RESUMEN
Prostate adenocarcinoma (PRAD) is a prevalent global malignancy which depends more on lipid metabolism for tumor progression compared to other cancer types. Although Stearoyl-coenzyme A desaturase (SCD) is documented to regulate lipid metabolism in multiple cancers, landscape analysis of its implications in PRAD are still missing at present. Here, we conducted an analysis of diverse cancer datasets revealing elevated SCD expression in the PRAD cohort at both mRNA and protein levels. Interestingly, the elevated expression was associated with SCD promoter hypermethylation and genetic alterations, notably the L134V mutation. Integration of comprehensive tumor immunological and genomic data revealed a robust positive correlation between SCD expression levels and the abundance of CD8+ T cells and macrophages. Further analyses identified significant associations between SCD expression and various immune markers in tumor microenvironment. Single-cell transcriptomic profiling unveiled differential SCD expression patterns across distinct cell types within the prostate tumor microenvironment. The Gene Ontology and Kyoto Encyclopedia of Genes and Genome analyses showed that SCD enriched pathways were primarily related to lipid biosynthesis, cholesterol biosynthesis, endoplasmic reticulum membrane functions, and various metabolic pathways. Gene Set Enrichment Analysis highlighted the involvement of elevated SCD expression in crucial cellular processes, including the cell cycle and biosynthesis of cofactors pathways. In functional studies, SCD overexpression promoted the proliferation, metastasis and invasion of prostate cancer cells, whereas downregulation inhibits these processes. This study provides comprehensive insights into the multifaceted roles of SCD in PRAD pathogenesis, underscoring its potential as both a therapeutic target and prognostic biomarker.
Asunto(s)
Adenocarcinoma , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata , Estearoil-CoA Desaturasa , Microambiente Tumoral , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Humanos , Masculino , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Metilación de ADNRESUMEN
Objective: To investigate the clinicopathological features, prognosis and the expression of HER2 and PD-L1 in invasive stratified mucin-producing carcinoma of the cervix (ISMC). Methods: The clinicopathological data of 18 ISMC cases with radical resection of the cervix diagnosed in the Daping Hospital, Army Medical University from January 2018 to December 2023 were collected and retrospectively analyzed. PD-L1 and HER2 immunohistochemical staining and HER2 FISH were conducted. Results: The patient ages ranged from 31 to 72 years, with an average of 45 years. Approximately 8% of cervical adenocarcinoma cases in our hospital during the same period. Eleven cases were pure ISMC, and 7 cases were mixed-type ISMC, with the component of squamous cell carcinoma or usual-type adenocarcinoma. One case showed concurrent small cell neuroendocrine carcinoma (SCNEC). Three cases were diagnosed through biopsy (3/18). Five cases were of Silva pattern B and 13 cases of Silva pattern C. Three cases showed regional lymph node metastasis. Thirteen patients were disease-free at the end of the follow-up, while the ISMC patient with concurrent SCNEC developed distant metastasis. Fifteen cases (15/18) had PD-L1 expression with CPS≥1, and 7 cases (7/18) had PD-L1 TPS≥1%. One case of HER2 3+ and one case of HER2 2+ were both positive for FISH amplification; two cases HER2 1+, 14 cases HER2 0. Conclusions: Cervical ISMC is rare, has a wide spectrum of morphology, and can coexist with other types of cervical cancer. PD-L1 is positive in most of the ISMC cases, while HER2 is amplified or lowly expressed in a small portion of them. Thus, it is possible to treat ISMC patients with therapies targeting PD-L1 and therapy targeting HER2.
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Antígeno B7-H1 , Receptor ErbB-2 , Neoplasias del Cuello Uterino , Humanos , Femenino , Persona de Mediana Edad , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/cirugía , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Adulto , Anciano , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Estudios Retrospectivos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/cirugía , Metástasis Linfática , Pronóstico , Amplificación de Genes , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/genética , Adenocarcinoma/cirugía , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/cirugía , Adenocarcinoma Mucinoso/genética , Cuello del Útero/patología , Cuello del Útero/metabolismo , Cuello del Útero/cirugíaRESUMEN
BACKGROUND: Queiroz et al. showed that the application of cluster methodology for classifying gastric cancer is suitable and efficient within a Brazilian cohort, which is known for its population heterogeneity. The study highlighted the potential utilization of this method within public health services due to its low-cost, presenting a viable means to improve the diagnosis and prognosis of gastric cancer. BACKGROUND: Our Brazilian cohort with gastric cancer has a distinct distribution between mutated and normal p53. BACKGROUND: New genetic marker-based classifications improve gastric cancer diagnosis accuracy. BACKGROUND: Machine learning integration enhances predictive value in gastric cancer diagnosis. BACKGROUND: Molecular biomarkers complement clinical decisions, advancing personalized medicine. OBJECTIVE: Gastric adenocarcinoma remains an aggressive disease with a poor prognosis, as evidenced by a 5-year survival rate of approximately 31%. The histological classifications already proposed do not accurately reflect the high biological heterogeneity of this neoplasm, particularly in diverse populations, and new classification systems using genetic markers have recently been proposed. Following these newly proposed models, we aimed to assess the cluster distribution in a Brazilian cohort. Furthermore, we evaluated whether the inclusion of other clinical and histological parameters could enhance the predictive value. METHODS: We used a previously described four-immunohistochemistry/EBER-ISH marker to classify a cohort of 30 Brazilian patients with gastric adenocarcinoma into five different clusters and compared the distribution with other genetically diverse populations. Furthermore, we used artificial intelligence methods to evaluate whether other clinical and pathological parameters could improve the results of the methodology. RESULTS: Disclosing the genetic variability between populations, we observed a more balanced distribution of the aberrant/normal p53 ratio (0.6) between patients negative for the other markers tested, unlike previous studies with Asian and North American populations. In addition, decision tree analysis reinforced the efficiency of these new classifications, as the stratification accuracy was not altered with or without additional data. CONCLUSION: Our study underscores the importance of local research in characterizing diverse populations and highlights the complementary role of molecular biomarkers in personalized medicine for gastric adenocarcinoma, enhancing diagnostic accuracy and potentially improving survival rates.
