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INTRODUCTION: Brainstem is a rare yet challenging site for primary brain tumors. We present the patient characteristics, treatment-related details, and survival outcomes of patients with brain stem gliomas treated over a decade, from August 2010 to July 2022, at a tertiary care center in northern India. MATERIALS AND METHODS: Twenty-seven patients of brainstem gliomas were treated in our hospital from August 2010 to July 2022. All of these patients were treated with radiation therapy based on a radiological diagnosis only. Data were collected and analyzed from patient registration, treatment, and follow-up records. RESULTS: Of the 27 patients, 18 were male and 9 were female. Fourteen patients (51.85%) were in the pediatric age group (<12 years). The most common symptom at onset was hemiparesis, seen in 62.96%. The majority of the patients (24; 88.88%) had pontine involvement at the time of treatment. Overall survival at a minimum 2-year follow-up post-treatment was 22.22% in the entire cohort. Age, sex, or size of tumor at presentation was not seen to have any significant impact on survival of patients. CONCLUSION: With the advancement in surgical techniques and molecular analysis of brain tumors, there is likely to be a change in the management of brainstem gliomas; however, radiation therapy has been used for the management of these tumors for decades now. Radiation therapy continues to show rapid and significant radiological and clinical improvement in the majority of such patients, and it would continue to play an important part in multi-modality management.
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Primary aldosteronism (PA) is the most common form of endocrine hypertension and is characterized by inappropriately elevated aldosterone production via a renin-independent mechanism. Driver somatic mutations for aldosterone excess have been found in approximately 90% of aldosterone-producing adenomas (APAs). Other causes of lateralized adrenal PA include aldosterone-producing nodules (APNs). Using next-generation sequencing, we identified recurrent in-frame deletions in SLC30A1 in four APAs and one APN (p.L51_A57del, n = 3; p.L49_L55del, n = 2). SLC30A1 encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). The identified SLC30A1 variants are situated close to the zinc-binding site (His43 and Asp47) in transmembrane domain II and probably cause abnormal ion transport. Cases of PA with SLC30A1 mutations showed male dominance and demonstrated increased aldosterone and 18-oxocortisol concentrations. Functional studies of the SLC30A151_57del variant in a doxycycline-inducible adrenal cell system revealed pathological Na+ influx. An aberrant Na+ current led to depolarization of the resting membrane potential and, thus, to the opening of voltage-gated calcium (Ca2+) channels. This resulted in an increase in cytosolic Ca2+ activity, which stimulated CYP11B2 mRNA expression and aldosterone production. Collectively, these data implicate zinc transporter alterations as a dominant driver of aldosterone excess in PA.
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Adenoma , Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Proteínas de Transporte de Catión , Hiperaldosteronismo , Masculino , Humanos , Aldosterona/genética , Adenoma Corticosuprarrenal/genética , Hiperaldosteronismo/genética , Adenoma/genética , Adenoma/complicaciones , Mutación , Zinc/metabolismo , Neoplasias de la Corteza Suprarrenal/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Proteínas de Transporte de Catión/genéticaRESUMEN
Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive soft tissue tumor with a high propensity of local recurrence after surgery. Radiotherapy as an adjuvant therapy has been shown to reduce recurrent rates of this disease. Surface mould brachytherapy is an effective and safe modality for the delivery of radiotherapy in soft tissue tumors, though its utilization and popularity have decreased in recent years. Here, we presented a case of a recurrent DFSP of the scalp who was treated with surgery followed by adjuvant surface mould brachytherapy to avoid dose inhomogeneity likely to occur in this anatomic region with external beam radiotherapy in the absence of intensity-modulated radiotherapy. The treatment was delivered successfully with minimal adverse reactions, and the patient is disease-free at 18 months post-treatment with no treatment toxicity.
