RESUMEN
Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.
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Progresión de la Enfermedad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteogenómica , Fumar/genética , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinógenos/toxicidad , Estudios de Cohortes , Citosina Desaminasa/metabolismo , Asia Oriental , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Genoma Humano , Humanos , Metaloproteinasas de la Matriz/metabolismo , Mutación/genética , Análisis de Componente PrincipalRESUMEN
INTRODUCTION: Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes. Our aim was to identify prognostic genetic markers for patients with neuroblastoma, who were treated with the Taiwan Pediatric Oncology Group (TPOG) neuroblastoma N2002 protocol, to improve risk stratification and inform treatment. METHODS: Our analysis was based on 53 primary neuroblastoma specimens, diagnosed pre-chemotherapy, and 11 paired tumor relapse specimens. Deep sequencing of 113 target genes was performed using a custom panel. Multiplex ligation-dependent probe amplification was performed to identify clinical outcomes related to copy-number variations. RESULTS: We identified 128 variations associated with survival, with the number of variations being higher in the relapse than that in the diagnostic specimen (p = .03). The risk of event and mortality was higher among patients with a tumor mutational burden ≥10 than that in patients with a lower burden (p < .0001). Multivariate analysis identified tumor mutational burden, MYCN amplification, and chromosome 3p deletion as significant prognostic factors, independent of age at diagnosis, sex, and tumor stage. The 5-year event-free survival and overall survival rate was lower among patients with high tumor burden than in patients with low tumor burden. Furthermore, there was no survival of patients with an ALK F1147L variation at 5 years after diagnosis. CONCLUSIONS: Genome sequencing to determine the tumor mutational burden and ALK variations can improve the risk classification of neuroblastoma and inform treatment.
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Mutación , Neuroblastoma , Humanos , Neuroblastoma/genética , Neuroblastoma/mortalidad , Neuroblastoma/patología , Masculino , Femenino , Preescolar , Lactante , Niño , Pronóstico , Biomarcadores de Tumor/genética , Tasa de Supervivencia , Estudios de Seguimiento , Variaciones en el Número de Copia de ADN , Carga Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , AdolescenteRESUMEN
Osimertinib (OSI), a third-generation tyrosine kinase inhibitor (TKI), efficiently benefits lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor (EGFR) mutations. However, combined OSI and immune checkpoint inhibitor in EGFR-mutant patients increases the incidence of interstitial lung disease (ILD), although the mechanism is unknown. Here, we investigated the interaction between dendritic cells (DCs), a potential critical player in ILD, and OSI. Seventeen LUAD patients received TKI therapy, and only the OSI therapy group (N = 10) showed a significant increase in CD40 and CD83 on immature DCs (iDCs), and an elevated trend for both markers on mature DCs (mDCs) during short- and long-term OSI therapy. Our results indicated that OSI therapy may potentially activate DC functions, which might increase the potential immune toxicity when combined with onco-immunotherapy.
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Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Enfermedades Pulmonares Intersticiales , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Adenocarcinoma del Pulmón/tratamiento farmacológico , Receptores ErbB/genética , Inhibidores de Proteínas Quinasas/efectos adversos , Células Dendríticas/metabolismo , Células Dendríticas/patología , MutaciónRESUMEN
BACKGROUND: Medulloblastoma (MB) is commonly classified into four molecular groups, that is, WNT, SHH, group 3, and group 4, for prognostic and therapeutic purposes. METHODS: Here we applied immunohistochemistry (IHC) and RNA sequencing (RNA-seq) for the molecular classification of MB, and utilized multiplex ligation-dependent probe amplification (MLPA) to determine chromosomal alterations and specific gene amplifications. RESULTS: We retrospectively enrolled 37 pediatric MB patients. Twenty-three had genomic material available for gene/RNA analysis. For IHC, ß-catenin, GAB1, and YAP were the biomarkers to segregate MB into three subgroups, WNT (1/23), SHH (5/23), and non-WNT/non-SHH (17/23). However, four cases (17.3%) were found to be misclassified after analysis by RNA-seq. The result of MLPA revealed two group 3 tumors carrying MYC amplification, and three SHH tumors harboring MYCN amplification. While IHC provided rapid subgroup stratification, it might result in incorrect subgrouping. Thus, validation of the IHC result with genomic data analysis by RNA-seq or other tools would be preferred. In addition, MLPA can detect important genetic alterations and is helpful for the identifications of high-risk patients. CONCLUSIONS: Our study revealed that integration of these diagnostic tools can provide a precise and timely classification of MB, optimizing an individualized, risk-directed postoperative adjuvant therapy for these patients. This workflow can be applied in a countrywide fashion to guide future clinical trials for patients with MB.
