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1.
Oncol Rep ; 47(1)2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34821374

RESUMO

The objective of the present study was to clarify the expression characteristics of long non­coding RNA (lncRNA) FGD5 antisense RNA 1 (FGD5­AS1) in pancreatic cancer, as well as its biological function and underlying mechanism. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was utilized for the detection of FGD5­AS1 and microRNA (miR)­577 expression levels in pancreatic cancer tissues. Transfection was performed to upregulate or downregulate FGD5­AS1 in pancreatic cancer cell lines. MTT and Transwell assays were then utilized to detect the proliferation, migration and invasion of cancer cells, respectively. Subsequently, dual­luciferase reporter gene assay, RNA immunoprecipitation assay, RNA pull­down assay, RT­qPCR, western blotting, and Pearson's correlation analysis were employed to confirm the regulatory relationships among FGD5­AS1, miR­577, low­density lipoprotein receptor­related protein 6 (LRP6) and ß­catenin. Western blotting was employed to determine the expression levels of Axin2, cyclin D1 and c­Myc. The expression level of FGD5­AS1 was upregulated in pancreatic cancer tissues and cell lines. FGD5­AS1 knockdown inhibited pancreatic cancer cell proliferation, migration and invasion. By contrast, miR­577 was significantly inhibited in pancreatic cancer cells and tissues; its downregulation promoted pancreatic cancer cell proliferation, migration and invasion, and reversed the effects of FGD5­AS1 knockdown on pancreatic cancer cells. In addition, it was revealed that miR­577 was a target of FGD5­AS1, and FGD5­AS1 could modulate the expression levels of LRP6, ß­catenin, Axin2, cyclin D1 and c­Myc via suppressing miR­577. In conclusion, in pancreatic cancer, highly expressed FGD5­AS1 activated the Wnt/ß­catenin signaling and promoted cancer cell proliferation, migration and invasion via suppression of miR­577.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , MicroRNAs/genética , Neoplasias Pancreáticas/genética , RNA Antissenso/genética , RNA Longo não Codificante/genética , Via de Sinalização Wnt , beta Catenina/genética , Adulto , Idoso , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oncogenes , Regulação para Cima , Adulto Jovem
2.
Methods Mol Biol ; 2257: 375-422, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34432288

RESUMO

Cancer is also determined by the alterations of oncogenes and tumor suppressor genes. These gene expressions can be regulated by microRNAs (miRNA). At this point, researchers focus on addressing two main questions: "How are oncogenes and/or tumor suppressor genes regulated by miRNAs?" and "Which other mechanisms in cancer cells are regulated by miRNAs?" In this work we focus on gathering the publications answering these questions. The expression of miRNAs is affected by amplification, deletion or mutation. These processes are controlled by oncogenes and tumor suppressor genes, which regulate different mechanisms of cancer initiation and progression including cell proliferation, cell growth, apoptosis, DNA repair, invasion, angiogenesis, metastasis, drug resistance, metabolic regulation, and immune response regulation in cancer cells. In addition, profiling of miRNA is an important step in developing a new therapeutic approach for cancer.


Assuntos
Neoplasias , Apoptose/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , MicroRNAs/genética , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Oncogenes
3.
Ann Anat ; 239: 151824, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34478856

RESUMO

BACKGROUND: Tail regeneration in lizards is the only case of large multi-tissue organ regeneration in amniotes. METHODS: The present Review summarizes numerous immunolocalization and gene-expression studies indicating that after tail amputation in lizards the stump is covered in 7-10 days by the migration of keratinocytes. This allows the accumulation of mesenchymal-fibroblasts underneath the wound epidermis and forms a regenerative blastema and a new tail. RESULTS: During migration keratinocytes transit from a compact epidermis into relatively free keratinocytes in a process of "Epithelial Mesenchymal Transition" (EMT). While EMT has been implicated in carcinogenesis no malignant transformation is observed during these cell movements in the regenerative blastema. Immunolabeling for E-cadherin and snail shows that these proteins are present in the cytoplasm and nuclei of migrating keratinocytes. The basal layer of the wound epithelium of the apical blastema express onco-proteins (wnt2b, egfr, c-myc, fgfs, fgfr, rhov, etc.) and tumor suppressors (p53/63, fat2, ephr, apc, retinoblastoma, arhgap28 etc.). This suggests that their balanced action regulates proliferation of the blastema. CONCLUSIONS: While apical epidermis and mesenchyme are kept under a tight proliferative control, in more proximal regions of the regenerating tail the expression of tumor-suppressors triggers the differentiation of numerous tissues, forming the large myomeres, axial cartilage, simple spinal cord and nerves, new scales, arteries and veins, fat deposits, dermis and other connective tissues. Understanding gene expression patterns of developmental pathways activated during tail regeneration in lizards is useful for cancer research and for future attempts to induce organ regeneration in other amniotes including humans.