Asunto(s)
Adenocarcinoma , Biomarcadores de Tumor , Neoplasias Gástricas , Proteína p53 Supresora de Tumor , Neoplasias Gástricas/genética , Neoplasias Gástricas/clasificación , Neoplasias Gástricas/patología , Humanos , Brasil , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/análisis , Masculino , Femenino , Adenocarcinoma/genética , Adenocarcinoma/clasificación , Adenocarcinoma/patología , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Estudios de Cohortes , Anciano , Análisis por Conglomerados , Mutación , Inmunohistoquímica , Adulto , Pronóstico , Anciano de 80 o más AñosRESUMEN
BACKGROUND: The study aimed to identify the optimal model for predicting rectal cancer liver metastasis (RCLM). This involved constructing various prediction models to aid clinicians in early diagnosis and precise decision-making. METHODS: A retrospective analysis was conducted on 193 patients diagnosed with rectal adenocarcinoma were randomly divided into training set (n = 136) and validation set (n = 57) at a ratio of 7:3. The predictive performance of three models was internally validated by 10-fold cross-validation in the training set. Delineation of the tumor region of interest (ROI) was performed, followed by the extraction of radiomics features from the ROI. The least absolute shrinkage and selection operator (LASSO) regression algorithm and multivariate Cox analysis were employed to reduce the dimensionality of radiomics features and identify significant features. Logistic regression was employed to construct three prediction models: clinical, radiomics, and combined models (radiomics + clinical). The predictive performance of each model was assessed and compared. RESULTS: KRAS mutation emerged as an independent predictor of liver metastasis, yielding an odds ratio (OR) of 8.296 (95%CI: 3.471-19.830; p < 0.001). 5 radiomics features will be used to construct radiomics model. The combined model was built by integrating radiomics model with clinical model. In both the training set (AUC:0.842, 95%CI: 0.778-0.907) and the validation set (AUC: 0.805; 95%CI: 0.692-0.918), the AUCs for the combined model surpassed those of the radiomics and clinical models. CONCLUSIONS: Our study reveals that KRAS mutation stands as an independent predictor of RCLM. The radiomics features based on MR play a crucial role in the evaluation of RCLM. The combined model exhibits superior performance in the prediction of liver metastasis. CLINICAL TRIAL NUMBER: Not applicable.
Asunto(s)
Neoplasias Hepáticas , Imagen por Resonancia Magnética , Mutación , Proteínas Proto-Oncogénicas p21(ras) , Neoplasias del Recto , Humanos , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/genética , Neoplasias del Recto/patología , Femenino , Masculino , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/genética , Persona de Mediana Edad , Estudios Retrospectivos , Proteínas Proto-Oncogénicas p21(ras)/genética , Imagen por Resonancia Magnética/métodos , Anciano , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/genética , Adenocarcinoma/secundario , Adulto , Valor Predictivo de las Pruebas , RadiómicaRESUMEN
Hydrogen sulfide (H2S) is a critical molecule that participates in various molecular, physiological, and pathophysiological processes in biological systems. Emerging evidence has revealed that H2S is implicated in the progression of colon cancer and immune escape. Against this backdrop, the present study aimed to construct a prognostic risk feature for colon adenocarcinoma (COAD) by leveraging hydrogen sulfide-related genes (HSRG). Transcriptomic data and corresponding clinical-pathological information of colon cancer were obtained from The Cancer Genome Atlas and gene expression omnibus databases. Univariate Cox regression analysis was employed to assess the prognostic relevance of HSRG. Consensus clustering was utilized to perform molecular subtyping of COAD, followed by comparison of immune cell infiltration, drug sensitivity, and immune therapy response between subtypes. Differential expression gene and gene set enrichment analyses were conducted between subtypes. Univariate, lasso, and multivariate Cox regression analyses were applied to construct a prognostic model derived from HSRG. A nomogram model for predicting COAD prognosis was constructed and evaluated. In this study, we identified 12 HSRGs that were associated with COAD prognosis. Consensus clustering analysis revealed 3 COAD molecular subtypes that exhibited significant differences in terms of prognosis, tumor immune cell infiltration, drug sensitivity, and immune therapy response. Gene set enrichment analysis demonstrated that immunoregulatory processes were significantly suppressed in the poor-prognosis subtype while Wnt-related pathways and processes were significantly upregulated. Based on the differentially expressed genes between subtypes, we constructed a risk model comprising 11 genes that effectively distinguished high-risk patients from low-risk patients with significant associations with patient survival outcomes, drug treatment, pathological staging, and T staging. The HSRG-derived risk feature was an independent prognostic factor for COAD in drug treatment and pathological staging and could be integrated into a nomogram for prognosis prediction. Calibration curve, receiver operating characteristic curve, and decision curve analysis demonstrated excellent performance of the nomogram in evaluating COAD prognosis. Our study systematically assessed the prognostic significance of HSRG in COAD, identified HSRG-based molecular subtypes and risk features, and highlighted their potential utility in predicting prognosis and treatment response.
