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Somatic mutations that accumulate in normal tissues are associated with ageing and disease1,2. Here we performed a comprehensive genomic analysis of 1,737 morphologically normal tissue biopsies of 9 organs from 5 donors. We found that somatic mutation accumulations and clonal expansions were widespread, although to variable extents, in morphologically normal human tissues. Somatic copy number alterations were rarely detected, except for in tissues from the oesophagus and cardia. Endogenous mutational processes with the SBS1 and SBS5 mutational signatures are ubiquitous among normal tissues, although they exhibit different relative activities. Exogenous mutational processes operate in multiple tissues from the same donor. We reconstructed the spatial somatic clonal architecture with sub-millimetre resolution. In the oesophagus and cardia, macroscopic somatic clones that expanded to hundreds of micrometres were frequently seen, whereas in tissues such as the colon, rectum and duodenum, somatic clones were microscopic in size and evolved independently, possibly restricted by local tissue microstructures. Our study depicts a body map of somatic mutations and clonal expansions from the same individual.
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Células Clonales/metabolismo , Salud , Mutagénesis , Mutación , Especificidad de Órganos , Anciano de 80 o más Años , Biopsia , Cadáver , Cardias/metabolismo , Proliferación Celular , Células Clonales/citología , Esófago/metabolismo , Femenino , Genómica , Humanos , MasculinoRESUMEN
OBJECTIVE: To investigate pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) safety and efficacy in preventing hematological toxicity during concurrent chemoradiotherapy (CCRT) for small-cell lung cancer (SCLC). METHODS: We retrospectively assessed 80 SCLC patients treated with CCRT from January 2013 to December 2018 who received PEG-rhG-CSF within 48 hours after the end of chemotherapy, defined as prophylactic use, as the experimental group. An additional 80 patients who were not treated with PEG-rhG-CSF were matched 1:1 by the propensity score matching method and served as the control group. The main observations were differences in hematological toxicity, neutrophil changes, febrile neutropenia (FN) incidence and adverse reactions. Progression-free survival (PFS) and overall survival (OS) were analyzed with regular assessment and follow-up. RESULTS: The leukocyte, neutrophil, erythrocyte, and platelet counts and hemoglobin level decreased after CCRT, but the experimental group had slightly higher leukocyte and neutrophil counts than the control group (P < 0.05). The incidences of grade III-IV leukopenia (18.75% vs. 61.25%) and neutropenia (23.75% vs. 67.5%) in the experimental group were significantly lower than those in the control group (P < 0.05). The absolute neutrophil count was 4.17 ± 0.79 (× 109/L) on day 1 and peaked 6.81 ± 2.37 (× 109/L) on day 10 in the experimental group; the value in the control group was 2.81 ± 0.86 (× 109/L) on day 1. It decreased significantly and reached the minimum 0.91 ± 0.53 (× 109/L) on day 10 (P < 0.05). The experimental group had a lower FN incidence than the control group (P < 0.05). There was also no significant acute esophagitis or pulmonary toxicity. The treatment had no significant effect on PFS (11.4 months vs. 8.7 months, P = 0.958) or OS (23.9 months vs. 17.3 months, P = 0.325) over an 18.6-month median follow-up time. CONCLUSION: PEG-rhG-CSF has good efficacy and safety in preventing hematological toxicity in SCLC patients during CCRT and has no significant effects on PFS or OS.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioradioterapia/efectos adversos , Factor Estimulante de Colonias de Granulocitos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Polietilenglicoles , Proteínas Recombinantes/efectos adversos , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/radioterapiaRESUMEN
Background: Immune checkpoint inhibitor (ICI) has become pivotal in the treatment of advanced lung cancer, yet the absence of reliable biomarkers for assessing treatment response poses a significant challenge. This study aims to explore the predictive value of various lymphocyte subsets in different lung cancer subtypes, thus potentially identifying novel biomarkers to improve ICI treatment stratification and outcomes. Methods: We conducted a retrospective analysis of 146 stage III or IV lung cancer patients undergoing ICI treatment. The study focused on exploring the relationship between various lymphocyte subsets and the efficacy of ICIs, aiming to determine their predictive value for post-treatment outcomes. Results: Subgroup analysis revealed a positive correlation (P=0.01) between lower CD3+CD8+ T lymphocyte levels and treatment response in squamous cell carcinoma patients. However, no significance was observed in lung adenocarcinoma patients. Additionally, the predictive ability of lymphocyte subsets for different immunotherapy drugs varies. In individuals receiving anti-programmed cell death ligand 1 (PD-L1) treatment, a lower CD3+CD8+ T lymphocyte levels is significantly associated with a positive treatment outcome (P=0.002), while there is no difference for programmed death 1 (PD-1) drugs. Among patients under 60, higher expression of CD3+CD4+ T lymphocytes (P=0.03) combined with lower CD3+CD8+ T lymphocyte levels (P=0.006) showed a statistically significant association with improved treatment response. However, in patients aged over 60, no discernible correlation was ascertained between lymphocyte subsets and therapeutic response. Through prognostic analysis, two distinct lymphocyte subsets were identified, both exerting considerable impact on progression-free survival subsequent to ICIs treatment: CD3+CD4+ T lymphocytes [hazard ratio (HR) =0.50, P=0.006] and CD3+CD8+ T lymphocytes (HR =1.78, P=0.02). Conclusions: Our findings underscore the significant heterogeneity in the predictive value of distinct lymphocyte subsets for lung cancer patients undergoing ICI treatment. These findings are particularly salient when considering various pathological types, immunotherapeutic agents, and patient age groups.