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Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Cerebelosas/patología , Niño , Humanos , Inmunohistoquímica , Meduloblastoma/patología , Reacción en Cadena de la Polimerasa Multiplex , Estudios Retrospectivos , Análisis de Secuencia de ARNRESUMEN
OBJECTIVE: The goal of the study was to identify the potential nutrigenetic effects to inulin, a prebiotic fiber, in mice with different human apolipoprotein E (APOE) genetic variants. Specifically, we compared responses to inulin for the potential modulation of the systemic metabolism and neuroprotection via gut-brain axis in mice with human APOE ϵ3 and ϵ4 alleles. METHOD: We performed experiments with young mice expressing the human APOE3 (E3FAD mice and APOE4 gene (E4FAD mice). We fed mice with either inulin or control diet for 16 weeks starting from 3 months of age. We determined gut microbiome diversity and composition using16s rRNA sequencing, systemic metabolism using in vivo MRI and metabolomics, and blood-brain barrier (BBB) tight junction expression using Western blot. RESULTS: In both E3FAD and E4FAD mice, inulin altered the alpha and beta diversity of the gut microbiome, increased beneficial taxa of bacteria and elevated cecal short chain fatty acid and hippocampal scyllo-inositol. E3FAD mice had altered metabolism related to tryptophan and tyrosine, while E4FAD mice had changes in the tricarboxylic acid cycle, pentose phosphate pathway, and bile acids. Differences were found in levels of brain metabolites related to oxidative stress, and levels of Claudin-1 and Claudin-5 BBB tight junction expression. DISCUSSION: We found that inulin had many similar beneficial effects in the gut and brain for both E3FAD and E4FAD mice, which may be protective for brain functions and reduce risk for neurodegeneration. . E3FAD and E4FAD mice also had distinct responses in several metabolic pathways, suggesting an APOE-dependent nutrigenetic effects in modulating systemic metabolism and neuroprotection.
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Inulina , Prebióticos , Animales , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/genética , Eje Cerebro-Intestino , Modelos Animales de Enfermedad , Genotipo , Humanos , Ratones , Neuroprotección , NutrigenómicaRESUMEN
BACKGROUND: Mercaptopurine-induced neutropenia can interrupt chemotherapy and expose patients to infection during childhood acute lymphoblastic leukemia (ALL) treatment. Previously, six candidate gene variants associated with mercaptopurine intolerance were reported. Herein, we investigated the association between the mean tolerable dose of mercaptopurine and these genetic variants in Taiwanese patients. METHODS: In total, 294 children with ALL were treated at the National Taiwan University Hospital from April 1997 to December 2017. Germline variants were analyzed for NUDT15, SUCLA2, TPMT, ITPA, PACSIN2, and MRP4. Mean daily tolerable doses of mercaptopurine in the continuation phase of treatment were correlated with these genetic variants. RESULTS: Mercaptopurine intolerance was significantly associated with polymorphisms in NUDT15 (P value < 0.0001). Patients with SUCLA2 variants received lower mercaptopurine doses (P value = 0.0119). The mean mercaptopurine doses did not differ among patients with TPMT, ITPA, MRP4, and PACSIN2 polymorphisms (P value = 0.9461, 0.5818, and 0.7951, respectively). After multivariable linear regression analysis, only NUDT15 variants retained their clinically significant correlation with mercaptopurine intolerance (P value < 0.0001). CONCLUSION: In this cohort, the major genetic determinant of mercaptopurine intolerance was NUDT15 in Taiwanese patients. IMPACT: NUDT15 causes mercaptopurine intolerance in children with ALL. The NUDT15 variant is a stronger predictor of mercaptopurine intolerance than TPMT in a Taiwanese cohort. This finding is similar with studies performed on Asian populations rather than Caucasians. Pre-emptive genotyping of the patients' NUDT15 before administering mercaptopurine may be more helpful than genotyping TPMT in Asians.