Asunto(s)
Adenocarcinoma , Neoplasias del Colon , Sulfuro de Hidrógeno , Humanos , Neoplasias del Colon/genética , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias del Colon/mortalidad , Sulfuro de Hidrógeno/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Pronóstico , Nomogramas , Masculino , Femenino , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Transcriptoma , Persona de Mediana EdadRESUMEN
BACKGROUND: Obesity is a risk factor for esophageal adenocarcinoma (EAC). It was reported that obesity -associated inflammation correlates with insulin resistance and increased risk of EAC. The objective of the study is to investigate the role of obesity associated inflammatory mediators in the development of EAC. METHODS: We included 23 obese and nonobese patients with EAC or with or without Barrett's esophagus (BE) after IRB approval. We collected 23 normal, 10 BE, and 19 EAC tissue samples from endoscopy or esophagectomy. The samples were analyzed for the expression levels of pro-apoptotic and anti-apoptotic factors, PKC-δ, cIAP2, FLIP, IGF-1, Akt, NF-kB and Ki67 by immunofluorescence and RT-PCR. We compared the expression levels between normal, BE, and EAC tissue using Students' t-test between two groups. RESULTS: Our results showed decreased gene and protein expression of pro-apoptotic factors (bad, bak and bax) and increased expression of anti-apoptotic factors (bcl-2, Bcl-xL) in BE and EAC compared to normal tissues. There was increased gene and protein expression of PKC-δ, cIAP2, FLIP, NF-kB, IGF-1, Akt, and Ki67 in BE and EAC samples compared to normal esophagus. Further, an increased folds changes in mRNA expression of proapoptotic factors, antiapoptotic factors, PKC-δ, IGF-1, Akt, and Ki-67 was associated with obesity. CONCLUSION: Patients with EAC had increased expression of cIAP2 and FLIP, and PKC-δ which is associated with inhibition of apoptosis and possible progression of esophageal adenocarcinoma.
Asunto(s)
Adenocarcinoma , Apoptosis , Esófago de Barrett , Neoplasias Esofágicas , Obesidad , Humanos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Obesidad/metabolismo , Obesidad/genética , Obesidad/complicaciones , Masculino , Esófago de Barrett/genética , Esófago de Barrett/metabolismo , Esófago de Barrett/patología , Persona de Mediana Edad , Femenino , Apoptosis/genética , Anciano , Regulación Neoplásica de la Expresión Génica , Adulto , FN-kappa B/metabolismo , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/metabolismo , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis/genéticaRESUMEN
Background: As one of the malignant tumors with the highest incidence and fatality in the world, colon adenocarcinoma (COAD) has a very complex pathogenic mechanism, which has not yet been fully elucidated. Ubiquitin can regulate cell proliferation, cell cycle, apoptosis, DNA damage repair, and other processes by changing the activity of substrate proteins or causing ubiquitin-proteasome degradation. These are the key links in the pathogenesis of COAD, and ubiquitin plays an important role in the occurrence and development of COAD. Methods: We integrated transcriptomics, single-cell and clinical omics, and TCGA and GEO databases of COAD patient data. Cox and Lasso regression was employed to assess ubiquitination genes in COAD for generating ubiquitination-related features. The aim was to evaluate the prognostic value of these features for tumors and their impact on the immune microenvironment. At the same time, the expression level of model genes was further analyzed using single-cell data. Finally, the expression and function of ASNS, a key gene for this trait, were detected in vitro. Results: In our study, based on identifiable changes in the expression of marker genes, this feature can be used to classify patients with COAD. Kaplan-Meier survival analysis indicated that those with elevated risk scores in each cohort experienced inferior outcomes. There is good validation in both the training queue and the validation queue. The results of the immune infiltration analysis showed that the immune infiltration rate was significantly increased in the high-risk group. After the knockdown of ASNS, an important gene in the signature, the activity and migration capacity of SW620 and RKO cell lines and colony formation capacity were dramatically reduced in cell tests. Conclusion: We screened ubiquitination-related genes and constructed ubiquitination-related features, which can be used as reliable prognostic indicators of COAD. ASNS was identified as a possible biomarker for COAD.
