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Effective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 864 SARS-CoV-2 sequences from cases in the New York City metropolitan area during the COVID-19 outbreak in spring 2020. The majority of cases had no recent travel history or known exposure, and genetically linked cases were spread throughout the region. Comparison to global viral sequences showed that early transmission was most linked to cases from Europe. Our data are consistent with numerous seeds from multiple sources and a prolonged period of unrecognized community spreading. This work highlights the complementary role of genomic surveillance in addition to traditional epidemiological indicators.
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COVID-19 , Genoma Viral , Pandemias , Filogenia , SARS-CoV-2/genética , Secuenciación Completa del Genoma , COVID-19/epidemiología , COVID-19/genética , COVID-19/transmisión , Femenino , Humanos , Masculino , Ciudad de Nueva YorkRESUMEN
The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.ajpath.2020.07.001. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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The dynamics of viral load (VL) of the severe acute respiratory syndrome coronavirus 2 and its association with different clinical parameters remain poorly characterized in the US patient population. Herein, we investigate associations between VL and parameters, such as severity of symptoms, disposition (admission versus direct discharge), length of hospitalization, admission to the intensive care unit, length of oxygen support, and overall survival in 205 patients from a tertiary care center in New York City. VL was determined using quantitative PCR and log10 transformed for normalization. Associations were tested with univariate and multivariate regression models. Diagnostic VL was significantly lower in hospitalized patients than in patients not hospitalized (log10 VL = 3.3 versus 4.0; P = 0.018) after adjusting for age, sex, race, body mass index, and comorbidities. Higher VL was associated with shorter duration of the symptoms in all patients and hospitalized patients only and shorter hospital stay (coefficient = -2.02, -2.61, and -2.18; P < 0.001, P = 0.002, and P = 0.013, respectively). No significant association was noted between VL, admission to intensive care unit, length of oxygen support, and overall survival. Our findings suggest a higher shedding risk in less symptomatic patients, an important consideration for containment strategies. Furthermore, we identify a novel association between VL and history of cancer. Larger studies are warranted to validate our findings.
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Betacoronavirus/patogenicidad , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/terapia , Neumonía Viral/epidemiología , Neumonía Viral/terapia , Carga Viral , Adulto , COVID-19 , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Ciudad de Nueva York/epidemiología , Pandemias , Factores de Riesgo , SARS-CoV-2RESUMEN
Fibrolipoma of the heart is an unusual benign tumorous entity encountered, if present, during an ordinary imaging workout or at autopsy. It is often clinically silent but it can also be symptomatic depending on the size and location of the tumor. We report a case of an 82-year-old man with a medical history of malignant pleural mesothelioma. The decedent was referred to our department to undergo a forensic autopsy after a fall. Postmortem examination revealed a large encapsulated gelatinous, yellowish cardiac mass with its pedicle on the subendocardial region of the left ventricular anterior wall and interventricular septum, protruding into the left ventricular cavity. Histological examination confirmed the diagnosis of cardiac fibro-lipoma, a rare histologic variant of lipoma, irrelevant to the cause of death in the present case. The rarity of the occurrence of fibro-lipomas provides clinical implications for the inclusion of the entity in the differential diagnosis of a cardiac mass.