Assuntos
Genes Supressores de Tumor , Lagartos , Oncogenes , Regeneração , Cauda/crescimento & desenvolvimento , Animais , Diferenciação Celular , Derme , Epiderme
4.
Dev Cell ; 56(24): 3307-3308, 2021 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-34932947

RESUMO

With age, clones carrying somatic mutations in well-known cancer driver genes progressively populate adult tissues, yet cancer transformation is rare. In a recent issue of Nature, Colom et al. showed that competition between mutated clones with different fitness could act as a tumor-protective mechanism.


Assuntos
Neoplasias , Adulto , Transformação Celular Neoplásica/genética , Células Clonais , Humanos , Mutação/genética , Neoplasias/genética , Oncogenes
5.
Cells ; 10(12)2021 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-34944094

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) and High-Grade Serous Ovarian Cancer (HGSOC) are aggressive malignancies that share similarities; however, different ages of onset may reflect distinct tumor behaviors. Thus, our aim was to compare somatic mutations in potential driver genes in 109 TNBC and 81 HGSOC from young (Y ≤ 40 years) and elderly (E ≥ 75 years) patients. METHODS: Open access mutational data (WGS or WES) were collected for TNBC and HGSOC patients. Potential driver genes were those that were present in the Cancer Gene Census-CGC, the Candidate Cancer Gene Database-CCGD, or OncoKB and those that were considered pathogenic in variant effect prediction tools. RESULTS: Mutational signature 3 (homologous repair defects) was the only gene that was represented in all four subgroups. The median number of mutated CGCs per sample was similar in HGSOC (Y:3 vs. E:4), but it was higher in elderly TNBC than it was in young TNBC (Y:3 vs. E:6). At least 90% of the samples from TNBC and HGSOC from Y and E patients presented at least one known affected TSG. Besides TP53, which was mutated in 67-83% of the samples, the affected TSG in TP53 wild-type samples were NF1 (yHGSOC and yTNBC), PHF6 (eHGSOC and yTNBC), PTEN, PIK3R1 and ZHFX3 (yTNBC), KMT2C, ARID1B, TBX3, and ATM (eTNBC). A few samples only presented one affected oncogene (but no TSG): KRAS and TSHR in eHGSOC and RAC1 and PREX2 (a regulator of RAC1) in yTNBC. At least ⅔ of the tumors presented mutated oncogenes associated with tumor suppressor genes; the Ras and/or PIK3CA signaling pathways were altered in 15% HGSOC and 20-35% TNBC (Y vs. E); DNA repair genes were mutated in 19-33% of the HGSOC tumors but were more frequently mutated in E-TNBC (56%). However, in HGSOC, 9.5% and 3.3% of the young and elderly patients, respectively, did not present any tumors with an affected CGC nor did 4.65% and none of the young and elderly TNBC patients. CONCLUSION: Most HGSOC and TNBC from young and elderly patients present an affected TSG, mainly TP53, as well as mutational signature 3; however, a few tumors only present an affected oncogene or no affected cancer-causing genes.