Asunto(s)
Adenocarcinoma , Biomarcadores de Tumor , Neoplasias del Colon , Ubiquitinación , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias del Colon/genética , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/metabolismo , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Pronóstico , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica , Transcriptoma , Línea Celular Tumoral , Masculino , Femenino , MultiómicaRESUMEN
The Human Leukocyte Antigen (HLA) system contains a set of genes involved at many levels in the innate and adaptive immune response. Among the non-classical HLA class I genes, HLA-G stands out for the numerous studies about its pivotal role in regulating/modulating immune responses. Also, its involvement in extravillous cytotrophoblast function, viral infections, autoimmunity, and cancer has been extensively documented. The present study explores for the first time the relationship between natural alleles of HLA-G, rather than STSs, SNPs, or partial gene polymorphisms, and the development of gastric adenocarcinoma, by analyzing the genetic profile of a cohort of 40 Spanish patients with this type of tumor using DNA extracted from paired biopsies of tumoral and adjacent non-tumoral gastric tissue. Our results reveal a significant statistical relationship between the presence of the HLA-G*01:01:01 allele and the development of gastric cancer, while other common alleles such as -G*01:04 or -G*01:05N did not demonstrate a significant correlation. Studying the involvement of HLA genes in the development of many diseases is relevant to understanding their pathophysiology. However, the absence of specific mechanisms underlying these associations suggests that investigating complete HLA natural alleles' extended haplotypes or complotypes may offer a more precise and valuable approach to elucidating the association of HLA with the pathogenesis of disease.
Asunto(s)
Adenocarcinoma , Alelos , Antígenos HLA-G , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Antígenos HLA-G/genética , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Masculino , Femenino , Persona de Mediana Edad , Predisposición Genética a la Enfermedad , Anciano , Haplotipos , Adulto , Frecuencia de los Genes , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: We aimed to explore the role of structural maintenance of chromosomes 4 (SMC4) in malignant progression and immunology of colon adenocarcinoma (COAD). METHODS: The expression, genetic and protein features, and immune cell infiltration of SMC4 in pan-cancer were provided by public databases and websites. The protein expression of SMC4 in COAD tissues was screened by immunohistochemical assay. Si-RNA-mediated transfection was performed in COAD cells and the proliferation viability was measured using MTT, colony formation and EdU assays. Cell autophagy was detected by AO staining, western blots, and immunofluorescence staining. The migratory ability was determined using scratch and transwell assays. The expression of epithelial-to-mesenchymal transition (EMT) markers and transcriptional factors were detected using western blots. RESULTS: The expression of SMC4 was upregulated in pan-cancer and had relationships with prognosis, TMB, and MSI of cancer patients. Particularly, SMC4 protein was highly expressed in COAD tissues and correlated with poor prognosis of patients. Depletion of SMC4 inhibited cell proliferation, induced autophagy, and decreased migration through EMT progression in COAD cells. In addition, SMC4 was associated with infiltration of neutrophils, M2 macrophages, and CD4 + T cells in COAD, and had positive association with M2 macrophage markers and immune checkpoints. CONCLUSION: SMC4 was correlated with patients' poor prognosis, proliferation, metastasis, and immune cell infiltrates, and might function as a potential diagnosis and prognostic biomarker in COAD.
Asunto(s)
Adenocarcinoma , Biomarcadores de Tumor , Proteínas de Ciclo Celular , Movimiento Celular , Proliferación Celular , Neoplasias del Colon , Transición Epitelial-Mesenquimal , Humanos , Neoplasias del Colon/patología , Neoplasias del Colon/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/diagnóstico , Adenocarcinoma/inmunología , Adenocarcinoma/metabolismo , Transición Epitelial-Mesenquimal/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Autofagia , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Masculino , Femenino , Regulación hacia Arriba , Adenosina TrifosfatasasRESUMEN
Nucleolar and spindle-associated protein 1 (NUSAP1), a microtubule-associated protein, has been recently identified to exhibit aberrant expression patterns that correlate with malignant tumorigenesis and progression across various cancer types. However, the specific regulatory mechanisms and potential targeting therapies of NUSAP1 in lung adenocarcinoma (LUAD) remain largely elusive. In this study, by conducting bioinformatics analyses as well as in vitro and in vivo experiments, we identified that NUSAP1 was significantly upregulated in LUAD, with a notable correlation with poorer overall survival, higher scores for immunogenicity and immune infiltration, as well as increased sensitivity to conventional chemotherapeutic drugs such as paclitaxel, docetaxel and vinorelbine in LUAD. Functionally, NUSAP1 overexpression significantly promoted LUAD cell proliferation, while its knockdown markedly suppressed this process. Interestingly, our results revealed that NUSAP1 upregulation was mediated by estrogen via ERß activation. Furthermore, we identified entinostat as a novel inhibitor of NUSAP1. Pharmacological targeting ERß/NUSAP1 axis with fulvestrant (ERß antagonist) or entinostat (novel NUSAP1 inhibitor) significantly reduced LUAD growth both in vitro and in vivo, which may represent effective alternative therapeutic strategies for patients with LUAD.