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Antimetabolitos Antineoplásicos/efectos adversos , Mercaptopurina/efectos adversos , Neutropenia/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirofosfatasas/genética , Antimetabolitos Antineoplásicos/administración & dosificación , Humanos , Mercaptopurina/administración & dosificación , Metiltransferasas/genética , Neutropenia/inducido químicamente , Neutropenia/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , TaiwánRESUMEN
TP53 alterations are frequent relapse-acquired mutations in childhood acute lymphoblastic leukemia (ALL). The present study evaluated the clinical significance of relapsed childhood ALL in Taiwan. Diagnostic and/or relapsed bone marrow or peripheral blood was obtained from 111 children with relapsed ALL who were initially treated by using Taiwan Pediatric Oncology Group (TPOG) ALL protocols from January 1997 to May 2018. Mutations were detected by PCR and sequencing, as well as by multiplex ligation-dependent probe amplification to detect copy number alterations. Copy number and/or sequence alterations of TP53 were detected in 29% (28 of 98) and in 46% (6 of 13) of patients with relapsed B-cell and T-cell ALL, respectively. This incidence was much higher than that in several similar studies conducted in Caucasian populations. Seventy percent of all TP53 alterations were gained at relapse in 67 matched samples by back-tracking matched diagnostic samples. TP53 alterations were associated with lower 5-year event-free survival (EFS) and overall survival (OS) rates (P = .013 and P = .0002, respectively). Multivariate analysis confirmed the prognostic significance of TP53 alterations. Forty-five patients received hematopoietic stem-cell transplantations post-relapse. Patients with TP53 alterations (14/45) had inferior 5-year EFS and OS than patients without TP53 alterations after transplantation (P = .002 and P = .001, respectively). The significance of these TP53 alterations for patients who received transplantations was confirmed by multivariate analysis. In conclusion, TP53 alterations were enriched and useful as prognostic markers in relapsed childhood ALL.
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Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Proteína p53 Supresora de Tumor/genética , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Mutación/genética , Pronóstico , Recurrencia , Tasa de Supervivencia , TaiwánRESUMEN
An imputation algorithm for human leukocyte antigen (HLA) is helpful for exploring novel disease associations. However, population-specific HLA imputation references are essential for achieving high imputation accuracy. In this study, a subset of 1012 individuals from the Taiwan Biobank (TWB) who underwent both whole-genome SNP array and NGS-based HLA typing were used to establish Taiwanese HLA imputation references. The HIBAG package was used to generate the imputation references for eight HLA loci at a two- and three-field resolution. Internal validation was carried out to evaluate the call threshold and accuracy for each HLA gene. HLA class II genes found to be associated with rheumatoid arthritis (RA) were validated in this study by the imputed HLA alleles. Our Taiwanese population-specific references achieved average HLA imputation accuracies of 98.11% for two-field and 98.08% for three-field resolution. The frequency distribution of imputed HLA alleles among 23,972 TWB subjects were comparable with PCR-based HLA alleles in general Taiwanese reported in the allele frequency net database. We replicated four common HLA alleles (HLA-DRB1*03:01, DRB1*04:05, DQA1*03:03, and DQB1*04:01) significantly associated with RA. The population-specific references provide an informative tool to investigate the associations of HLA variants and human diseases in large-scale population-based studies.