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Fibroma/patología , Neoplasias Cardíacas/patología , Ventrículos Cardíacos/patología , Hallazgos Incidentales , Lipoma/patología , Accidentes por Caídas , Anciano de 80 o más Años , Humanos , MasculinoRESUMEN
A specific subtype of non-small-cell lung cancer (NSCLC) characterized with an EML4-ALK fusion gene, which drives constitutive oncogenic activation of anaplastic lymphoma kinase (ALK), shows a good clinical response to ALK inhibitors. We have reported multiple examples implying the biological significance of methylation on non-histone proteins including oncogenic kinases in human carcinogenesis. Through the process to search substrates for various methyltransferases using an in vitro methyltransferase assay, we found that a lysine methyltransferase, SET and MYND domain-containing 2 (SMYD2), could methylate lysine residues 1451, 1455, and 1610 in ALK protein. Knockdown of SMYD2 as well as treatment with a SMYD2 inhibitor in two NSCLC cell lines with an EML4-ALK gene significantly attenuated the phosphorylation levels of the EML4-ALK protein. Substitutions of each of these three lysine residues to an alanine partially or almost completely diminished in vitro methylation of ALK. In addition, we found that exogenous introduction of EML4-ALK protein with the substitution of lysine 1610 to an alanine in these two cell lines reduced the phosphorylation levels of AKT, one of the downstream oncogenic molecules in the EML4-ALK pathway, and suppressed the growth of the two cell lines. We further showed that the combination of a SMYD2 inhibitor and an ALK inhibitor additively suppressed the growth of these two NSCLC cells, compared with single-agent treatment. Our results shed light on a novel mechanism that modulates the kinase activity of the ALK fused gene product and imply that SMYD2-mediated ALK methylation might be a promising target for development of a novel class of treatment for tumors with the ALK fused gene.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Proliferación Celular/genética , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias Pulmonares/genética , Proteínas de Fusión Oncogénica/genética , Transducción de Señal/genética , Quinasa de Linfoma Anaplásico , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/patología , Metilación , Fosforilación/genética , Proteínas Tirosina Quinasas Receptoras/genéticaRESUMEN
Organochlorine (OC) pesticides and polychlorinated biphenyls (PCB) are compounds characterized as persistent organic pollutants (POP) in the environment. These compounds are monitored globally since they enter the human body and accumulate in tissues, resulting in consequent adverse effects. In this study concentrations of selected OC compounds were determined in human autopsy lungs from Epirus, a relatively restricted region in northwestern Greece. This is the first epidemiologic study from Greece reporting on monitoring of environmental pollutants in human autopsy material. Thirty lungs collected from that number of autopsy cases were analyzed: 19 males and 11 females. The age range was 14-91 yr (mean ± SD = 61.8 ± 22.5 yr). Twenty-two cases (73%) were positive for at least one pollutant and eight cases were negative (27%). PCB were the most abundant class of contaminants, detected in 15 out of the 30 cases (50%). Dichlorodiphenyltrichloroethane (DDT) and hexachlorocyclohexanes (HCH) were second and third in abundance with 9 (30%) and 8 (27%) positive cases, respectively. The frequency of detection showed a tendency to increase with age of individuals. The patterns of OC found in human autopsy lungs were similar to those reported previously for other human specimens. Our results demonstrated a similar trend in contamination sources and distribution has occurred in western Greece as noted globally.
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Contaminantes Ambientales/química , Hidrocarburos Clorados/química , Pulmón/química , Residuos de Plaguicidas/química , Plaguicidas/química , Bifenilos Policlorados/química , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cadáver , Femenino , Grecia , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Genómica/métodos , Microambiente TumoralRESUMEN
PURPOSE: Adult granulosa cell tumor (AGCT) is characterized by the somatic FOXL2 p.C134W mutation, and recurrences have been associated with TERT promoter and KMT2D-truncating mutations. Conversely, the molecular underpinnings of the rare juvenile granulosa cell tumor (JGCT) have not been well elucidated. To this end, we applied a tumor-only integrated approach to investigate the genomic, transcriptomic, and epigenomic landscape of 31 JGCTs to identify putative oncogenic drivers. EXPERIMENTAL DESIGN: Multipronged analyses of 31 JGCTs were performed utilizing a clinically validated next-generation sequencing (NGS) panel targeting 580 cancer-related genes for genomic interrogation, in addition to targeted RNA NGS for transcriptomic exploration. Genome-wide DNA methylation profiling was conducted using an Infinium Methylation EPIC array targeting 866,562 CpG methylation sites. RESULTS: We identified frequent KMT2C-truncating mutations along with other mutated genes implicated in the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, in addition to previously reported hotspot AKT1 and DICER1 mutations. Targeted transcriptome sequencing revealed recurrent TERT rearrangements (13%) involving partners CLPTM1L or DROSHA, and differential gene expression analysis showed FGFR1 upregulation in the TERT non-rearranged JGCTs under direct promoter control. Genome-wide DNA methylation rendered a clear delineation between AGCTs and JGCTs at the epigenomic level, further supporting its diagnostic utility in distinguishing among these tumors. CONCLUSIONS: This is the largest comprehensive molecular study of JGCTs, where we further expand our current understanding of JGCT pathogenesis and demonstrate putative oncogenic drivers and TERT rearrangements in a subset of tumors. Our findings further offer insights into possible targeted therapies in a rare entity.