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BACKGROUND: The ubiquitin-proteasome and autophagy-lysosomal systems collaborate in regulating the levels of intracellular proteins. Dysregulation of protein homeostasis is a central feature of malignancy. The gene encoding 26S proteasome non-ATPase regulatory subunit 2 (PSMD2) of the ubiquitin-proteasome system is an oncogene in various types of cancer. However, the detailed role of PSMD2 in autophagy and its relationship to tumorigenesis in esophageal squamous cell carcinoma (ESCC) remain unknown. In the present study, we have investigated the tumor-promoting roles of PSMD2 in the context of autophagy in ESCC. METHODS: Molecular approaches including DAPgreen staining, 5-Ethynyl-2'-deoxyuridine (EdU), cell counting kit 8 (CCK8), colony formation, transwell assays, and cell transfection, xenograft model, immunoblotting and Immunohistochemical analysis were used to investigate the roles of PSMD2 in ESCC cells. Data-independent acquisition (DIA) quantification proteomics analysis and rescue experiments were used to study the roles of PSMD2 in ESCC cells. RESULTS: We demonstrate that the overexpression of PSMD2 promotes ESCC cell growth by inhibiting autophagy and is correlated with tumor progression and poor prognosis of ESCC patients. DIA quantification proteomics analysis shows a significant positive correlation between argininosuccinate synthase 1 (ASS1) and PSMD2 levels in ESCC tumors. Further studies indicate that PSMD2 activates the mTOR pathway by upregulating ASS1 to inhibit autophagy. CONCLUSIONS: PSMD2 plays an important role in repressing autophagy in ESCC, and represents a promising biomarker to predict prognosis and a therapeutic target of ESCC patients.
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BACKGROUND: Two staging systems, the 8th staging system by the American Joint Committee on Cancer (AJCC) and the 11th Japanese classification by Japan Esophageal Society (JES), are currently applied in the clinic for predicting the prognosis of patients with esophageal squamous cell carcinoma (ESCC). The differences between the two staging systems have been widely researched. However, little studies focus on the differences in specific staging between the two systems. Therefore, we aimed to compare the performance of different staging in predicting overall survival (OS) of Chinese patients with ESCC. METHODS: This retrospective study included 268 patients who underwent radical esophagectomy and mediastinal lymph node dissection for ESCC between January 2008 and December 2013. Patients were staged by the 8th AJCC and 11th JES staging systems. OS was estimated using the Kaplan-Meier method and compared between N stages and between stage groupings using the log-rank test. Cox proportional hazards regression analysis was performed to identify factors independently related to outcome. Further, we compared the concordance indexes (C-indexes) of the two staging systems. RESULTS: The mean age was 61.25 ± 7.056 years, median follow-up was 44.82 months, and 5-year OS rate was 47%. The OS was well predicted by the 8th AJCC N staging (P < 0.001) and the 11th JES N staging (P < 0.001), with a c-index of 0.638 (95% CI: 0.592-0.683) for AJCC N staging and 0.627 (95% CI: 0.583-0.670) for JES N staging (P = 0.13). In addition, the OS was also well predicted by stage groupings of the 8th AJCC (P < 0.001) and the 11th JES systems (P < 0.001), with a c-index of 0.658 (95% CI: 0.616-0.699) for 8th AJCC stage grouping and 0.629 (95% CI: 0.589-0.668) for the11th JES stage grouping (P = 0.211). CONCLUSIONS: The prognostic effect of 11th JES staging system is comparable with that of AJCC 8th staging system for patients with ESCC. Therefore, both systems are applicable to clinical practice.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Estadificación de Neoplasias , Anciano , Humanos , Persona de Mediana Edad , Pueblos del Este de Asia , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/cirugía , Pronóstico , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