Asunto(s)
Adenocarcinoma del Pulmón , Proliferación Celular , Estrógenos , Neoplasias Pulmonares , Proteínas Asociadas a Microtúbulos , Humanos , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Estrógenos/metabolismo , Animales , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Línea Celular Tumoral , Ratones , Proliferación Celular/efectos de los fármacos , Regulación hacia Arriba , Ratones Desnudos , Femenino , Adenocarcinoma/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/genética , Regulación Neoplásica de la Expresión Génica , Receptor beta de Estrógeno/metabolismo , Receptor beta de Estrógeno/genética , Ratones Endogámicos BALB CRESUMEN
The role of circadian rhythm genes (CRGs) in gastric cancer (GC) is poorly understood. This study aimed to develop a CRG signature to improve understanding of prognosis and immunotherapy responses in GC patients. We integrated the The Cancer Genome Atlas-Stomach adenocarcinoma (TCGA-STAD) dataset with CRGs to develop a prognostic signature for GC. The signature's predictive ability was validated using Kaplan-Meier and ROC curves. The CIBERSORT algorithm evaluated immune cell proportions, and tumor immune dysfunction and exclusion score, as well as immune phenotype score, determined the response to immunotherapy for STAD patients. Finally, we assessed signature genes expression using real-time quantitative polymerase chain reaction. We developed a 4-CRG signature for STAD, demonstrating accurate prognostic ability. The low-risk group showed increased B cell memory and CD8 + T cells, and decreased M2 Macrophages compared to the high-risk group. Patients in the low-risk group had a higher likelihood of benefiting from immunotherapy. Additionally, gastric cancer tissues exhibited elevated expression of OPN3 and decreased expression of TP53 compared to adjacent tissue. This study successfully established a prognostic signature for CRGs, accurately predicting prognosis and immunotherapeutic response among STAD patients, providing insights for the development of personalized therapeutic strategies for these patients.
Asunto(s)
Ritmo Circadiano , Regulación Neoplásica de la Expresión Génica , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/terapia , Pronóstico , Ritmo Circadiano/genética , Masculino , Femenino , Biomarcadores de Tumor/genética , Inmunoterapia/métodos , Persona de Mediana Edad , Estimación de Kaplan-Meier , Perfilación de la Expresión Génica , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adenocarcinoma/mortalidadRESUMEN
KRAS mutations are the most common oncogenic mutations in lung adenocarcinoma in Black Americans. Polyisoprenylated Cysteinyl amide Inhibitors (PCAIs) constitute a group of potential cancer therapy agents that we designed to specifically disrupt and suppress hyperactive G-protein signaling, such as that caused by mutated RAS proteins. Here we determine the effects of PCAIs on the viability, G-protein levels, downstream mediators, and apoptosis-related proteins on the KRAS-mutated, Black American-derived lung adenocarcinoma cell line, NCI-H23. Of the 17 PCAIs tested, compounds NSL-YHJ-2-27 and NSL-YHJ-2-46 showed the most potency with EC50 values of 2.7 and 3.3 µM, respectively. Western blotting was used to determine the effect of the PCAIs on the phosphorylation levels of MAPK pathway enzymes. After 48 h exposure to 5 µM of the PCAIs, NSL-YHJ-2-46, the MAPK proteins BRAF, MEK1/2, ERK1/2, and p90RSK were activated through phosphorylation by 90, 190, 150 and 120%, respectively. However, CRAF/RAF1 phosphorylation decreased by 40%, suggesting significant changes in the KRAS/MAPK signaling patterns. Furthermore, 5 µM of NSL-YHJ-2-27 depleted the singly polyisoprenylated monomeric G-proteins RAC 1/2/3 and CDC42 by 77 and 76%, respectively. The depletion of these key cytoskeletal proteins may account for the observed inhibition of cell migration and invasion, and spheroid invasion observed on exposure to NSL-YHJ-2-27 and NSL-YHJ-2-46. Treatment with 5 µM of NSL-YHJ-2-27 suppressed full-length inactive caspase 3 and 7 levels by 72 and 91%, respectively. An analysis of cells treated with the fluorescently labeled active caspase 3/7 irreversible inhibitor, CaspaTagTM Caspase-3/7 in situ reagent revealed a 124% increase in active caspase at 3 µM over controls. These findings clearly show the direct effects of the PCAIs on the RAS signaling pathway. Given the profound increases observed in RPS6KA1/p90RSK phosphorylation, future work will involve a determination whether the proapoptotic isoforms of RPS6KA1/p90RSK are phosphorylated due to the PCAIs treatments. These results support the potential use of the PCAIs as targeted therapies against cancers with KRAS mutations.
Asunto(s)
Amidas , Apoptosis , Movimiento Celular , Neoplasias Pulmonares , Sistema de Señalización de MAP Quinasas , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Amidas/farmacología , Mutación , Fosforilación/efectos de los fármacos , Cisteína/farmacología , Antineoplásicos/farmacología , Proteína de Unión al GTP cdc42/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/genéticaRESUMEN
SMARCB1/SMARCA4-deficient malignancies of the female genital tract are rare entities, characterized by similar histologic features, such as sheet-like growth patterns and rhabdoid cells. Previous studies have shown mutually exclusive loss of SMARCA4/BRG1 and SMARCB1/INI1. Herein, we describe a unique cervical mixed carcinoma in a 77-year-old patient. The tumor consisted of 3 components, gastric-type adenocarcinoma, squamous carcinoma, and undifferentiated carcinoma. While the undifferentiated carcinoma was negtive for CK7, CK5/6 and p63, it was positive for pan-CK. DNA-based next-generation sequencing revealed a nonsense mutation in SMARCA4, copy number loss in SMARCB1, and a nonsense mutation in ARID1A. Different molecular alterations of the switch/sucrose nonfermenting complex subunits in the present case may provide further insights into the functions of the switch/sucrose nonfermenting complex in the progression of tumors.