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Tumor de Células de la Granulosa , Neoplasias Ováricas , Telomerasa , Adulto , ARN Helicasas DEAD-box/genética , Epigénesis Genética , Epigenómica , Femenino , Tumor de Células de la Granulosa/diagnóstico , Tumor de Células de la Granulosa/genética , Tumor de Células de la Granulosa/patología , Humanos , Mutación , Neoplasias Ováricas/patología , Ribonucleasa III/genética , Telomerasa/genéticaRESUMEN
Acute necrotizing eosinophilic myocarditis (ANEM) is a rare entity with sudden onset and rapidly progressive course, usually leading to a fatal outcome. It is characterized by focal or widespread myocyte necrosis. The entity's clinical presentation is quite variable, rendering the antemortem diagnosis difficult. A case of a 66-year-old woman dying suddenly, initially considered to have suffered a myocardial infarction and finally proved at autopsy to have died due to ANEM resulting in myocardial rupture, is presented. Left ventricular wall rupture is in the majority of cases, a complication of myocardial infarction and its association with acute myocarditis has been very rarely reported. The case reported herein highlights the infrequent presentation of ANEM as cardiac rupture. Myocardial rupture is associated with a high mortality rate, even if immediate surgical repair and intervention are provided.
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Eosinofilia/patología , Rotura Cardíaca/patología , Ventrículos Cardíacos/patología , Miocarditis/patología , Enfermedad Aguda , Anciano , Edema/patología , Femenino , Patologia Forense , Rotura Cardíaca/etiología , Humanos , Miocardio/patología , Miocitos Cardíacos/patología , NecrosisRESUMEN
In diagnostic breast pathology, there is no reliable applicable immunostain to help discern atypical and in situ apocrine lesions from benign apocrine tissue. At present, the diagnosis of non-invasive apocrine lesions remains challenging with current diagnoses rendered based on discrete morphologic characteristics on conventional hematoxylin and eosin staining. Interobserver variability is significant even among subspecialists partly due to lack of adjuvant diagnostic immunohistochemical stains. Herein, we set to elucidate the potential utility of EZH2 and Ki-67 immunostains as tangible tools in non-invasive apocrine proliferations. A cohort of apocrine breast lesions [Benign apocrine hyperplasia (BAH), n = 10; Atypical apocrine hyperplasia (AAH), n = 16; Apocrine ductal carcinoma in situ (ADCIS), n = 12] were subjected to EZH2 immunostaining and analyzed via H-scoring of nuclear expression. Mean H-scores for EZH2 progressively increased from BAH (23.5), to AAH (47.4) and ADCIS (196.4), and showed a significant difference utilizing the Kruskal-Wallis test (p < 0.0001). Further interrogation of Ki-67 demonstrated incremental expression from BAH to AAH and ADCIS at 1.6 %, 4.7 % and 24.7 %, respectively (p < 0.0001, Kruskal-Wallis test), suggesting an association with increased proliferation. Our results demonstrate that a combination of EZH2 and Ki-67 immunostaining may be employed in differentiating among challenging apocrine breast lesions and suggest a putative diagnostic utility for EZH2 and Ki-67 in non-invasive apocrine breast lesions.
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Neoplasias de la Mama/patología , Mama/patología , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Antígeno Ki-67/metabolismo , Glándulas Apocrinas/patología , Biomarcadores de Tumor/metabolismo , Mama/metabolismo , Neoplasias de la Mama/diagnóstico , Células Epiteliales/patología , Femenino , Humanos , Hiperplasia/patología , Metaplasia/patología , Lesiones Precancerosas/patologíaRESUMEN
Protein lysine methyltransferases (PKMTs) constitute a large family of approximately 50 chromatin modifiers that mono-, di- and/or tri-methylate lysine residues on histone and non-histone substrates. With the advent of The Cancer Genome Atlas, it became apparent that this family of chromatin modifiers harbors frequent genetic and expression alterations in multiple types of cancer. In this regard, past and ongoing preclinical studies have provided insight into the mechanisms of action of some of these enzymes, laying the ground for the ongoing development of PKMT inhibitors as novel anticancer therapeutics. The purpose of this review is to summarize existing data obtained by different research groups through immunohistochemical analysis of the protein expression levels of PKMTs, and their respective clinicopathologic associations. We focused on studies that used immunohistochemistry to associate protein expression levels of specific PKMTs, as well as several established histone methylation marks, with clinicopathologic features and survival outcomes in various cancer types. We also review ongoing clinical trials of PKMT inhibitors in cancer treatment. This review underscores the clinical relevance and potential of targeting the family of PKMT enzymes as the next generation of cancer therapy.