Assuntos
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Mutação/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Análise Mutacional de DNA , Reparo do DNA/genética , Feminino , Genes Supressores de Tumor , Variação Genética , Humanos , Gradação de Tumores , Oncogenes
6.
Cells ; 10(12)2021 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-34943931

RESUMO

Phosphatase and tensin homolog deleted on chromosome 10, or PTEN, is a well-characterized tumor suppressor with both lipid and protein phosphatase activities. PTEN is often downregulated by epigenetic mechanisms such as hypermethylation, which leads to constitutive activation of the PI3K-Akt pathway. Large datasets from next-generation sequencing, however, revealed that mutations in PTEN may not only hamper protein function but may also affect interactions with downstream effectors, leading to variable oncogenic readouts. Here, two novel PTEN mutations, Q171R and Y65S, identified in Filipino colorectal cancer patients, were phenotypically characterized in NIH3T3 and HCT116 cells, alongside the C124S canonical mutant and wild-type controls. The novel mutants increased cellular proliferation, resistance to apoptosis and migratory capacity. They induced gross morphological changes including cytoplasmic shrinkage, increased cellular protrusions and extensive cytoskeletal reorganization. The mutants also induced a modest increase in Akt phosphorylation. Further mechanistic studies will help determine the differential oncogenic potencies of these mutants, and resolve whether the structural constraints imposed by the mutations may have altered associations with downstream effectors.


Assuntos
Genes Supressores de Tumor , Mutação/genética , Oncogenes , PTEN Fosfo-Hidrolase/genética , Actinas/metabolismo , Animais , Apoptose , Caspase 3/metabolismo , Caspase 7/metabolismo , Movimento Celular/genética , Proliferação de Células , Forma Celular , Citoesqueleto/metabolismo , Células HCT116 , Humanos , Camundongos , Proteínas Mutantes/metabolismo , Células NIH 3T3 , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo
7.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(10): 1063-1070, 2021 Oct 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34911835

RESUMO

OBJECTIVES: The biomarkers targeting colorectal cancer (CRC) prognosis are short of high accuracy and sensitivity in clinic. Through bioinformatics analysis, we aim to identify and confirm a series of key genes referred to the diagnosis and prognosis of CRC. METHODS: GSE31905, GSE35279, and GSE41657 were selected as complete RNA sequencing data sets of CRC and colorectal mucosa (CRM) tissues from the NCBI-GEO database, and the differentially expressed genes (DEGs) were analyzed. The common DEGs in these 3 data sets were obtained by Venn map, and enriched by STRING network system and Cytoscape software. The Kaplan-Meier plotter website was used to verify the correlation between the enriched genes and the prognosis of CRC. RESULTS: For the whole RNA sequencing data sets of CRC and normal intestinal mucosa samples, the DEGs of CRC and CRM in the 3 data sets (|log2FC|>2 and P<0.05) were screened by GEO2R tool in NCBI-GEO database. By using Venn graph analysis software, the intersection of up-regulated/down-regulated genes in 3 GSE datasets was obtained, and a total 105 up-regulated genes and 140 down-regulated genes were found in the 3 samples. The up-regulated/down-regulated genes were introduced into the STRING network system to obtain the interacting genes. The interacting gene sets were introduced into Cytoscape software, and 61 up-regulated genes were found by Molecular Complex Detection (MCODE) plug-in. Through the Kaplan-Meier plotter website, we found that EPHB2, KLK8, DIAPH3, STC2, OXTR, MMP7, MET, KRT85, KRT6B, KRT23, and KLK10 genes were highly expressed in CRC, and were related to the prognosis. CONCLUSIONS: The above 11 genes verified by bioinformatics retrieval and analysis can predict the poor prognosis of CRC to a certain extent, and they provide a possible target for the diagnosis and treatment of CRC.


Assuntos
Neoplasias Colorretais , Biologia Computacional , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/genética , Forminas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glicoproteínas , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Oncogenes , Prognóstico , Mapas de Interação de Proteínas
8.
BMC Genomics ; 22(1): 833, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34789165