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Artritis Reumatoide/genética , Genética de Población , Antígenos HLA/genética , Polimorfismo de Nucleótido Simple , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/inmunología , Bases de Datos Genéticas , Genotipo , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Fenotipo , Reproducibilidad de los Resultados , Taiwán , Secuenciación Completa del GenomaRESUMEN
We conducted a genome-wide association study to discover genetic variants associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We genotyped 502 HCC cases and 749 non-HCC controls using the Axiom-CHB genome-wide array. After identifying single-nucleotide polymorphism clusters located in the human leukocyte antigen (HLA) region which were potentially associated with HCC, HLA-DQB1 genotyping was performed to analyze 994 anti-HCV seropositives collected in the period 1991-2013 in a community-based cohort for evaluating long-term predictability of HLA variants for identifying the risk of HCC. Cox proportional hazards models were used to estimate the hazard ratios and 95% confidence intervals of HLA genotypes for determining the aforementioned HCC risk. Eight single-nucleotide polymorphisms in the proximity of HLA-DQB1 were associated with HCC (P < 8.7 × 10-8 ) in the genome-wide association study. Long-term follow-up showed a significant association with HLA-DQB1*03:01 and DQB1*06:02 (P < 0.05). The adjusted hazard ratios associated with HCC were 0.45 (0.30-0.68) and 2.11 (1.34-3.34) for DQB1*03:01 and DQB1*06:02, respectively. After stratification by HCV genotypes, DQB1*03:01 showed protective effects only in patients with HCV genotype 1, whereas DQB1*06:02 conferred risk of HCC only in patients with HCV non-1 genotypes. HLA imputation analyses revealed that HLA-DRB1*15:01, which is in linkage disequilibrium with DQB1*06:02, also increased the risk of HCC (odds ratio, 1.96; 95% confidence interval, 1.31-2.93). Haplotype analysis supported that DQB1*03:01 and DQB1*06:02 are primarily protective and susceptible variants, respectively. Conclusion: HLA-DQB1 was independently associated with HCC; HCV genotypes modified the effects of HLA-DQB1 on the risk of HCC. (Hepatology 2018;67:651-661).
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Carcinoma Hepatocelular/etiología , Estudio de Asociación del Genoma Completo , Cadenas beta de HLA-DQ/genética , Hepacivirus/genética , Neoplasias Hepáticas/etiología , Polimorfismo de Nucleótido Simple , Alelos , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/virología , Estudios de Casos y Controles , Genotipo , Haplotipos , Hepacivirus/clasificación , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/virología , RiesgoRESUMEN
OBJECTIVES: With the increasing popularity of CT screening, more cases of early-stage lung cancer are being diagnosed. However, 24.5% of stage I non-small-cell lung cancer (NSCLC) patients still experience treatment failure post-surgery. Biomarkers to predict lung cancer patients at high risk of recurrence are needed. MATERIALS AND METHODS: We collected protein mass spectrometry data from the Taiwan Lung Cancer Moonshot Project and performed bioinformatics analysis on proteins with differential expressions between tumor and adjacent normal tissues in 74 stage I lung adenocarcinoma (LUAD) cases, aiming to explore the tumor microenvironment related prognostic biomarkers. Findings were further validated in 6 external cohorts. RESULTS: The analysis of differentially expressed proteins revealed that the most enriched categories of diseases and biological functions were cellular movement, immune cell trafficking, and cancer. Utilizing proteomic profiling of the tumor microenvironment, we identified five prognostic biomarkers (ADAM10, MIF, TEK, THBS2, MAOA). We then developed a risk score model, which independently predicted recurrence-free survival and overall survival in stage I LUAD. Patients with high risk scores experienced worse recurrence-free survival (adjusted hazard ratio = 8.28, p < 0.001) and overall survival (adjusted hazard ratio = 6.88, p = 0.013). Findings had been also validated in the external cohorts. CONCLUSION: The risk score model derived from proteomic profiling of tumor microenvironment can be used to predict recurrence risk and prognosis of stage I LUAD.
