RESUMO
BACKGROUND & AIMS: Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathologic consequences are poorly understood. METHODS: We disrupted active DNA demethylation genes Tet1 and/or Tdg from ApcMin mice and characterized the methylome and transcriptome of colonic adenomas. Data were compared to human colonic adenocarcinomas (COAD) in The Cancer Genome Atlas. RESULTS: There were increased numbers of small intestinal adenomas in ApcMin mice expressing the TdgN151A allele, whereas Tet1-deficient and Tet1/TdgN151A-double heterozygous ApcMin colonic adenomas were larger with features of erosion and invasion. We detected reduction in global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-mutant ApcMin mice and hypermethylation of CpG islands in Tet1-mutant ApcMin adenomas. Up-regulation of inflammatory, immune, and interferon response genes was present in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. This up-regulation was also seen in murine colonic organoids and human CRC lines infected with lentiviruses expressing TET1 or TDG short hairpin RNA. A 127-gene inflammatory signature separated colonic adenocarcinomas into 4 groups, closely aligned with their microsatellite or chromosomal instability and characterized by different levels of DNA methylation and DNMT1 expression that anticorrelated with TET1 expression. Tumors with the CpG island methylator phenotype (CIMP) had concerted high DNMT1/low TET1 expression. TET1 or TDG knockdown in CRC lines enhanced killing by natural killer cells. CONCLUSIONS: Our findings reveal a novel epigenetic regulation, linked to the type of genomic instability, by which TET1/TDG-mediated DNA demethylation decreases methylation levels and inflammatory/interferon/immune responses. CIMP in CRC is triggered by an imbalance of methylating activities over demethylating activities. These mice represent a model of CIMP CRC.
Assuntos
Adenocarcinoma , Adenoma , Neoplasias do Colo , Neoplasias Colorretais , Animais , Humanos , Camundongos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenoma/genética , Adenoma/patologia , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ilhas de CpG/genética , Metilação de DNA , Proteínas de Ligação a DNA/genética , Epigênese Genética , Oxigenases de Função Mista/genética , Fenótipo , Proteínas Proto-Oncogênicas/genéticaRESUMO
BACKGROUND: Because of the broad clinical spectrum, heritable autoinflammatory diseases present a management and therapeutic challenge. The most common genetic interferonopathy, Aicardi Goutières Syndrome (AGS), is associated with early onset neurologic disability and systemic inflammation. The chronic inflammation of AGS is the result of dysregulation of interferon (IFN) expression by one of nine genes within converging pathways. While each AGS subtype shares common features, distinct patterns of severity and potential for systemic complications amongst the genotypes are emerging. Multilineage cytopenias are a potentially serious, but poorly understood, complication of AGS. As immunomodulatory treatment options are developed, it is important to characterize the role of the disease versus treatment in hematologic abnormalities. This will allow for better understanding and management of cytopenia. METHODS: In total, 142 individuals with molecularly-confirmed AGS were included. Information on genotype, demographics, and all available hematologic laboratory values were collected from existing medical records. As part of a clinical trial, a subset of this cohort (n = 52) were treated with a janus kinase inhibitor (baricitinib), and both pre- and post-treatment values were included. Abnormal values were graded based on Common Terminology Criteria for Adverse Events (CTCAE v5.0), supplemented with grading definitions for thrombocytosis, and were compared across genotypes and baricitinib exposure. RESULTS: In total, 11,184 laboratory values were collected over a median of 2.54 years per subject (range 0-22.68 years). To reduce bias from repeated sampling within a limited timeframe, laboratory results were restricted to the most abnormal value within a month (n = 8485). The most common abnormalities were anemia (noted in 24% of subjects prior to baricitinib exposure), thrombocytopenia (9%), and neutropenia (30%). Neutropenia was most common in the SAMHD1 cohort and increased with baricitinib exposure (38/69 measurements on baricitinib versus 14/121 while not on baricitinib). Having an abnormality prior to treatment was associated with having an abnormality on treatment for neutropenia and thrombocytopenia. CONCLUSION: By collecting available laboratory data throughout the lifespan, we were able to identify novel patterns of hematologic abnormalities in AGS. We found that AGS results in multilineage cytopenias not limited to the neonatal period. Neutropenia, anemia, and thrombocytopenia were common. Moderate-severe graded events of neutropenia, anemia, and leukopenia were more common on baricitinib, but rarely of clinical consequence. Based on these results, we would recommend careful monitoring of hematologic parameters of children affected by AGS throughout the lifespan, especially while on therapy, and consideration of AGS as a potential differential diagnosis in children with neurologic impairment of unclear etiology with hematologic abnormalities. Trial registration ClinicalTrials.gov Identifier: NCT01724580 ClinicalTrials.gov Identifier: NCT03921554.
Assuntos
Anemia , Neutropenia , Trombocitopenia , Doenças Autoimunes do Sistema Nervoso , Criança , Humanos , Recém-Nascido , Inflamação , Malformações do Sistema NervosoAssuntos
Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Azetidinas/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Malformações do Sistema Nervoso/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adolescente , Idade de Início , Azetidinas/efeitos adversos , Biomarcadores , Criança , Desenvolvimento Infantil/efeitos dos fármacos , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Lactente , Interferons/genética , Interferons/metabolismo , Inibidores de Janus Quinases/efeitos adversos , Análise dos Mínimos Quadrados , Masculino , Purinas , Pirazóis , Sulfonamidas/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: People with disabilities face significant health disparities. Studies show that healthcare professionals harbor negative attitudes towards disability, compromising the quality of care. These attitudes, in unwritten, unofficial, and even unintended ways can be passed from providers to learners in the medical education setting. OBJECTIVE: Using a Critical Disability Studies (CDS) paradigm, the authors uncovered the disability-related hidden curriculum within Case-Based Learning (CBL) and proposed guidelines for promoting a disability-conscious medical education that resists ableism. METHODS: The study team conducted a qualitative analysis of all CBL cases from the pre-clerkship curriculum (n = 53) at Sidney Kimmel Medical College. The authors employed a directed content analysis approach to develop a codebook based on case examination, literature review, and CDS concepts. Two researchers coded all cases and assessed intercoder reliability. The results informed the development of an explanatory model. RESULTS: Only four of 53 cases overtly mentioned disability, none of which defined disability according to CDS. Coding did not identify content challenging stereotypical views of disability. Additionally, two cases included content fueling negative attitudes of disability. CONCLUSION: By inadequately addressing disability from a CDS perspective, harmful assumptions of disability may go unchallenged, driving a hidden curriculum within CBL. This phenomenon leaves medical students ill-prepared to care for people with disabilities and creates physicians ill-equipped to teach the next generation. Since many health professions utilize CBL to educate students, these cases provide an untapped opportunity to resist ableism and better prepare students to address the negative attitudes driving health disparities experienced by people with disabilities.