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This study was conducted in locally advanced supraglottic and hypopharyngeal squamous cell carcinoma patients to ascertain the efficacy and toxicity profile of a two drug combination neo adjuvant chemotherapy (NACT) schedule containing Taxane and Platinum; prior to definitive concurrent chemo-radiotherapy (Def CCRT); sixty patients with stage III, IVA and IVB locally advanced squamous cell cancers of larynx and hypopharynx were randomised to two arms. Thirty patients in study group were treated with NACT with Paclitaxel (175 mg/m2) and Carboplatin (AUC 5-7) for 3, 3 weekly cycles; followed by CCRT in the patients who showed at-least a partial response (PR). These patients were compared with the 30 patients of control group who received upfront CCRT. More patients in Study arm developed grade 3 dysphagia (p = 0.001) and mucositis (p = 0.003). Renal, hematogenous and skin toxicities were identical in two arms. At 3 months post treatment complete response (CR) at primary site was 83.3% and 66.6% (p = 0.245) in study and control arms respectively. At 6 months post treatment; 20 patients (66.6%) in the study group and 17 patients (56.6%) in the control group continued to be in clinic-radiological CR (p = 0.20). NACT with Paclitaxel and Carboplatin is tolerated with manageable toxicities in patients with LAHNSCC (Locally advanced head and neck squamous cell carcinoma), with increased Grade 3 dysphagia and mucositis as compared to patients getting upfront CCRT. A longer follow-up period with a larger sample size is required to further evaluate any statistically significant benefit of adding NACT prior to CCRT.
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BACKGROUND: Biliary tract cancers (BTCs) including intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder cancer, are rare but aggressive malignancies with few effective standard of care therapies. METHODS: We implemented integrative clinical sequencing of advanced BTC tumors from 124 consecutive patients who progressed on standard therapies (N=92 with MI-ONCOSEQ and N=32 with commercial gene panels) enrolled between 2011-2020. RESULTS: Genomic profiling of paired tumor and normal DNA and tumor transcriptome (RNA) sequencing identified actionable somatic and germline genomic alterations in 54 patients (43.5%), and potentially actionable alterations in 79 (63.7%) of the cohort. Of these, patients who received matched targeted therapy (22; 40.7%) had a median overall survival of 28.1 months compared to 13.3 months in those who did not receive matched targeted therapy (32; P < 0.01), or 13.9 months in those without actionable mutations (70; P < 0.01). Additionally, we discovered recurrent activating mutations in FGFR2, and a novel association between KRAS and BRAF mutant tumors with high expression of immune modulatory protein NT5E (CD73) that may represent novel therapeutic avenues. CONCLUSIONS: Overall, the identification of actionable/ potentially actionable aberrations in a large proportion of cases, and improvement in survival with precision oncology supports molecular analysis and clinical sequencing for all patients with advanced BTC.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Humanos , Medicina de Precisión , Neoplasias de los Conductos Biliares/genética , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/terapia , Neoplasias del Sistema Biliar/patología , Mutación , Genómica , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patologíaRESUMEN
Detection of de novo variants (DNVs) is critical for studies of disease-related variation and mutation rates. To accelerate DNV calling, we developed a graphics processing units-based workflow. We applied our workflow to whole-genome sequencing data from three parent-child sequenced cohorts including the Simons Simplex Collection (SSC), Simons Foundation Powering Autism Research (SPARK), and the 1000 Genomes Project (1000G) that were sequenced using DNA from blood, saliva, and lymphoblastoid cell lines (LCLs), respectively. The SSC and SPARK DNV callsets were within expectations for number of DNVs, percent at CpG sites, phasing to the paternal chromosome of origin, and average allele balance. However, the 1000G DNV callset was not within expectations and contained excessive DNVs that are likely cell line artifacts. Mutation signature analysis revealed 30% of 1000G DNV signatures matched B-cell lymphoma. Furthermore, we found variants in DNA repair genes and at Clinvar pathogenic or likely-pathogenic sites and significant excess of protein-coding DNVs in IGLL5; a gene known to be involved in B-cell lymphomas. Our study provides a new rapid DNV caller for the field and elucidates important implications of using sequencing data from LCLs for reference building and disease-related projects.