This study investigates aberrant DNA methylations as potential diagnosis and prognosis markers for esophageal squamous-cell carcinoma (ESCC), which if diagnosed at advanced stages has <30% five-year survival rate. Comparing genome-wide methylation sites of 91 ESCC and matched adjacent normal tissues, we identified 35,577 differentially methylated CpG sites (DMCs) and characterized their distribution patterns. Integrating whole-genome DNA and RNA-sequencing data of the same samples, we found multiple dysregulated transcription factors and ESCC-specific genomic correlates of identified DMCs. Using featured DMCs, we developed a 12-marker diagnostic panel with high accuracy in our dataset and the TCGA ESCC dataset, and a 4-marker prognostic panel distinguishing high-risk patients. In-vitro experiments validated the functions of 4 marker host genes. Together these results provide additional evidence for the important roles of aberrant DNA methylations in ESCC development and progression. Our DMC-based diagnostic and prognostic panels have potential values for clinical care of ESCC, laying foundations for developing targeted methylation assays for future non-invasive cancer detection methods.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Islas de CpG/genética , ADN , Metilación de ADN/genética , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Humanos , PronósticoRESUMEN
The majority of human genes have multiple polyadenylation sites, which are differentially used through the process of alternative polyadenylation (APA). Dysregulation of APA contributes to numerous diseases, including cancer. However, specific genes subject to APA that impact oncogenesis have not been well characterized, and many cancer APA landscapes remain underexplored. Here, we used dynamic analyses of APA from RNA-seq (DaPars) to define both the 3'UTR APA profile in esophageal squamous cell carcinoma (ESCC) and to identify 3'UTR shortening events that may drive tumor progression. In four distinct squamous cell carcinoma datasets, BID 3'UTRs were recurrently shortened and BID mRNA levels were significantly upregulated. Moreover, system correlation analysis revealed that CstF64 is a candidate upstream regulator of BID 3'UTR length. Mechanistically, a shortened BID 3'UTR promoted proliferation of ESCC cells by disrupting competing endogenous RNA (ceRNA) cross-talk, resulting in downregulation of the tumor suppressor gene ZFP36L2. These in vitro and in vivo results were supported by human patient data whereby 3'UTR shortening of BID and low expression of ZFP36L2 are prognostic factors of survival in ESCC. Collectively, these findings demonstrate that a key ceRNA network is disrupted through APA and promotes ESCC tumor progression.Significance: High-throughput analysis of alternative polyadenylation in esophageal squamous cell carcinoma identifies recurrent shortening of the BID 3'UTR as a driver of disease progression.
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Regiones no Traducidas 3'/genética , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/genética , Factor de Estimulación del Desdoblamiento/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Factor de Estimulación del Desdoblamiento/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Poliadenilación , Pronóstico , RNA-Seq , Tasa de Supervivencia , Factores de Transcripción/genética , Transcriptoma , Células Tumorales Cultivadas , Secuenciación del Exoma , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Radiotherapy remains the mainstay for treatment of various types of human cancer; however, the clinical efficacy is often limited by radioresistance, in which the underlying mechanism is largely unknown. Here, using esophageal squamous cell carcinoma (ESCC) as a model, we demonstrate that guanine nucleotide exchange factor 2 (VAV2), which is overexpressed in most human cancers, plays an important role in primary and secondary radioresistance. We have discovered for the first time that VAV2 is required for the Ku70/Ku80 complex formation and participates in non-homologous end joining repair of DNA damages caused by ionizing radiation. We show that VAV2 overexpression substantially upregulates signal transducer and activator of transcription 1 (STAT1) and the STAT1 inhibitor Fludarabine can significantly promote the sensitivity of radioresistant patient-derived ESCC xenografts in vivo in mice to radiotherapy. These results shed new light on the mechanism of cancer radioresistance, which may be important for improving clinical radiotherapy.