Asunto(s)
ADN Helicasas , Proteínas de Unión al ADN , Proteínas Nucleares , Proteína SMARCB1 , Factores de Transcripción , Neoplasias del Cuello Uterino , Humanos , Femenino , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Anciano , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , ADN Helicasas/genética , ADN Helicasas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Codón sin Sentido , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/genética , Adenocarcinoma/metabolismoRESUMEN
BACKGROUND: Gastric cancer (GC) is the fourth leading cause of cancer mortality worldwide. Peritoneal metastasis (PM) is a significant cause of death in patients with GC, and presents a major challenge in clinical diagnosis and treatment. Predicting the occurrence of PM in high-risk patients, and diagnosing and treating PM in advance to improve patient survival, remains an unsolved problem in clinical practice. Given the low positive rate of cytology and difficulty in diagnosing occult PM, new molecular markers and detection technologies for early diagnosis require urgent validation. The primary objective of this study is to observe and evaluate the predictive effect of intraoperative peritoneal lavage fluid (PLF) circulating tumour cells (CTC) and circulating tumour DNA (ctDNA) levels in patients with pT4NxM0/pT1-3N+M0 GC on metachronous PM after R0 resection. METHODS AND ANALYSIS: This prospective single-centre clinical study is conducted at Renji Hospital, Shanghai Jiao Tong University School of Medicine. In this study, 200 cases of patients with pT4NxM0/pT1-3N+M0 gastric adenocarcinoma older than 18 years will be screened. Participants will undergo intraoperative PLF CTC and ctDNA testing and will be followed up for 2 years, with imaging assessments performed every 3-6 months until PM occurrs. The primary outcome is the incidence of PM 1 year after surgery, which will be estimated using Clopper-Pearson method, with 95% CIs calculated and compared between groups. Secondary outcome include the incidence of PM 2 years after surgery, overall survival and disease progression. Data will be analysed using the Kaplan-Meier method and the log-rank test. ETHICS AND COMMUNICATION: Informed consent has been obtained from all subjects. This protocol has been approved by the Ethics Committee of Renji Hospital, Shanghai Jiao Tong University School of Medicine (LY2023-142-B). The findings will be disseminated through peer-reviewed manuscripts, reports and presentations. TRIAL REGISTRATION NUMBER: ChiCTR2300074910.
Asunto(s)
ADN Tumoral Circulante , Células Neoplásicas Circulantes , Lavado Peritoneal , Neoplasias Peritoneales , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirugía , Estudios Prospectivos , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/genética , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Masculino , Femenino , Líquido Ascítico/metabolismo , China , Persona de Mediana Edad , Biomarcadores de Tumor/sangre , Adenocarcinoma/cirugía , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/secundario , Valor Predictivo de las Pruebas , Gastrectomía/métodos , Estadificación de NeoplasiasRESUMEN
Background: Recent research has found a new way of cell death: disulfidptosis. Under glucose starvation, abnormal accumulation of disulfide molecules such as Cystine in Solute Carrier Family 7 Member 11 (SLC7A11) overexpression cells induced disulfide stress to trigger cell death. The research on disulfidptosis is still in its early stages, and its role in the occurrence and development of colorectal malignancies is still unclear. Method: In this study, we employed bioinformatics methods to analyze the expression and mutation characteristics of disulfidptosis-related genes (DRGs) in colorectal cancer. Consensus clustering analysis was used to identify molecular subtypes of Colorectal Adenocarcinoma (COAD) associated with disulfidptosis. The biological behaviors between subtypes were analyzed to explore the impact of disulfidptosis on the tumor microenvironment. Constructing and validating a prognostic risk model for COAD using diverse data. The influence of key genes on prognosis was evaluated through SHapley Additive exPlanations (SHAP) analysis, and the predictive capability of the model was assessed using Overall Survival analysis, Area Under Curve and risk curves. The immunological status of different patients and the prediction of drug treatment response were determined through immune cell infiltration, TMB, MSI status, and drug sensitivity analysis. Single-cell analysis was employed to explore the expression of genes at the cellular level, and finally validated the expression of key genes in clinical samples. Result: By integrating the public data from two platforms, we identified 2 colorectal cancer subtypes related to DRGs. Ultimately, we established a prognosis risk model for COAD using 7 genes (FABA4+GIPC2+EGR3+HOXC6+CCL11+CXCL10+ITLN1). SHAP analysis can further explained the positive or negative impact of gene expression on prognosis. By dividing patients into high-risk and low-risk groups, we found that patients in the high-risk group had poorer prognosis, higher TMB, and a higher proportion of MSI-H and MSI-L statuses. We also predicted that drugs such as 5-Fluorouracil, Oxaliplatin, Gefitinib, and Sorafenib would be more effective in low-risk patients, while drugs like Luminesib and Staurosporine would be more effective in high-risk patients. Single-cell analysis revealed that these 7 genes not only differ at the level of immune cells but also in epithelial cells, fibroblasts, and myofibroblasts, among other cell types. Finally, the expression of these key genes was verified in clinical samples, with consistent results. Conclusions: Our research findings provide evidence for the role of disulfidptosis in COAD and offer new insights for personalized and precise treatment of COAD.