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Adenocarcinoma del Pulmón , Biomarcadores de Tumor , Neoplasias Pulmonares , Estadificación de Neoplasias , Proteómica , Microambiente Tumoral , Humanos , Pronóstico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/diagnóstico , Femenino , Biomarcadores de Tumor/metabolismo , Masculino , Proteómica/métodos , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/diagnóstico , Persona de Mediana Edad , Anciano , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Taiwán/epidemiología , Biología Computacional/métodosRESUMEN
The lack of expression of terminal deoxynucleotidyl transferase (TdT) is frequently associated with KMT2A-rearranged subtype of pediatric acute lymphoblastic leukemia (ALL). However, this association has not been investigated extensively in the Asian population. A retrospective analysis of TdT expression in pediatric B-cell ALL (B-ALL) was performed in patients treated using the Taiwan Pediatric Oncology Group (TPOG) ALL 2002 and 2013 protocols. Among the 331 patients with B-ALL, 12 patients showed TdT negativity at initial diagnosis. Among these, eight patients showed KMT2A rearrangement (66.7%). Other patients showing negative TdT expression had ETV6::RUNX1, MEF2D-rearranged, and other B-ALL subtypes. However, in the context of KMT2A-rearranged B-ALL (n = 20), only eight patients showed TdT negativity. The 5-year event-free survival and overall survival of patients with and without TdT expression were 83.8% versus 46.8% (P <0.001) and 86.3% versus 55.4% (P = 0.004), respectively. Moreover, several aberrant markers, such as CD2, CD56, CD7, and CD117, were rarely expressed in the B-ALL samples, and if expressed, they were enriched in specific genetic subtypes. The results of this study indicate that immunophenotypic features are correlated with specific genetic subtypes of childhood B-ALL.
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ADN Nucleotidilexotransferasa , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , ADN Nucleotidilexotransferasa/metabolismo , Estudios Retrospectivos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnósticoRESUMEN
BACKGROUND: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer. METHODS: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing. FINDINGS: Between Dec 1, 2015, and July 31, 2019, 12â011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12â011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12â011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis. INTERPRETATION: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer. FUNDING: Ministry of Health and Welfare of Taiwan.
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Adenocarcinoma in Situ , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Femenino , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/epidemiología , Fumadores , Estudios Prospectivos , Detección Precoz del Cáncer/métodos , Taiwán/epidemiología , Tomografía Computarizada por Rayos X/métodos , Tamizaje MasivoRESUMEN
Immune checkpoint inhibitors (ICIs) targeting PD-L1 immunotherapy are state-of-the-art treatments for advanced non-small cell lung cancer (NSCLC). However, the treatment response of certain patients with NSCLC is unsatisfactory because of an unfavorable tumor microenvironment (TME) and poor permeability of antibody-based ICIs. In this study, we aimed to discover small-molecule drugs that can modulate the TME to enhance ICI treatment efficacy in NSCLC in vitro and in vivo. We identified a PD-L1 protein-modulating small molecule, PIK-93, using a cell-based global protein stability (GPS) screening system. PIK-93 mediated PD-L1 ubiquitination by enhancing the PD-L1-Cullin-4A interaction. PIK-93 reduced PD-L1 levels on M1 macrophages and enhanced M1 antitumor cytotoxicity. Combined PIK-93 and anti-PD-L1 antibody treatment enhanced T cell activation, inhibited tumor growth, and increased tumor-infiltrating lymphocyte (TIL) recruitment in syngeneic and human peripheral blood mononuclear cell (PBMC) line-derived xenograft mouse models. PIK-93 facilitates a treatment-favorable TME when combined with anti-PD-L1 antibodies, thereby enhancing PD-1/PD-L1 blockade cancer immunotherapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Animales , Ratones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Microambiente Tumoral , Linfocitos Infiltrantes de TumorRESUMEN
Particulate matter 2.5 (PM2.5) is a risk factor for lung cancer. In this study, we investigated the molecular mechanisms of PM2.5 exposure on lung cancer progression. We found that short-term exposure to PM2.5 for 24 h activated the EGFR pathway in lung cancer cells (EGFR wild-type and mutant), while long-term exposure of lung cancer cells to PM2.5 for 90 days persistently promoted EGFR activation, cell proliferation, anchorage-independent growth, and tumor growth in a xenograft mouse model in EGFR-driven H1975 cancer cells. We showed that PM2.5 activated AhR to translocate into the nucleus and promoted EGFR activation. AhR further interacted with the promoter of TMPRSS2, thereby upregulating TMPRSS2 and IL18 expression to promote cancer progression. Depletion of TMPRSS2 in lung cancer cells suppressed anchorage-independent growth and xenograft tumor growth in mice. The expression levels of TMPRSS2 were found to correlate with nuclear AhR expression and with cancer stage in lung cancer patient tissue. Long-term exposure to PM2.5 could promote tumor progression in lung cancer through activation of EGFR and AhR to enhance the TMPRSS2-IL18 pathway.