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Neoplasias , Humanos , Alelos , Mutación , Neoplasias/genética , Secuenciación Completa del GenomaRESUMEN
As recently demonstrated by the COVID-19 pandemic, large-scale pathogen genomic data are crucial to characterize transmission patterns of human infectious diseases. Yet, current methods to process raw sequence data into analysis-ready variants remain slow to scale, hampering rapid surveillance efforts and epidemiological investigations for disease control. Here, we introduce an accelerated, scalable, reproducible, and cost-effective framework for pathogen genomic variant identification and present an evaluation of its performance and accuracy across benchmark datasets of Plasmodium falciparum malaria genomes. We demonstrate superior performance of the GPU framework relative to standard pipelines with mean execution time and computational costs reduced by 27× and 4.6×, respectively, while delivering 99.9% accuracy at enhanced reproducibility.
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COVID-19 , Enfermedades Transmisibles , Malaria , COVID-19/epidemiología , COVID-19/genética , Genómica/métodos , Humanos , Pandemias , Reproducibilidad de los ResultadosRESUMEN
In October 2020, 62 scientists from nine nations worked together remotely in the Second Baylor College of Medicine & DNAnexus hackathon, focusing on different related topics on Structural Variation, Pan-genomes, and SARS-CoV-2 related research. The overarching focus was to assess the current status of the field and identify the remaining challenges. Furthermore, how to combine the strengths of the different interests to drive research and method development forward. Over the four days, eight groups each designed and developed new open-source methods to improve the identification and analysis of variations among species, including humans and SARS-CoV-2. These included improvements in SV calling, genotyping, annotations and filtering. Together with advancements in benchmarking existing methods. Furthermore, groups focused on the diversity of SARS-CoV-2. Daily discussion summary and methods are available publicly at https://github.com/collaborativebioinformatics provides valuable insights for both participants and the research community.
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COVID-19 , SARS-CoV-2 , Animales , Genoma Viral , Humanos , VertebradosRESUMEN
Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.
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Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Proteogenómica , Acetilación , Adulto , Anciano , Anciano de 80 o más Años , Análisis por Conglomerados , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Proteínas de Neoplasias/metabolismo , Fosforilación , Unión Proteica , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal , UbiquitinaciónRESUMEN
Diverse subtypes of renal cell carcinomas (RCCs) display a wide spectrum of histomorphologies, proteogenomic alterations, immune cell infiltration patterns, and clinical behavior. Delineating the cells of origin for different RCC subtypes will provide mechanistic insights into their diverse pathobiology. Here, we employed single-cell RNA sequencing (scRNA-seq) to develop benign and malignant renal cell atlases. Using a random forest model trained on this cell atlas, we predicted the putative cell of origin for more than 10 RCC subtypes. scRNA-seq also revealed several attributes of the tumor microenvironment in the most common subtype of kidney cancer, clear cell RCC (ccRCC). We elucidated an active role for tumor epithelia in promoting immune cell infiltration, potentially explaining why ccRCC responds to immune checkpoint inhibitors, despite having a low neoantigen burden. In addition, we characterized an association between high endothelial cell types and lack of response to immunotherapy in ccRCC. Taken together, these single-cell analyses of benign kidney and RCC provide insight into the putative cell of origin for RCC subtypes and highlight the important role of the tumor microenvironment in influencing ccRCC biology and response to therapy.
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Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Neoplasias Renales/patología , Neoplasias Renales/terapia , Análisis de la Célula Individual , Carcinoma de Células Renales/inmunología , Supervivencia Celular , Células Endoteliales/patología , Células Epiteliales/patología , Humanos , Inmunoterapia , Riñón/patología , Neoplasias Renales/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Células Mieloides/patología , Resultado del TratamientoAsunto(s)
COVID-19/epidemiología , Neoplasias/radioterapia , Hipofraccionamiento de la Dosis de Radiación , COVID-19/prevención & control , Estudios Clínicos como Asunto , Humanos , Neoplasias/patología , Oncología por Radiación/estadística & datos numéricos , Oncología por Radiación/tendencias , SARS-CoV-2 , Resultado del TratamientoRESUMEN
IMPORTANCE: Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain. OBJECTIVE: To determine which patients derived the greatest degree of clinical benefit from NGS profiling. DESIGN, SETTING, AND PARTICIPANTS: Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020. MAIN OUTCOMES AND MEASURES: Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer. RESULTS: During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses. CONCLUSIONS AND RELEVANCE: The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.