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer. Approximately 80% of patients initially diagnosed with locally advanced or metastatic disease survive only 4-11 months after diagnosis. Tremendous efforts have been made toward understanding the biology of PDAC. RESULTS: In this study, we first utilized next-generation sequencing technique and existing microarray datasets to identify significant differentially expressed genes between PDAC and non-tumor adjacent tissue. By comparing top significant survival genes in PDAC Gene Expression Profiling Interactive Analysis database and PDAC transcriptome data from patients, our integrated analysis discovered five potential central genes (i.e., MYEOV, KCNN4, FAM83A, S100A16, and DDX60L). Subsequently, we analyzed the cellular functions of the potential novel oncogenes MYEOV and DDX60L, which are highly expressed in PDAC cells. Notably, the knockdown of MYEOV and DDX60L significantly inhibited the metastasis of cancer cells and induced apoptosis. Further RNA sequencing analyses showed that massive signaling pathways, particularly the TNF signaling pathway and nuclear factor-kappa B (NF-κB) signaling pathway, were affected in siRNA-treated cancer cells. The siDDX60L and siMYEOV significantly inhibited the expression of chemokine CXCL2, which may potentially affect the tumor microenvironment in PDAC tissues. CONCLUSIONS: The present findings identified the novel oncogene DDX60L, which was highly expressed in PDAC. Transcriptome profiling through siRNA knockdown of DDX60L uncovered its functional roles in the PDAC in humans.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Biomarcadores Tumorais , Carcinoma Ductal Pancreático/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Neoplasias , Oncogenes , Neoplasias Pancreáticas/genética , Microambiente Tumoral
9.
BMC Bioinformatics ; 22(1): 537, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34727887

RESUMO

BACKGROUND: Identification of molecular mechanisms that determine tumour progression in cancer patients is a prerequisite for developing new disease treatment guidelines. Even though the predictive performance of current machine learning models is promising, extracting significant and meaningful knowledge from the data simultaneously during the learning process is a difficult task considering the high-dimensional and highly correlated nature of genomic datasets. Thus, there is a need for models that not only predict tumour volume from gene expression data of patients but also use prior information coming from pathway/gene sets during the learning process, to distinguish molecular mechanisms which play crucial role in tumour progression and therefore, disease prognosis. RESULTS: In this study, instead of initially choosing several pathways/gene sets from an available set and training a model on this previously chosen subset of genomic features, we built a novel machine learning algorithm, PrognosiT, that accomplishes both tasks together. We tested our algorithm on thyroid carcinoma patients using gene expression profiles and cancer-specific pathways/gene sets. Predictive performance of our novel multiple kernel learning algorithm (PrognosiT) was comparable or even better than random forest (RF) and support vector regression (SVR). It is also notable that, to predict tumour volume, PrognosiT used gene expression features less than one-tenth of what RF and SVR algorithms used. CONCLUSIONS: PrognosiT was able to obtain comparable or even better predictive performance than SVR and RF. Moreover, we demonstrated that during the learning process, our algorithm managed to extract relevant and meaningful pathway/gene sets information related to the studied cancer type, which provides insights about its progression and aggressiveness. We also compared gene expressions of the selected genes by our algorithm in tumour and normal tissues, and we then discussed up- and down-regulated genes selected by our algorithm while learning, which could be beneficial for determining new biomarkers.


Assuntos
Aprendizado de Máquina , Neoplasias , Algoritmos , Humanos , Neoplasias/genética , Oncogenes , Carga Tumoral
10.
World J Gastroenterol ; 27(38): 6387-6398, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34720529

RESUMO

Specificity protein (Sp) transcription factors (TFs) Sp1, Sp3 and Sp4, and the orphan nuclear receptor 4A1 (NR4A1) are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patient survival. Results of knockdown and overexpression of Sp1, Sp3 and Sp4 in pancreatic and other cancer lines show that these TFs are individually pro-oncogenic factors and loss of one Sp TF is not compensated by other members. NR4A1 is also a pro-oncogenic factor and both NR4A1 and Sp TFs exhibit similar functions in pancreatic cancer cells and regulate cell growth, survival, migration and invasion. There is also evidence that Sp TFs and NR4A1 regulate some of the same genes including survivin, epidermal growth factor receptor, PAX3-FOXO1, α5- and α6-integrins, ß1-, ß3- and ß4-integrins; this is due to NR4A1 acting as a cofactor and mediating NR4A1/Sp1/4-regulated gene expression through GC-rich gene promoter sites. Several studies show that drugs targeting Sp downregulation or NR4A1 antagonists are highly effective inhibitors of Sp/NR4A1-regulated pathways and genes in pancreatic and other cancer cells, and the triterpenoid celastrol is a novel dual-acting agent that targets both Sp TFs and NR4A1.