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Neoplasias Pulmonares , Material Particulado , Humanos , Ratones , Animales , Material Particulado/toxicidad , Interleucina-18 , Transducción de Señal , Neoplasias Pulmonares/patología , Receptores ErbB/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismoRESUMEN
Gut dysbiosis has been identified as a crucial factor of Alzheimer's disease (AD) development for apolipoprotein E4 (APOE4) carriers. Inulin has shown the potential to mitigate dysbiosis. However, it remains unclear whether the dietary response varies depending on sex. In the study, we fed 4-month-old APOE4 mice with inulin for 16 weeks and performed shotgun metagenomic sequencing to determine changes in microbiome diversity, taxonomy, and functional gene pathways. We also formed the same experiments with APOE3 mice to identify whether there are APOE-genotype dependent responses to inulin. We found that APOE4 female mice fed with inulin had restored alpha diversity, significantly reduced Escherichia coli and inflammation-associated pathway responses. However, compared with APOE4 male mice, they had less metabolic responses, including the levels of short-chain fatty acids-producing bacteria and the associated kinases, especially those related to acetate and Erysipelotrichaceae. These diet- and sex- effects were less pronounced in the APOE3 mice, indicating that different APOE variants also play a significant role. The findings provide insights into the higher susceptibility of APOE4 females to AD, potentially due to inefficient energy production, and imply the importance of considering precision nutrition for mitigating dysbiosis and AD risk in the future.
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Enfermedad de Alzheimer , Microbioma Gastrointestinal , Femenino , Masculino , Animales , Ratones , Apolipoproteína E4/genética , Apolipoproteína E3 , Disbiosis , Inulina/farmacología , Antiinflamatorios , Escherichia coliRESUMEN
INTRODUCTION: Lung cancer is the global leading cause of cancer death. Taiwan initiated several health policies including smoking cessation, precision therapy, and low-dose computed tomography (LDCT) screening in 1997. We aimed to investigate the effect of public policies on lung cancer survival. METHODS: We retrieved the nationwide cancer registry from the Ministry of Health and Welfare to evaluate the smoking prevalence and lung cancer incidence and mortality from 1994 to 2020. We also conducted a retrospective analysis of clinical characteristics and survival on 17,298 patients with lung cancer from 2006 to 2019 using the National Taiwan University Hospital database. RESULTS: Taiwan initiated an anti-smoking campaign in 1997, reimbursed tyrosine kinase inhibitors since 2004, and conducted an LDCT screening trial in 2015. Lung cancer incidence keeps rising but the annual percent change in mortality rate gradually decreased from 0.41% to -2.41%. The National Taiwan University Hospital data revealed that the 5-year survival substantially improved from 22.1% in 2006 to 2011 to 54.9% in 2015 to 2020. Improvement was observed in all stages, especially late stages (stage III: from 17.2% to 35.2%; stage IV: from 7.9% to 16.5%). Furthermore, a remarkable shift in cancer stage was observed (stage 0, I, and IIincreased from 19.3% to 62.8%, and stage III and IV decreased from 70.9% to 33.8%). The prominent improvement in survival was primarily driven by the stage shift from advanced to localized, potentially curable disease. CONCLUSIONS: This real-world evidence suggested an association between improved survival and LDCT screening and the diagnostic shift from late to early-stage of lung cancer, highlighting the importance of early detection for lung cancer control.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/epidemiología , Estudios Retrospectivos , Bases de Datos Factuales , Política de Salud , Sistema de RegistrosRESUMEN