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Biomarcadores de Tumor , Neoplasias , Biomarcadores de Tumor/genética , Estudios de Cohortes , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológicoRESUMEN
We present a proteogenomic study of 108 human papilloma virus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs). Proteomic analysis systematically catalogs HNSCC-associated proteins and phosphosites, prioritizes copy number drivers, and highlights an oncogenic role for RNA processing genes. Proteomic investigation of mutual exclusivity between FAT1 truncating mutations and 11q13.3 amplifications reveals dysregulated actin dynamics as a common functional consequence. Phosphoproteomics characterizes two modes of EGFR activation, suggesting a new strategy to stratify HNSCCs based on EGFR ligand abundance for effective treatment with inhibitory EGFR monoclonal antibodies. Widespread deletion of immune modulatory genes accounts for low immune infiltration in immune-cold tumors, whereas concordant upregulation of multiple immune checkpoint proteins may underlie resistance to anti-programmed cell death protein 1 monotherapy in immune-hot tumors. Multi-omic analysis identifies three molecular subtypes with high potential for treatment with CDK inhibitors, anti-EGFR antibody therapy, and immunotherapy, respectively. Altogether, proteogenomics provides a systematic framework to inform HNSCC biology and treatment.
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Antineoplásicos Inmunológicos/uso terapéutico , Infecciones por Papillomavirus/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Adulto , Anciano , Anciano de 80 o más Años , Receptores ErbB/genética , Femenino , Humanos , Inmunoterapia/métodos , Masculino , Persona de Mediana Edad , Infecciones por Papillomavirus/tratamiento farmacológico , Infecciones por Papillomavirus/virología , Proteogenómica/métodos , Proteómica/métodos , Adulto JovenRESUMEN
Somatic mutations driving aldosterone production have been identified in approximately 90% of aldosterone-producing adenomas (APAs) using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided DNA sequencing approach. In the present study, using CYP11B2-guided whole-exome sequencing (WES) and targeted amplicon sequencing, we detected 2 somatic variants in CLCN2 in 2 APAs that were negative for currently known aldosterone-driver mutations. The CLCN2 gene encodes the voltage-gated chloride channel ClC-2. CLCN2 germline variants have previously been shown to cause familial hyperaldosteronism type II. Somatic mutations in CLCN2 were identified in 2 of 115 APAs, resulting in a prevalence of 1.74%. One of the CLCN2 somatic mutations (c.G71A,p.G24D) was identical to a previously described germline variant causing early-onset PA, but was present only as a somatic mutation. The second CLCN2 mutation, which affects the same region of the gene, has not been reported previously (c.64-2_74del). These findings prove that WES of CYP11B2-guided mutation-negative APAs can help determine rarer genetic causes of sporadic PA.
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PURPOSE: Translational studies have shown that CDK12 mutations may delineate an immunoresponsive subgroup of prostate cancer, characterized by high neo-antigen burden. Given that these mutations may define a clinically distinct subgroup, we sought to describe outcomes to standard drugs and checkpoint inhibitors (CPI). PATIENTS AND METHODS: Clinical data from consecutive patients with CDK12 mutations were retrospectively collected from 7 centers. Several clinical-grade sequencing assays were used to assess CDK12 status. Descriptive statistics included PSA50 response rate (≥ 50% decline in prostate-specific antigen from baseline) and clinical/radiographic progression-free survival (PFS). RESULTS: Of 52 patients with CDK12-mutated prostate cancer, 27 (52%) had detected biallelic CDK12 alterations. At diagnosis, 44 (88%) had Gleason grade group 4-5, 52% had T3-T4, and 14 (27%) had M1 disease. Median follow-up was 8.2 years (95% CI, 5.6 to 11.1 years), and 49 (94%) developed metastatic disease. Median overall survival from metastasis was 3.9 years (95% CI, 3.2 to 8.1 years). Unconfirmed PSA50 response rates to abiraterone and enzalutamide in the first-line castration-resistant prostate cancer setting were 11 of 17 (65%) and 9 of 12 (75%), respectively. Median PFS on first-line abiraterone and enzalutamide was short, at 8.2 months (95% CI, 6.6 to 12.6 months) and 10.6 months (95% CI, 10.2 months to not reached), respectively. Nineteen patients received CPI therapy. PSA50 responses to CPI were noted in 11%, and PFS was short; however, the estimated 9-month PFS was 23%. PFS was higher in chemotherapy-näive versus chemotherapypretreated patients (median PFS: not reached v 2.1 months, P = .004). CONCLUSION: CDK12 mutations define an aggressive prostate cancer subgroup, with a high rate of metastases and short overall survival. CPI may be effective in a minority of these patients, and exploratory analysis supports using anti-programmed cell death protein 1 drugs early. Prospective studies testing CPI in this subset of patients with prostate cancer are warranted.
