RESUMO
Despite regulating overlapping gene enhancers and pathways, CREBBP and KMT2D mutations recurrently co-occur in germinal center (GC) B cell-derived lymphomas, suggesting potential oncogenic cooperation. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d induces a more severe mouse lymphoma phenotype (vs either allele alone) and unexpectedly confers an immune evasive microenvironment manifesting as CD8+ T-cell exhaustion and reduced infiltration. This is linked to profound repression of immune synapse genes that mediate crosstalk with T-cells, resulting in aberrant GC B cell fate decisions. From the epigenetic perspective, we observe interaction and mutually dependent binding and function of CREBBP and KMT2D on chromatin. Their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Together, our data provide an example where chromatin modifier mutations cooperatively shape and induce an immune-evasive microenvironment to facilitate lymphomagenesis.
Assuntos
Linfoma Difuso de Grandes Células B , Animais , Camundongos , Linfócitos B/metabolismo , Cromatina/genética , Cromatina/metabolismo , Centro Germinativo/metabolismo , Linfoma Difuso de Grandes Células B/genética , Mutação , Microambiente Tumoral/genéticaRESUMO
People with Li-Fraumeni syndrome (LFS) harbor a germline pathogenic variant in the TP53 tumor suppressor gene, face a near 100% lifetime risk of cancer, and routinely undergo intensive surveillance protocols. Liquid biopsy has become an attractive tool for a range of clinical applications, including early cancer detection. Here, we provide a proof-of-principle for a multimodal liquid biopsy assay that integrates a targeted gene panel, shallow whole-genome, and cell-free methylated DNA immunoprecipitation sequencing for the early detection of cancer in a longitudinal cohort of 89 LFS patients. Multimodal analysis increased our detection rate in patients with an active cancer diagnosis over uni-modal analysis and was able to detect cancer-associated signal(s) in carriers prior to diagnosis with conventional screening (positive predictive value = 67.6%, negative predictive value = 96.5%). Although adoption of liquid biopsy into current surveillance will require further clinical validation, this study provides a framework for individuals with LFS. SIGNIFICANCE: By utilizing an integrated cell-free DNA approach, liquid biopsy shows earlier detection of cancer in patients with LFS compared with current clinical surveillance methods such as imaging. Liquid biopsy provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients. See related commentary by Latham et al., p. 23. This article is featured in Selected Articles from This Issue, p. 5.
Assuntos
Ácidos Nucleicos Livres , Síndrome de Li-Fraumeni , Humanos , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/patologia , Proteína Supressora de Tumor p53/genética , Detecção Precoce de Câncer , Ácidos Nucleicos Livres/genética , Genes p53 , Mutação em Linhagem Germinativa , Predisposição Genética para DoençaRESUMO
Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. Limited data exist to show how serial circulating tumor DNA (ctDNA) testing may perform as a predictive biomarker in patients receiving ICB. We conducted a prospective phase II clinical trial to assess ctDNA in five distinct cohorts of patients with advanced solid tumors treated with pembrolizumab (NCT02644369). We applied bespoke ctDNA assays to 316 serial plasma samples obtained at baseline and every three cycles from 94 patients. Baseline ctDNA concentration correlated with progression-free survival, overall survival, clinical response and clinical benefit. This association became stronger when considering ctDNA kinetics during treatment. All 12 patients with ctDNA clearance during treatment were alive with median 25 months follow up. This study demonstrates the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB.
Assuntos
DNA Tumoral Circulante , Neoplasias , Anticorpos Monoclonais Humanizados , Biomarcadores , DNA Tumoral Circulante/genética , Humanos , Neoplasias/tratamento farmacológico , Estudos ProspectivosRESUMO
We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Ciclo Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Mutação , Neoplasias Pancreáticas/genética , Transcrição Gênica , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/secundário , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Predisposição Genética para Doença , Humanos , Israel , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Camundongos , Invasividade Neoplásica , América do Norte , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fenótipo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma , Hipóxia TumoralRESUMO
The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4-8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.
Assuntos
Predisposição Genética para Doença , Saúde , Leucemia Mieloide Aguda/genética , Mutação , Adulto , Fatores Etários , Idoso , Progressão da Doença , Registros Eletrônicos de Saúde , Feminino , Humanos , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Mutagênese , Prevalência , Medição de RiscoRESUMO
Although previous research into specialisation has been dominated by the debate over the existence of specialisation versus versatility, it is suggested that research needs to move beyond the restrictions of this dispute. The current study explores the criminal careers of 200 offenders based on their criminal records, obtained from a police database in the North West of England, aiming to understand the patterns and nature of specialisation by determining the presence of differentiation within their general offending behaviours and examining whether the framework of Expressive and Instrumental offending styles can account for any specialised tendencies that emerge. Fifty-eight offences were subjected to Smallest Space Analysis. Results revealed that a model of criminal differentiation could be identified and that any specialisation is represented in terms of Expressive and Instrumental offending styles.