OBJECTIVES: About 20% of stage I lung adenocarcinoma (LUAD) patients suffer a relapse after surgical resection. While finer substages have been defined and refined in the AJCC staging system, clinical investigations on the tumor molecular landscape are lacking. MATERIALS AND METHODS: We performed whole exome sequencing, DNA copy number and microRNA profiling on paired tumor-normal samples from a cohort of 113 treatment-naïve stage I Taiwanese LUAD patients. We searched for molecular features associated with relapse-free survival (RFS) of stage I or its substages and validated the findings with an independent Caucasian LUAD cohort. RESULTS: We found sixteen nonsynonymous mutations harbored at EGFR, KRAS, TP53, CTNNB1 and six other genes associated with poor RFS in a dose-dependent manner via variant allele fraction (VAF). An index, maxVAF, was constructed to quantify the overall mutation load from genes other than EGFR. High maxVAF scores discriminated a small group of high-risk LUAD at stage I (median RFS: 4.5 versus 69.5 months; HR = 10.5, 95% CI = 4.22-26.12, P < 0.001). At the substage level, higher risk was found for patients with high maxVAF or high miR-31; IA (median RFS: 32.1 versus 122.8 months, P = 0.005) and IB (median RFS: 7.1 versus 26.2, P = 0.049). MicroRNAs, miR-182, miR-183 and miR-196a were found correlated with EGFR mutation and poor RFS in stage IB patients. CONCLUSION: Distinctive features of somatic gene mutation and microRNA expression of stage I LUAD are characterized to complement the survival prognosis by substaging. The findings open up more options for precision management of stage I LUAD patients.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , MicroARNs , Humanos , Secuenciación del Exoma , Neoplasias Pulmonares/genética , Adenocarcinoma del Pulmón/genética , MicroARNs/genética , Receptores ErbB/genéticaRESUMEN
Mercaptopurine intolerance is an adverse effect of mercaptopurine administration in pediatric patients with acute lymphoblastic leukemia (ALL). NUDT15 variants have emerged as major determinants of mercaptopurine intolerance, especially in the Asian population. Two variants, c.55_56insGAGTCG in exon 1 and c.415C > T in exon 3, were commonly detected in the same allele, named NUDT15*1/*2. Although rare, compound heterozygous mutations also occur, with the two variants on different alleles (NUDT15*3/*6), which may confer tolerance to considerably lesser mercaptopurine dosage. Sanger sequencing or pyrosequencing can determine the NUDT15 variants but not the phase. Here, we designed an allele-specific PCR (AS-PCR) with locked nucleic acid-modified primers. A cohort of 63 patients harboring heterozygous c.55_56insGAGTCG and c.415C > T NUDT15 variations was selected for haplotyping using AS-PCR. Of the 63 patients, 60 harbored the NUDT15*1/*2 variant and three harbored compound heterozygous mutations, including two NUDT15*3/*6 and one NUDT15*2/*7 variants. These findings suggest that AS-PCR can determine NUDT15 diplotype and identify patients with compound heterozygous NUDT15 variants, which may enable precise genetic diagnosis of NUDT15. Nevertheless, a larger clinical trial is required to understand the clinical significance of NUDT15*3/*6 in pediatric patients with ALL because of its low incidence rate and challenges in detecting this variant.
