS difference versus patients with baseline undetected ctDNA. ctDNA change had a positive predictive value of 88% and negative predictive value of 92% for identifying nondurable responses. CONCLUSIONS: Early changes in ctDNA fraction are strongly linked to duration of first-line ARPI treatment benefit and survival in mCRPC and may inform early therapy switches or treatment intensification. See related commentary by Sartor, p. 2745.
Asunto(s)
ADN Tumoral Circulante , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Estudios Prospectivos , Nitrilos/uso terapéutico , Antagonistas de Receptores Androgénicos/uso terapéuticoRESUMEN
As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide (TMZ) before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. We also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression.
Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/genética , Estudios Retrospectivos , Glioma/genética , Astrocitoma/genética , Mutación , Temozolomida/uso terapéutico , Genómica , Isocitrato Deshidrogenasa/genéticaRESUMEN
BACKGROUND: High-risk non-muscle-invasive bladder cancer (NMIBC) is treated with bacillus Calmette-Guérin (BCG), but relapse is common. Improvement of patient outcomes requires better understanding of links between BCG resistance and genomic driver alterations. OBJECTIVE: To validate the prognostic impact of common genomic alterations in NMIBC pretreatment and define somatic changes present in post-BCG relapses. DESIGN, SETTING, AND PARTICIPANTS: We retrieved tumour tissues and outcomes for 90 patients with BCG-naive NMIBC initiating BCG monotherapy. Post-BCG tissue was available from 34 patients. All tissues underwent targeted sequencing of tumour and matched normal. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between clinical outcomes and genomics were determined using Cox proportional hazard models. RESULTS AND LIMITATIONS: Of the patients, 58% were relapse free at data cut-off, 24% had NMIBC recurrence, and 18% experienced muscle-invasive progression. The risk of relapse was associated with ARID1A mutation (hazard ratio [HR] = 2.00; p = 0.04) and CCNE1 amplification (HR = 2.61; p = 0.02). Pre- and post-BCG tumours shared truncal driver alterations, with mutations in TERT and chromatin remodelling genes particularly conserved. However, shifts in somatic profiles were common and clinically relevant alterations in FGFR3, PIK3CA, TSC1, and TP53 were temporally variable, despite apparent clonal prevalence at one time point. Limitations include the difficulty of resolving the relative impact of BCG therapy versus surgery on genomics at relapse and biopsy bias. CONCLUSIONS: Somatic hypermutation and alterations in CCNE1 and ARID1A should be incorporated into future models predicting NMIBC BCG outcomes. Changes in tumour genomics over time highlight the importance of recent biopsy when considering targeted therapies, and suggest that relapse after BCG is due to persisting and evolving precursor populations. PATIENT SUMMARY: Changes in key cancer genes can predict bladder cancer relapse after treatment with bacillus Calmette-Guérin. Relapses after treatment can be driven by large-scale genetic changes within the cancer. These genetic changes help us understand how superficial bladder cancer can progress to be treatment resistant.
Asunto(s)
Neoplasias Vesicales sin Invasión Muscular , Neoplasias de la Vejiga Urinaria , Humanos , Vacuna BCG/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , InmunoterapiaRESUMEN
Oligodendrogliomas are typically associated with the most favorable prognosis among diffuse gliomas. However, many of the tumors progress, eventually leading to patient death. To characterize the changes associated with oligodendroglioma recurrence and progression, we analyzed two recurrent oligodendroglioma tumors upon diagnosis and after tumor relapse based on whole-genome and RNA sequencing. Relapsed tumors were diagnosed as glioblastomas with an oligodendroglioma component before the World Health Organization classification update in 2016. Both patients died within 12 months after relapse. One patient carried an inactivating POLE mutation leading to a clearly hypermutated progressed tumor. Strikingly, both relapsed tumors carried focal chromosomal rearrangements in PTPRD and CNTNAP2 genes with associated decreased gene expression. TP53 mutation was also detected in both patients after tumor relapse. In The Cancer Genome Atlas (TCGA) diffuse glioma cohort, PTPRD and CNTNAP2 expression decreased by tumor grade in oligodendrogliomas and PTPRD expression also in IDH-mutant astrocytomas. Low expression of the genes was associated with poor overall survival. Our analysis provides information about aggressive oligodendrogliomas with worse prognosis and suggests that PTPRD and CNTNAP2 expression could represent an informative marker for their stratification.