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Metilación de ADN/genética , N-Metiltransferasa de Histona-Lisina/genética , Histonas/química , Neoplasias/genética , Adolescente , Adulto , Ensayos Clínicos como Asunto , Proteína Potenciadora del Homólogo Zeste 2/genética , Epigenómica/métodos , Femenino , Histonas/metabolismo , Humanos , Inmunohistoquímica/métodos , Lisina/metabolismo , Estadificación de Neoplasias/métodos , Neoplasias/patología , Análisis de Supervivencia , Adulto JovenRESUMEN
The tumor microenvironment (TME) plays critical roles in tumor growth and progression, however key regulators of gene expression in the TME of cutaneous malignant peripheral nerve sheath tumor (C-MPNST) and spindle cell melanoma (SCM) have not been well elucidated. Herein, we investigate the epigenetic regulation of promoters and gene bodies and their effect on the TME composition of C-MPNSTs and SCMs. A cohort of 30 patients was analyzed using differential gene expression (DGE) and gene set enrichment analysis (GSEA) using the Nanostring platform. Methylation analysis was carried out utilizing an Infinium Methylation EPIC array targeting 866,562 methylation site (CpG) islands. DGE revealed overexpression of genes related to mast cells in the TME of SCMs, and a predominance of exhausted CD8+ T cells and macrophages in the TME of C-MPNSTs. Interestingly, we further observed promoter hypermethylation in key overexpressed genes and corresponding gene body hypomethylation. Analysis using ENCODE ChIP-sequencing data identified CTCF as the common transcription factor at the site of the hypomethylated probe. These findings support that the TME composition of C-MPNSTs and SCMs is at least partially independent on promoter methylation status, suggesting a possible relationship between gene body enhancers and expression of key TME genes in both entities.
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Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Melanoma/genética , Neoplasias de la Vaina del Nervio/genética , Neoplasias Cutáneas/genética , Microambiente Tumoral , Estudios de Cohortes , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Neoplasias de la Vaina del Nervio/patología , Neoplasias Cutáneas/patologíaRESUMEN
Squamous cell carcinoma of the head and neck (SCCHN) is a malignancy with poor outcomes, thus novel therapies are urgently needed. We recently showed that WHSC1 is necessary for the viability of SCCHN cells through H3K36 di-methylation. Here, we report the identification of its novel substrate, histone H1, and that WHSC1-mediated H1.4K85 mono-methylation may enhance stemness features in SCCHN cells. To identify proteins interacting with WHSC1 in SCCHN cells, WHSC1 immunoprecipitation and mass spectrometry identified H1 as a WHSC1-interacting candidate. In vitro methyltransferase assays showed that WHSC1 mono-methylates H1 at K85. We generated an H1K85 mono-methylation-specific antibody and confirmed that this methylation occurs in vivo. Sphere formation assays using SCC-35 cells stably expressing either wild-type (FLAG-H1.4-WT) or mutated (FLAG-H1.4K85A) vector with lysine 85 to alanine substitution which is not methylated, indicated a higher number of spheres in SCC-35 cells expressing the wild type than those with the mutant vector. SCC-35 cells expressing the wild type H1.4 proliferated faster than those expressing the mutated vector. RNA sequencing, RT-PCR and Western blotting of the FLAG-H1.4-WT or FLAG-H1.4K85A SCC-35 cells revealed that OCT4 levels were higher in wild type compared to mutant cells. These results were reproduced in SCC-35 cells genetically modified with CRISPR to express H1.4K85R. Chromatin immunoprecipitation showed that FLAG-H1.4K85A had decreased occupancy in the OCT4 gene compared to FLAG-H1.4-WT. This study supports that WHSC1 mono-methylates H1.4 at K85, it induces transcriptional activation of OCT4 and stemness features in SCCHN cells, providing rationale to target H1.4K85 mono-methylation through WHSC1 in SCCHN.