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Adenocarcinoma , Neoplasias Colorrectales , Microambiente Tumoral , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/mortalidad , Pronóstico , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/mortalidad , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Biología Computacional/métodos , Muerte CelularRESUMEN
Depressive disorder contributes to the initiation and prognosis of patients with cancer, but the interaction between cancer and depressive disorder remains unclear. We generated a gastric adenocarcinoma patient-derived xenograft mice model, treated with chronic unpredictable mild stimulation. Based on the RNA-sequence from the mouse model, patient data from TCGA, and MDD-related (major depressive disorder) genes from the GEO database, 56 hub genes were identified by the intersection of differential expression genes from the three datasets. Molecular subtypes and a prognostic signature were generated based on the 56 genes. A depressive mouse model was constructed to test the key changes in the signatures. The signature was constructed based on the NDUFA4L2, ANKRD45, and AQP3 genes. Patients with high risk-score had a worse overall survival than the patients with low scores, consistent with the results from the two GEO cohorts. The comprehensive results showed that a higher risk-score was correlated with higher levels of tumor immune exclusion, higher infiltration of M0 macrophages, M2 macrophages, and neutrophils, higher angiogenetic activities, and more enriched epithelial-mesenchymal transition signaling pathways. A higher risk score was correlated to a higher MDD score, elevated MDD-related cytokines, and the dysfunction of neurogenesis-related genes, and parts of these changes showed similar trends in the animal model. With the Genomics of Drug Sensitivity in Cancer database, we found that the gastric adenocarcinoma patients with high risk-score may be sensitive to Pazopanib, XMD8.85, Midostaurin, HG.6.64.1, Elesclomol, Linifanib, AP.24534, Roscovitine, Cytarabine, and Axitinib. The gene signature consisting of the NDUFA4L2, ANKRD45, and AQP3 genes is a promising biomarker to distinguish the prognosis, the molecular and immune characteristics, the depressive risk, and the therapy candidates for gastric adenocarcinoma patients.
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Adenocarcinoma , Neoplasias Gástricas , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Animales , Humanos , Adenocarcinoma/genética , Adenocarcinoma/patología , Ratones , Pronóstico , Regulación Neoplásica de la Expresión Génica , Depresión/genética , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Masculino , Modelos Animales de Enfermedad , FemeninoRESUMEN
Objective: To investigate the clinicopathological, immunohistochemical, and molecular genetic characteristics of microsecretory adenocarcinoma (MSA) of the salivary gland, and to improve the understanding of this rare tumor. Methods: Cases originally diagnosed as MSA at the Department of Oral Pathology, the Ninth People's Hospital of Shanghai Jiao Tong University School of Medicine were retrospectively collected. The cases of polymorphous adenocarcinoma and adenocarcinoma, not otherwise specified from January 2000 to January 2020 were reviewed to identify potential misdiagnosed MSA cases. Clinicopathological analysis and follow-up of all confirmed MSA cases were performed, and relevant literature was reviewed. Results: A total of 4 MSA cases were identified, including 2 screened from the polymorphous adenocarcinoma cohort. Of the 4 MSA patients, 3 were male and 1 was female, with an average age of 53 years (range, 37-67 years). Three cases occurred in the palate, and one in the buccal region. The clinical manifestation was usually a slow-growing painless mass. Tumors were generally small, with a maximum diameter ranging from 0.7 to 1.8 cm (average, 1.2 cm). Microscopically, the tumor was unencapsulated and showed an infiltrative growth pattern. The tumor cells appeared small in size and showed bland, cubic and flattened cytological features, forming microcystic lumens and glandular tubes. Significant basophilic secretions were seen in the lumens. Between the tumor nests there was fibro-myxoid stroma. Immunohistochemistry showed diffusely or partially positive staining for cytokeratin 7, S-100, SOX-10, p63 and vimentin and negative staining for p40, mammaglobin, and calponin. The proliferation index of Ki-67 was relatively low (1%-3%). Four MSA cases all harbored SS18 gene rearrangement as shown by fluorescence in situ hybridization (FISH), including 2 cases with MEF2C::SS18 fusion gene through RNA-targeted next generation sequencing. All 4 patients underwent surgical resection without any adjuvant treatments. Three patients were followed up for a period of 2 to 203 months. No tumor recurrence, metastasis, or disease-related death was found. Conclusions: Salivary gland MSA is a novel and rare low-grade carcinoma with unique and consistent histological morphology, immunophenotype, and molecular changes. Immunohistochemical staining and SS18 break apart FISH are useful for the diagnosis of the tumor with atypical morphology and high-grade transformation.