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Reparación del ADN , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Proteínas Proto-Oncogénicas c-vav/metabolismo , Tolerancia a Radiación , Animales , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/radioterapia , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas Proto-Oncogénicas c-vav/genéticaRESUMEN
Importance: Although thoracic twice-daily radiotherapy (TDRT) is one of the standards of care for small cell lung cancer, its association with brain metastases remains unknown. Objective: To investigate the association of TDRT vs once-daily radiotherapy (ODRT) with brain metastases after prophylactic cranial irradiation in patients with small cell lung cancer. Design, Setting, and Participants: In this multicenter cohort study, data on 778 consecutive patients with small cell lung cancer who had undergone thoracic radiotherapy (609 received ODRT and 169 received TDRT), chemotherapy, and prophylactic cranial irradiation were retrieved from the databases of 8 hospitals in China between July 1, 2003, and June 30, 2016. A 1:1 propensity score matching approach was used to control for confounding between the ODRT and TDRT groups. Confounding covariates included 8 demographic variables and 8 treatment-related covariates. Data analysis was conducted from November 1, 2017, to May 31, 2018, and reanalyzed for revision. Exposures: The ODRT group received 50 to 66 Gy given in 25 to 33 fractions. The TDRT group received 45 Gy given in 30 fractions. Main Outcomes and Measures: The primary end point was brain metastases. Secondary end points included progression-free survival and overall survival. Results: Of the 778 patients (median age, 55 years [interquartile range, 48-61 years]), 204 were women and 574 were men. At a median follow-up of 23.6 months (interquartile range, 14.2-38.2 months), 131 patients (16.8%) experienced brain metastases. The rate of brain metastasis at 3 years in the TDRT group was significantly higher than in the ODRT group (26.0% vs 16.9%; hazard ratio, 1.55; 95% CI, 1.06-2.26; P = .03). Of the 338 matched patients (169 in the ODRT group vs 169 in the TDRT group), 60 (17.8%) experienced brain metastases, with a rate at 3 years of 14.9% in the ODRT group vs 26.0% in the TDRT group (hazard ratio, 1.71; 95% CI, 1.02-2.88; P = .04). Progression-free survival was similar in both the whole cohort and the matched cohort. Median overall survival in the ODRT group tended to be significantly longer than in the TDRT group after matching (47.2 vs 32.8 months; hazard ratio, 1.41; 95% CI, 0.99-2.01; P = .06). Conclusions and Relevance: In this study, patients with small cell lung cancer who received thoracic TDRT appeared to have a higher risk of brain metastases than those who received ODRT, which supports the need for further prospective randomized clinical trials, especially in China and other parts of Asia.
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Neoplasias Encefálicas/secundario , Neoplasias Pulmonares/radioterapia , Carcinoma Pulmonar de Células Pequeñas/radioterapia , Anciano , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/radioterapia , Irradiación Craneana/efectos adversos , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/mortalidadRESUMEN
Systemic inflammation and hematological markers have prognostic value in patients with esophageal squamous cell carcinoma (ESCC). The objective of this study was to evaluate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), combined neutrophil-platelet (CNP) score, and hemoglobin (Hb) to inform treatment decisions and predict outcomes in patients with locally advanced ESCC treated with chemoradiotherapy (CRT). A total of 168 patients with locally advanced ESCC were retrospectively evaluated. Patients were stratified by marker value using a receiver operating characteristic curve analysis to determine the cutoff point. Logistic regression was used to identify markers associated with sensitivity to treatment. Overall survival (OS) was calculated by the Kaplan-Meier method. Multivariate Cox logistic regression modeling was used to assess the influences of OS. Smoking history, tumour site, clinical stage, NLR, PLR, CNP, and Hb (p ≤ 0.05) were associated with the sensitivity to therapy. In multivariate analysis, a high CNP score was independently associated with poor treatment sensitivity (OR = 2.066, p = 0.021). Univariate analysis revealed that PLR, CNP, and Hb levels were associated with OS, and Cox multivariate analysis found that CNP (HR = 1.47, p = 0.027) and Hb level (HR = 0.44, p = 0.007) were independent predictors of OS. In conclusion, CNP and Hb are inexpensive and universally available prognostic markers in patients with locally advanced ESCC patients. CNP score is a systemic inflammatory marker that predicted sensitivity to CRT.