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Leprosy, caused by Mycobacterium leprae, has plagued humanity for thousands of years and continues to cause morbidity, disability and stigmatization in two to three million people today. Although effective treatment is available, the disease incidence has remained approximately constant for decades so new approaches, such as vaccine or new drugs, are urgently needed for control. Research is however hampered by the pathogen's obligate intracellular lifestyle and the fact that it has never been grown in vitro. Consequently, despite the availability of its complete genome sequence, fundamental questions regarding the biology of the pathogen, such as its metabolism, remain largely unexplored. In order to explore the metabolism of the leprosy bacillus with a long-term aim of developing a medium to grow the pathogen in vitro, we reconstructed an in silico genome scale metabolic model of the bacillus, GSMN-ML. The model was used to explore the growth and biomass production capabilities of the pathogen with a range of nutrient sources, such as amino acids, glucose, glycerol and metabolic intermediates. We also used the model to analyze RNA-seq data from M. leprae grown in mouse foot pads, and performed Differential Producibility Analysis to identify metabolic pathways that appear to be active during intracellular growth of the pathogen, which included pathways for central carbon metabolism, co-factor, lipids, amino acids, nucleotides and cell wall synthesis. The GSMN-ML model is thereby a useful in silico tool that can be used to explore the metabolism of the leprosy bacillus, analyze functional genomic experimental data, generate predictions of nutrients required for growth of the bacillus in vitro and identify novel drug targets.
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Genoma Bacteriano , Lepra/microbiología , Redes y Vías Metabólicas , Mycobacterium leprae/genética , Mycobacterium leprae/metabolismo , Animales , Humanos , Ratones , Ratones Desnudos , Mycobacterium leprae/crecimiento & desarrolloRESUMEN
To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteogenómica , Adenocarcinoma del Pulmón/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinogénesis/genética , Carcinogénesis/patología , Variaciones en el Número de Copia de ADN/genética , Metilación de ADN/genética , Femenino , Humanos , Neoplasias Pulmonares/inmunología , Masculino , Persona de Mediana Edad , Mutación/genética , Proteínas de Fusión Oncogénica , Fenotipo , Fosfoproteínas/metabolismo , Proteoma/metabolismoRESUMEN
Both KRAS and EGFR are essential mediators of pancreatic cancer development and interact with Argonaute 2 (AGO2) to perturb its function. Here, in a mouse model of mutant KRAS-driven pancreatic cancer, loss of AGO2 allows precursor lesion (PanIN) formation yet prevents progression to pancreatic ductal adenocarcinoma (PDAC). Precursor lesions with AGO2 ablation undergo oncogene-induced senescence with altered microRNA expression and EGFR/RAS signaling, bypassed by loss of p53. In mouse and human pancreatic tissues, PDAC progression is associated with increased plasma membrane localization of RAS/AGO2. Furthermore, phosphorylation of AGO2Y393 disrupts both the wild-type and oncogenic KRAS-AGO2 interaction, albeit under different conditions. ARS-1620 (G12C-specific inhibitor) disrupts the KRASG12C-AGO2 interaction, suggesting that the interaction is targetable. Altogether, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression.