Asunto(s)
Adenocarcinoma , Neoplasias de las Glándulas Salivales , Humanos , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/genética , Masculino , Femenino , Persona de Mediana Edad , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/genética , Anciano , Adulto , Estudios Retrospectivos , Factores de Transcripción SOXE/metabolismo , Factores de Transcripción SOXE/genética , Inmunohistoquímica , Vimentina/metabolismo , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Antígeno Ki-67/metabolismoRESUMEN
BACKGROUND: Primary malignant neoplasms of the spermatic cord are extremely rare, with most reported cases being sarcomas or metastatic carcinomas. However, primary adenocarcinoma of the spermatic cord has not been previously reported. CASE PRESENTATION: A 34-year-old male with a solid mass in the right spermatic cord, was eventually diagnosed with primary adenocarcinoma. Histological examination revealed a moderately-to-poorly differentiated adenocarcinoma exhibiting glandular, cribriform, or nested growth patterns, characterized by medium to large-sized cells and focal extracellular mucus. Immunohistochemical analysis demonstrated positive staining for CK (AE1/AE3), CK8/18, CK19, MOC31 (EP-CAM), and Ber-EP4, while negative staining was observed for CK7, D2-40, WT-1, MC, PAX-8, NKX3.1, PSA, CEA, TTF-1, and NapsinA. Furthermore, a complete loss of INI-1 expression and consistent BRG1 expression were noted in all tumor cells. Next-generation sequencing revealed SMARCB1 deletion, low tumor mutation burden (TMB-L), and microsatellite stability (MSS). CONCLUSION: We reported the first case of primary adenocarcinoma of the spermatic cord with SMARCB1 (INI-1) deficiency. This case contributes to the expanding understanding of rare neoplasms and underscores the importance of further research into therapeutic strategies targeting SMARCB1-deficient tumors.
Asunto(s)
Adenocarcinoma , Biomarcadores de Tumor , Neoplasias de los Genitales Masculinos , Cordón Espermático , Humanos , Masculino , Adenocarcinoma/patología , Adenocarcinoma/genética , Cordón Espermático/patología , Adulto , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Neoplasias de los Genitales Masculinos/patología , Neoplasias de los Genitales Masculinos/genética , Neoplasias de los Genitales Masculinos/química , Inmunohistoquímica , Proteína SMARCB1/genética , Factores de Transcripción/genéticaRESUMEN
Stomach adenocarcinoma (STAD) is a prevalent malignancy that is highly aggressive and heterogeneous. Intratumor heterogeneity (ITH) showed strong link to tumor progression and metastasis. High ITH may promote tumor evolution. An ITH-related signature (IRS) was created using as integrative technique including 10 machine learning methods based on TCGA, GSE15459, GSE26253, GSE62254 and GSE84437 datasets. The relevance of IRS in predicting the advantages of immunotherapy was assessed using a number of prediction scores and three immunotherapy datasets (GSE78220, IMvigor210 and GSE91061). Vitro experiments were performed to verify the biological functions of AKR1B1. The RSF + Enet (alpha = 0.1) projected model was proposed as the ideal IRS because it had the highest average C-index. The IRS demonstrated a strong performance in serving as an independent risk factor for the clinical outcome of STAD patients. It performed exceptionally well in predicting the overall survival rate of STAD patients, as seen by the TCGA cohort's AUC of 1-, 3-, and 5-year ROC curves, which were 0.689, 0.683, and 0.669, respectively. A low IRS score demonstrated a superior response to immunotherapy, as seen by a lower TIDE score, lower immune escape score, greater TMB score, higher PD1&CTLA4 immunophenoscore, higher response rate, and improved prognosis. Common chemotherapeutic and targeted treatment regimens had lower IC50 values in the group with higher IRS scores. Vitro experiment showed that AKR1B1 was upregulated in STAD and knockdown of AKR1B1 obviously suppressed tumor cell proliferation and migration. The present investigation produced the best IRS for STAD, which may be applied to prognostication, risk stratification, and therapy planning for STAD patients.
Asunto(s)
Adenocarcinoma , Inmunoterapia , Aprendizaje Automático , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Adenocarcinoma/genética , Adenocarcinoma/terapia , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Inmunoterapia/métodos , Pronóstico , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Masculino , Femenino , Biomarcadores de Tumor/genética , Proliferación Celular , Aldehído Reductasa/genética , Aldehído Reductasa/metabolismo , Persona de Mediana EdadRESUMEN
BACKGROUND: Gastric adenocarcinoma of the fundic gland type (GA-FG) is a newly described variant of gastric adenocarcinoma with lack of knowledges regarding its genetic features. METHODS: We performed whole-genome sequencing (WGS) in formalin-fixed paraffin-embedded (FFPE) tumor tissues and matched adjacent noncancerous specimens from 21 patients with GA-FG, and integrated published datasets from 1105 patients with traditional gastric adenocarcinoma with the purpose of dissecting genetic determinants both common to conventional gastric adenocarcinoma and unique to GA-FG disease. RESULTS: We characterized the genomic architecture of GA-FG disease, revealing the predominant proportion of C > T substitution among the six types of SNVs. GNAS was the most significantly mutated driver gene (14.29%). 42.8% of samples harbored "Kataegis." Distinct genomic alterations between GA-FG and conventional gastric cancer were identified. Specifically, low mutational burden and relatively moderate mutational frequencies of significantly mutated driver genes, coupled with the absence of non-silent alterations of formerly well-known drivers such as TP53, PIK3CA and KRAS were identified in GA-FG patients. Oncogenic signaling pathway analysis revealed mutational processes associated with focal adhesions and proteoglycans in cancer, highlighting both common and specific procedures during the development of GA-FG and conventional gastric cancer. CONCLUSION: Our study is the first to comprehensively depict the genomic landscape highlighting the multidimensional perturbations in GA-FG patients. These discoveries offered mechanistic insights for novel diagnostic and therapeutic strategies for patients with such disease.