Assuntos
Neoplasias Pancreáticas , Fatores de Transcrição , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Oncogenes , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Receptores Citoplasmáticos e Nucleares/genética , Fatores de Transcrição Sp/genética , Fatores de Transcrição Sp/metabolismo , Fatores de Transcrição/genética
12.
Nat Commun ; 12(1): 5906, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625563

RESUMO

Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour microenvironment (TME), multiplexed imaging methods can provide a rich source of information. However, the application of such technologies in mouse tissues is still in its infancy. Here we present a workflow for studying the TME using imaging mass cytometry with a panel of 27 antibodies on frozen mouse tissues. We optimise and validate image segmentation strategies and automate the process in a Nextflow-based pipeline (imcyto) that is scalable and portable, allowing for parallelised segmentation of large multi-image datasets. With these methods we interrogate the remodelling of the TME induced by a KRAS G12C inhibitor in an immune competent mouse orthotopic lung cancer model, highlighting the infiltration and activation of antigen presenting cells and effector cells.


Assuntos
Citometria por Imagem/métodos , Oncogenes , Microambiente Tumoral/imunologia , Animais , Anticorpos , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/imunologia , Modelos Animais de Doenças , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Oncogenes/efeitos dos fármacos , Linfócitos T , Microambiente Tumoral/efeitos dos fármacos
13.
Lung Cancer ; 161: 163-170, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34600407

RESUMO

OBJECTIVES: Programmed death-ligand 1 (PD-L1) expression is a predictive biomarker of response to immunotherapies targeting programmed death-1/PD-L1 in advanced-stage lung adenocarcinoma. The aim of this study was to investigate the associations between PD-L1 expression and clinicopathological features, prognosis, and driver oncogene alterations in patients with lung adenocarcinoma. MATERIALS AND METHODS: We evaluated PD-L1 expression in 1,005 surgically resected lung adenocarcinoma specimens, by immunohistochemistry using the 22C3 antibody. PD-L1 positivity was defined based on the proportion of stained tumor cells (TPS) on tissue microarrays: <1% (negative), 1-49% (weakly positive), and ≥ 50% (strongly positive). Correlations between PD-L1 expression and clinicopathological features, prognosis, and driver oncogene (EGFR, KRAS, ALK, ROS1, and RET) alterations in lung adenocarcinoma were analyzed. RESULTS: PD-L1 expression was negative in 726 (72%) of 1,005 tumors, weakly positive in 161 (16%), and strongly positive in 118 (12%). Male sex, smoking, elevated serum carcinoembryonic antigen levels, advanced pathological stages, high-grade tumors, predominantly solid tumors, tumors with lymphatic permeation or vascular or pleural invasion, tumors without EGFR mutations, and tumors with KRAS mutations were more common in patients with PD-L1-positive tumors (TPS ≥ 1%) than in those with PD-L1-negative tumors (TPS < 1%). PD-L1 positivity was not associated with ALK, ROS1, or RET fusion status. Although PD-L1 positivity was associated with poor overall survival and poor relapse-free survival in all patients, this was not statistically significant after adjusting for prognostic factors in the multivariate analysis. In the subgroup analysis according to driver oncogene alterations, PD-L1 positivity was associated with poor relapse-free survival only in patients with EGFR-mutated tumors. CONCLUSION: Surgically resected lung adenocarcinomas with increased PD-L1 expression were biologically aggressive tumors that frequently occurred in male smokers. PD-L1 expression and its prognostic significance differed according to driver oncogene alterations.