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BACKGROUND: Gliomas are rich in blood vessels and are the most primary and malignant type of brain tumor affecting the central nervous system. A few fluorine-18 (F)-labeled imaging agents can be used for imaging of tumor angiogenesis. In the current study, F-labeled recombinant human endostatin (rh-endostatin) was developed and evaluated as a probe for PET imaging of tumor angiogenesis. MATERIALS AND METHODS: F-fluorobenzoyl-endostatin (F-FB-endostatin) was synthesized from radiolabeling of rh-endostatin with N-succinimidyl-4-F-fluorobenzoate produced by a facile module-assisted radiosynthesis procedure. Blocking studies were used to measure the relative affinities of F-FB-endostatin to human glioblastoma U87MG cells in tumor tissues rich with vessels. In addition, biodistribution, metabolic stability, and small-animal PET imaging studies were carried out with F-FB-endostatin using Institute of Cancer Research and U87MG tumor-bearing mice. RESULTS: Noninvasive small-animal PET imaging indicated that F-FB-endostatin showed rapid and good tumor uptake. The probe was rapidly cleared from the blood and most organs, resulting in excellent tumor-to-normal tissue contrasts. Tumor uptake and rapid clearance were further confirmed with biodistribution studies. Metabolite assays showed that the probe was highly stable, making it suitable for in-vivo applications. CONCLUSION: F-FB-endostatin shows promising in-vivo properties. Therefore, the promising properties of F-FB-endostatin indicate that this probe can be a powerful tool to evaluate the antiangiogenic therapy for gliomas and thus warrants further investigation as a novel PET probe for imaging of tumor angiogenesis.
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Endostatinas , Glioma/irrigación sanguínea , Neovascularización Patológica/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Animales , Línea Celular Tumoral , Endostatinas/farmacocinética , Radioisótopos de Flúor , Glioma/diagnóstico por imagen , Humanos , Marcaje Isotópico , Ratones , Distribución TisularRESUMEN
Chemoradiotherapy is the most common treatment for inoperable esophageal cancer. However, there is no consensus on the delineation of the clinical target volume. Elective nodal irradiation (ENI) is recommended for inoperable esophageal cancer. A few studies have reported a decrease in the incidence of radiation-related toxicity of involved-field irradiation (IFI) for esophageal cancer. A systematic review and pooled analysis were performed to determine whether IFI in definitive chemoradiotherapy was more beneficial than ENI for esophageal cancer. The results showed no significant differences in the overall survival and local control rates between the IFI and ENI arms. Meanwhile, the incidences of esophageal and lung toxicities were significantly decreased in the IFI arm. These results suggest that IFI is a feasible treatment option for locally advanced esophageal cancer, especially to minimize irradiation-related toxicity.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Quimioradioterapia , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/genética , Humanos , Metilación , Metiltransferasas/metabolismo , Metiltransferasas/uso terapéutico , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Hematological markers of the systemic inflammatory response (SIR) including the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and the combination of NLR with PLR (CNP) are associated with prognosis of patients with esophageal squamous cell carcinoma (ESCC). However, their value in predicting the sensitivity to chemoradiotherapy in patients with ESCC is unclear. The aim of this study was to investigate whether these markers can be used as sensitivity predictors for chemoradiotherapy in patients with ESCC. PATIENTS AND METHODS: A total of 114 patients with newly diagnosed ESCC were retrospectively evaluated. They were treated with curative intent by primary radiotherapy only or concurrent chemoradiotherapy. These patients were grouped for further analysis according to the optimum cutoff values of NLR, PLR, and CNP. A univariate analysis was conducted to compare the ability of each of the hematological markers of SIR and clinicopathological characteristics. Multivariate analysis was performed to identify whether the markers were associated with the sensitivity to chemoradiotherapy. The relationship between clinicopathological characteristics and hematological markers was assessed. RESULTS: NLR, CNP, T stage, M stage, and clinical stage were significantly associated with the sensitivity to chemoradiotherapy. In multivariate analysis, CNP and clinical stage were the independent risk factors predicting a poorer sensitivity. CONCLUSION: This study validated novel, easy-to-use hematological markers and found that CNP, an SIR score, is an independent hematological marker of poor sensitivity to chemoradiotherapy in patients with ESCC. This may help guide the planning of follow-up regimens.