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Proteínas Argonautas/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Alelos , Animales , Línea Celular Tumoral , Membrana Celular/metabolismo , Senescencia Celular , Progresión de la Enfermedad , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Genotipo , Humanos , Masculino , Ratones , Ratones Transgénicos , Trasplante de Neoplasias , Neoplasias Pancreáticas/patología , Fosforilación , Unión Proteica , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Renal cell carcinomas (RCCs) are a heterogeneous group of neoplasms. Recent sequencing studies revealed various molecular features associated with histologic RCC subtypes, including chromophobe renal cell carcinoma (ChRCC). OBJECTIVE: To characterize the gene expression and biomarker signatures associated with ChRCC. DESIGN, SETTING, AND PARTICIPANTS: We performed integrative analysis on RNA sequencing data available from 1049 RCC specimens from The Cancer Genome Atlas and in-house studies. Our workflow identified genes relatively enriched in ChRCC, including Forkhead box I1 (FOXI1), Rh family C glycoprotein (RHCG), and LINC01187. We assessed the expression pattern of FOXI1 and RHCG protein by immunohistochemistry (IHC) and LINC01187 mRNA by RNA in situ hybridization (RNA-ISH) in whole tissue sections representing a cohort of 197 RCC cases, including both primary and metastatic tumors. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The FOXI1 and RHCG IHC staining, as well as the LINC01187 RNA-ISH staining, was evaluated in each case for intensity, pattern, and localization of expression. RESULTS AND LIMITATIONS: All primary and metastatic classic ChRCCs demonstrated homogeneous positive labeling for FOXI1, RHCG proteins, and LINC01187 transcript. Unclassified RCC with oncocytic features, oncocytoma, and hybrid oncocytic tumor, as well as all but two cases of eosinophilic ChRCC also stained positive. Importantly, metastatic and primary RCC of all other subtypes did not demonstrate any unequivocal staining for FOXI1, RHCG, or LINC01187. In normal kidney, FOXI1, RHCG, and LINC01187 were detected in the distal nephron segment, specifically in intercalated cells. Two cases of eosinophilic ChRCC with focal expression of FOXI1 and LINC01187, and Golgi-like RHCG staining were found to contain MTOR gene mutations upon DNA sequencing. CONCLUSIONS: We demonstrate a pipeline for the identification and validation of RCC subtype-specific biomarkers that can aid in the confirmation of cell of origin and may facilitate accurate classification and diagnosis of renal tumors. PATIENT SUMMARY: FOXI1, RHCG, and LINC01187 are lineage-specific signature genes for chromophobe renal cell carcinoma.
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Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Renales/genética , Neoplasias Renales/patología , Análisis de Secuencia de ARN , Carcinoma de Células Renales/clasificación , Estudios de Cohortes , Humanos , Neoplasias Renales/clasificaciónRESUMEN
BACKGROUND: Cancer remains the number one cause of disease-related mortality in children, and despite advances in the molecular understanding of leukemia and targeted therapies, refractory leukemia remains a leading cause of death. It therefore is essential to further define features, e.g., FLT3 alterations and KMT2A rearrangements, associated with inferior survival early to augment or alter therapeutic strategies to improve outcomes. METHODS: To gain insights into the genetic drivers predictive of aggressive clinical behavior among pediatric leukemia patients, we performed comprehensive integrative clinical sequencing (ICS), including paired tumor/normal DNA sequencing and RNA-seq, for pediatric patients who presented at our institution over a period of five years with acute lymphoblastic or myelogenous leukemia (ALL and AML; n=43) and high-risk clinical features (high white blood cell count, extramedullary disease, or refractory and/or relapsed disease). RESULTS: We found that RAS- and Ras-pathway aberrations, including N-RAS, NF1 and PTPN11, are frequent somatic mutations and, importantly, associated with decreased event free and overall survival (OS) (P=0.04, median event free survival 22.8 vs. 5.6 months; P=0.04, median OS 124 vs. 22.5 months). CONCLUSIONS: We thus propose that hyperactive Ras signaling confers inferior survival in high-risk pediatric acute leukemia and that Ras pathways should be molecularly characterized to inform clinical decision making and to identify patients for experimental clinical trials and RAS-targeted therapy.