Assuntos
Adenocarcinoma de Pulmão , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Quinase do Linfoma Anaplásico/genética , Antígeno B7-H1/genética , Biomarcadores Tumorais , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Masculino , Recidiva Local de Neoplasia , Oncogenes , Prognóstico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética
14.
BMC Bioinformatics ; 22(Suppl 4): 491, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34689757

RESUMO

BACKGROUND: Genetic information is becoming more readily available and is increasingly being used to predict patient cancer types as well as their subtypes. Most classification methods thus far utilize somatic mutations as independent features for classification and are limited by study power. We aim to develop a novel method to effectively explore the landscape of genetic variants, including germline variants, and small insertions and deletions for cancer type prediction. RESULTS: We proposed DeepCues, a deep learning model that utilizes convolutional neural networks to unbiasedly derive features from raw cancer DNA sequencing data for disease classification and relevant gene discovery. Using raw whole-exome sequencing as features, germline variants and somatic mutations, including insertions and deletions, were interactively amalgamated for feature generation and cancer prediction. We applied DeepCues to a dataset from TCGA to classify seven different types of major cancers and obtained an overall accuracy of 77.6%. We compared DeepCues to conventional methods and demonstrated a significant overall improvement (p < 0.001). Strikingly, using DeepCues, the top 20 breast cancer relevant genes we have identified, had a 40% overlap with the top 20 known breast cancer driver genes. CONCLUSION: Our results support DeepCues as a novel method to improve the representational resolution of DNA sequencings and its power in deriving features from raw sequences for cancer type prediction, as well as discovering new cancer relevant genes.


Assuntos
Aprendizado Profundo , Neoplasias , Humanos , Neoplasias/genética , Oncogenes , Análise de Sequência de DNA , Sequenciamento Completo do Exoma
15.
Cancer Treat Rev ; 100: 102291, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34587557

RESUMO

Non-small cell lung cancer (NSCLC) with oncogenic driver mutations such as EGFR or ALK has a high predilection for brain metastases (BMs) compared to unselected patients. Historically, whole brain radiotherapy (WBRT) was adopted widely for patients with BM. More recently, stereotactic radiosurgery (SRS) has become a standard approach for patients with 1 - 4 metastatic brain lesions. However, data on overall survival benefit with WBRT/SRS compared to target agents are conflicting, with a significant compromise of loss of neurocognitive function. Newer target agents with improved CNS efficacy have challenged the use of early radiotherapy in NSCLC patients with oncogenic driver mutations. Optimal treatment approach and timing of radiotherapy remain unclear, especially under the various clinical contexts. The purpose of this review is to summarize the available data on the possible benefits and risks of early radiotherapy for oncogenic-driven NSCLC patients with brain metastases. Clinical decisions should consider both intracranial efficacy and patient quality of life, given that patients are surviving long enough to experience the long-term consequences of radiation therapy.


Assuntos
Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Encefálicas/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Irradiação Craniana/métodos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Oncogenes , Radiocirurgia/métodos
16.
Front Cell Infect Microbiol ; 11: 704100, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34513727

RESUMO

Objective: To investigate variation in gut microbiome in female patients with invasive mole (IM) and choriocarcinoma (CC) and compare it with healthy controls. Methods: Fecal microbiome of 12 female patients with IM, 9 female patients with CC, and 24 healthy females were analyzed based on 16s rDNA sequencing. Alpha (α) diversity was evaluated using Shannon diversity index and Pielou evenness index, while beta (ß) diversity was assessed using principle coordinate analysis (PCoA) of unweighted Unifrac distances. The potential functional changes of microbiomes were predicted using Tax4Fun. The relative abundance of microbial taxa was compared using Welch's t test. The role of varied gut microbiota was analyzed via receiver operating characteristic (ROC) curve. Results: The α diversity and ß diversity were significantly different between IM patients and controls, but not between CC patients and controls. In addition, the abundance of cancer-related genes was significantly increased in IM and CC patients. Notably, a total of 19 families and 39 genera were found to have significant differences in bacterial abundance. ROC analysis indicated that Prevotella_7 may be a potential biomarker among IM, CC, and controls. Conclusion: Our study demonstrated that the diversity and composition of gut microbiota among IM patients, CC patients, and healthy females were significantly different, which provides rationale for using gut microbiota as diagnostic markers and treatment targets, as well as for further study of gut microbiota in gestational trophoblastic neoplasia (GTN).