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Mercaptopurina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Alelos , Antimetabolitos Antineoplásicos/uso terapéutico , Mercaptopurina/efectos adversos , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirofosfatasas/genéticaRESUMEN
INTRODUCTION: The role of a family history of lung cancer (LCFH) in screening using low-dose computed tomography (LDCT) has not been prospectively investigated with long-term follow-up. METHODS: A multicenter prospective study with up to three rounds of annual LDCT screening was conducted to determine the detection rate of lung cancer (LC) in asymptomatic first- or second-degree relatives of LCFH. RESULTS: From 2007 to 2011, there were 1102 participants enrolled, including 805 and 297 from simplex and multiplex families (MFs), respectively (54.2% women and 70.0% never-smokers). The last follow-up date was May 5, 2021. The overall LC detection rate was 4.5% (50 of 1102). The detection rate in MF was 9.4% (19 of 202) and 4.4% (4 of 91) in never-smokers and in those who smoked, respectively. The corresponding rates for simplex families were 3.7% (21 of 569) and 2.7% (6 of 223), respectively. Of these, 68.0% and 22.0% of cases with stage I and IV diseases, respectively. LC diagnoses within a 3-year interval from the initial screening tend to be younger, have a higher detection rate, and have stage I disease; thereafter, more stage III-IV disease and 66.7% (16 of 24) with negative or semipositive nodules in initial computed tomography scans. Within the 6-year interval, only maternal (modified rate ratio = 4.46, 95% confidence interval: 2.32-8.56) or maternal relative history of LC (modified rate ratio = 5.41, 95% confidence interval: 2.84-10.30) increased the risk of LC. CONCLUSIONS: LCFH is a risk factor for LC and is increased with MF history, among never-smokers, younger adults, and those with maternal relatives with LC. Randomized controlled trials are needed to confirm the mortality benefit of LDCT screening in those with LCFH.
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Neoplasias Pulmonares , Adulto , Humanos , Femenino , Masculino , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genética , Estudios Prospectivos , Detección Precoz del Cáncer/métodos , Tomografía Computarizada por Rayos X/métodos , Factores de Riesgo , Tamizaje MasivoRESUMEN
Introduction: Mild traumatic brain injury (mTBI) has been shown to negatively alter bacterial diversity and composition within the gut, known as dysbiosis, in rodents and humans. These changes cause secondary consequences systemically through decreased bacterial metabolites such as short chain fatty acids (SCFAs) which play a role in inflammation and metabolism. The goal of the study was to identify if giving prebiotic inulin prior to closed head injury (CHI) could mitigate gut dysbiosis, increase SCFAs, and improve recovery outcomes, including protecting cerebral blood flow (CBF) and white matter integrity (WMI) in young mice. Methods: We fed mice at 2 months of age with either inulin or control diet (with cellulose as fiber source) for two months before the CHI and continued till the end of the study. We analyzed gut microbiome composition and diversity, determined SCFAs levels, and measured CBF and WMI using MRI. We compared the results with Naïve and Sham-injury mice at 24 hours, 1.5 months, and 3-4 months post-injury. Results: We found that both CHI and Sham mice had time-dependent changes in gut composition and diversity after surgery. Inulin significantly reduced the abundance of pathobiont bacteria, such as E. coli, Desulfovibrio spp and Pseudomonas aeruginosa, in Sham and CHI mice compared to mice fed with control diet. On the other hand, inulin increased SCFAs-producing bacteria, such as Bifidobacterium spp and Lactobacillus spp, increased levels of SCFAs, including butyrate and propionate, and significantly altered beta diversity as early as 24 hours post-injury, which lasted up to 3-4 months post-injury. The mitigation of dysbiosis is associated with protection of WMI in fimbria, internal and external capsule, and CBF in the right hippocampus of CHI mice, suggesting protection of memory and cognitive functions. Discussion: The results indicate that giving inulin prior to CHI could promote recovery outcome through gut microbiome modulation. As inulin, microbiome analysis, and MRI are readily to be used in humans, the findings from the study may pave a way for a cost-effective, accessible intervention for those at risk of sustaining a head injury, such as military personnel or athletes in contact sports.