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Neoplasias de Cabeza y Cuello/patología , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Células Madre Neoplásicas/patología , Proteínas Represoras/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Apoptosis , Proliferación Celular , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Histonas/química , Histonas/genética , Humanos , Células Madre Neoplásicas/metabolismo , Proteínas Represoras/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Células Tumorales CultivadasRESUMEN
Effective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 864 SARS-CoV-2 sequences from cases in the New York City metropolitan area during the COVID-19 outbreak in Spring 2020. The majority of cases had no recent travel history or known exposure, and genetically linked cases were spread throughout the region. Comparison to global viral sequences showed that early transmission was most linked to cases from Europe. Our data are consistent with numerous seeds from multiple sources and a prolonged period of unrecognized community spreading. This work highlights the complementary role of genomic surveillance in addition to traditional epidemiological indicators.
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The aim of this study was to evaluate suicide trends among individuals < or = 24 years of age in the region of Epirus, northwestern Greece, from January 1998 to December 2008. Twenty-one cases were classified as suicides out of 242 total deaths (8.7%). The male to female suicide ratio was 4.25 (17 males and 4 females). The preferred suicide method for those aged > or = 19 years involved firearms, and for those aged < 19 years was hanging. Alcohol was implicated in more than 50% of the suicides and was consumed exclusively by those aged > 16 years. Suicides by self-shooting were more often related to drinking than suicides by other methods. Children and adolescents (aged up to 15 years), older adolescents (15-18 years) and young adults (19-24 years) had suicide rates of 0.05/100,000, 0.10/100,000 and 0.39/100,000 inhabitants per year, respectively. These suicide rates are the lowest reported so far in Europe. The main reason for this may be the traditional lifestyle of the local population and the strong family ties that protect against suicide, especially for the young.
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Consumo de Bebidas Alcohólicas/mortalidad , Suicidio/estadística & datos numéricos , Heridas por Arma de Fuego/mortalidad , Accidentes/estadística & datos numéricos , Adolescente , Asfixia/mortalidad , Niño , Femenino , Patologia Forense , Grecia/epidemiología , Homicidio/estadística & datos numéricos , Humanos , Masculino , Distribución por Sexo , Adulto JovenRESUMEN
Tenosynovial giant cell tumor (TGCT) is a benign neoplasm characterized by recurrent fusions involving the colony-stimulating factor 1 (CSF1) gene and translocation partners including collagen type VI alpha 3 chain (COL6A3) or S100 calcium-binding protein A10 (S100A10). Herein, we report three atypical TGCT cases with very unusual morphology comprising areas with increased cellular atypia, mitotic activity, and worrisome features that harbor unique non-CSF1 gene fusions. Anchored multiplex PCR (AMP) for next-generation sequencing utilizing a customized panel targeting 86 cancer-related genes was performed, and it identified novel non-CSF1-driven gene fusions: NIPBL-ERG, FN1-ROS1, and YAP1-MAML2. Screening of three control TGCTs with conventional morphology found translocations involving CSF1, with partner genes COL6A3, FN1, and newly identified KCNMA1. All novel fusions were further validated by reverse transcriptase-PCR (RT-PCR) and Sanger sequencing. Late and multiple local recurrences occurred in the atypical TGCTs, while no recurrences were reported in the conventional TGCTs. Our findings reveal that atypical TGCTs harbor gene fusions not implicating CSF1 and suggest that non-CSF1 fusions potentially confer greater propensity to recurrences and local aggressiveness while indicating the presence of alternate pathogenic mechanisms that warrant further investigation.
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OBJECTIVES: In this study we describe the tumor microenvironment, the signaling pathways and genetic alterations associated with the presence or absence of CD8+ T-cell infiltration in primary squamous cell carcinoma of the head and neck (SCCHN) tumors. MATERIALS AND METHODS: Two SCCHN multi-analyte cohorts were utilized, the Cancer Genome Atlas (TCGA) and the Chicago Head and Neck Genomics (CHGC) cohort. A well-established chemokine signature classified SCCHN tumors into high and low CD8+ T-cell inflamed phenotypes (TCIP-H, TCIP-L respectively). Gene set enrichment and iPANDA analyses were conducted to dissect differences in signaling pathways, somatic mutations and copy number aberrations for TCIP-H versus TCIP-L tumors, stratified by HPV status. RESULTS: TCIP-H SCCHN tumors were enriched in multiple immune checkpoints irrespective of HPV-status. HPV-positive tumors were enriched in markers of T-regulatory cells (Tregs) and HPV-negative tumors in protumorigenic M2 macrophages. TCIP-L SCCHN tumors were enriched for the ß-catenin/WNT and Hedgehog signaling pathways, had frequent mutations in NSD1, amplifications in EGFR and YAP1, as well as CDKN2A deletions. TCIP-H SCCHN tumors were associated with the MAPK/ERK, JAK/STAT and mTOR/AKT signaling pathways, and were enriched in CASP8, EP300, EPHA2, HRAS mutations, CD274, PDCD1LG2, JAK2 amplifications. CONCLUSIONS: Our findings support that combinatorial immune checkpoint blockade and depletion strategies targeting Tregs in HPV-positive and M2 macrophages in HPV-negative tumors may lead to improved antitumor immune responses in patients with TCIP-H SCCHN. We highlight novel pathways and genetic events that may serve as candidate biomarkers and novel targeted therapies to enhance the efficacy of immunotherapy in SCCHN patients.
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Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Microambiente TumoralRESUMEN
Squamous cell carcinoma of the head and neck is a lethal disease with suboptimal survival outcomes and standard therapies with significant comorbidities. Whole exome sequencing data recently revealed an abundance of genetic and expression alterations in a family of enzymes known as protein methyltransferases in a variety of cancer types, including squamous cell carcinoma of the head and neck. These enzymes are mostly known for their chromatin-modifying functions through methylation of various histone substrates, though evidence supports their function also through methylation of non-histone substrates. This review summarizes the current knowledge on the function of protein methyltransferases in squamous cell carcinoma of the head and neck and highlights their promising potential as the next generation of therapeutic targets in this disease.
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Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Proteína Metiltransferasas/antagonistas & inhibidores , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Ensayos Clínicos como Asunto , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Epigénesis Genética , Neoplasias de Cabeza y Cuello/enzimología , Humanos , Metilación , Mutación , Proteína Metiltransferasas/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/enzimologíaRESUMEN
Protein methyltransferase SUV39H2 was reported to methylate histone H2AX at lysine 134 and enhance the formation of phosphorylated H2AX (γ-H2AX), which causes chemoresistance of cancer cells. We found that a series of imidazo[1,2-a]pyridine compounds that we synthesized could inhibit SUV39H2 methyltransferase activity. One of the potent compounds, OTS193320, was further analyzed in in vitro studies. The compound decreased global histone H3 lysine 9 tri-methylation levels in breast cancer cells and triggered apoptotic cell death. Combination of OTS193320 with doxorubicin (DOX) resulted in reduction of γ-H2AX levels as well as cancer cell viability compared to a single agent OTS193320 or DOX. Further optimization of inhibitors and their in vivo analysis identified a compound, OTS186935, which revealed significant inhibition of tumor growth in mouse xenograft models using MDA-MB-231 breast cancer cells and A549 lung cancer cells without any detectable toxicity. Our results suggest that the SUV39H2 inhibitors sensitize cancer cells to DOX by reduction of γ-H2AX levels in cancer cells, and collectively demonstrate that SUV39H2 inhibition warrants further investigation as a novel anti-cancer therapy.
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Accumulating evidence has recently shown that protein methyltransferases and demethylases are crucial regulators in either maintaining pluripotent states or inducing differentiation of embryonic stem cells. These enzymes control pluripotent signatures by mediating activation or repression of histone marks, or through direct methylation of non-histone proteins. Importantly, chromatin modifiers can influence the fate of many differentiation-related genes by loosening chromatin and allowing for transcriptional activation of lineage-specific genes. Genome-wide studies have unraveled diverse changes in methylation patterns following embryonic stem cell differentiation, with redistribution of heterochromatic and euchromatic marks, underlying the importance of chromatin modifiers in governing the fate of embryonic stemness. Furthermore, the development of small molecule inhibitors targeting these agents may shed light in potential clinical implementation to reprogram embryonic stem cells for biomedical therapeutics. Ever since the pioneering introduction of induced pluripotent stem cells, the challenge for application in regenerative medicine and broader medical therapeutics has commenced.