Assuntos
Coriocarcinoma , Microbioma Gastrointestinal , Mola Hidatiforme Invasiva , Neoplasias Uterinas , Fezes , Feminino , Humanos , Oncogenes , Gravidez , RNA Ribossômico 16S/genética
17.
Mol Cell ; 81(18): 3672-3674, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34547231

RESUMO

Igelmann et al. report a novel metabolic cycle, which they name HTC, that converts NADH into the key antioxidant factor NADPH. The HTC is repressed by the tumor suppressors p53 and RB, and this determines whether oncogene-expressing cells undergo senescence (HTCoff) or malignant transformation (HTCon).


Assuntos
Senescência Celular , Neoplasias , Senescência Celular/genética , Humanos , Neoplasias/genética , Oncogenes/genética , Oxirredução , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
18.
PLoS Comput Biol ; 17(9): e1009450, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34570764

RESUMO

Understanding relationships between spontaneous cancer in companion (pet) canines and humans can facilitate biomarker and drug development in both species. Towards this end we developed an experimental-bioinformatic protocol that analyzes canine transcriptomics data in the context of existing human data to evaluate comparative relevance of canine to human cancer. We used this protocol to characterize five canine cancers: melanoma, osteosarcoma, pulmonary carcinoma, B- and T-cell lymphoma, in 60 dogs. We applied an unsupervised, iterative clustering method that yielded five co-expression modules and found that each cancer exhibited a unique module expression profile. We constructed cancer models based on the co-expression modules and used the models to successfully classify the canine data. These canine-derived models also successfully classified human tumors representing the same cancers, indicating shared cancer biology between canines and humans. Annotation of the module genes identified cancer specific pathways relevant to cells-of-origin and tumor biology. For example, annotations associated with melanin production (PMEL, GPNMB, and BACE2), synthesis of bone material (COL5A2, COL6A3, and COL12A1), synthesis of pulmonary surfactant (CTSH, LPCAT1, and NAPSA), ribosomal proteins (RPL8, RPS7, and RPLP0), and epigenetic regulation (EDEM1, PTK2B, and JAK1) were unique to melanoma, osteosarcoma, pulmonary carcinoma, B- and T-cell lymphoma, respectively. In total, 152 biomarker candidates were selected from highly expressing modules for each cancer type. Many of these biomarker candidates are under-explored as drug discovery targets and warrant further study. The demonstrated transferability of classification models from canines to humans enforces the idea that tumor biology, biomarker targets, and associated therapeutics, discovered in canines, may translate to human medicine.


Assuntos
Doenças do Cão/genética , Redes Reguladoras de Genes , Neoplasias/genética , Neoplasias/veterinária , Animais , Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/veterinária , Biologia Computacional , Doenças do Cão/classificação , Cães , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/veterinária , Linfoma de Células B/genética , Linfoma de Células B/veterinária , Linfoma de Células T/genética , Linfoma de Células T/veterinária , Melanoma/genética , Melanoma/veterinária , Anotação de Sequência Molecular , Terapia de Alvo Molecular , Neoplasias/classificação , Oncogenes , Osteossarcoma/genética , Osteossarcoma/veterinária , Especificidade da Espécie
19.
Nat Commun ; 12(1): 5574, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552099

RESUMO

In a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17-0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13-0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47-2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Replicação do DNA/genética , Desoxicitidina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores Tumorais/genética , Desoxicitidina/uso terapêutico , Feminino , Humanos , Isoxazóis/uso terapêutico , Mutação , Oncogenes/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Intervalo Livre de Progressão , Pirazinas/uso terapêutico , Reparo de DNA por Recombinação/genética , Proteínas de Ligação a Retinoblastoma/genética
20.
Lung Cancer ; 161: 98-107, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34560426

RESUMO

INTRODUCTION: Non-small-cell lung cancer (NSCLC) is one of the most common and deadly cancers. Several molecular drivers of oncogene addiction are now known to be strong predictive biomarkers for target therapies. Advances in large Next Generation Sequencing (LNGS) have improved the ability to detect potentially targetable mutations. However, the integration of LNGS into clinical management in an individualized manner remains challenging. METHODS: In this single-center observational study we included all patients with advanced NSCLC who underwent LNGS. Somatic and germline exome analysis was performed with a restriction on 323 cancer related genes. Variants were classified and Molecular Tumour Board (MTB) made therapeutic propositions. RESULTS: We performed LNGS analysis in 281 patients with advanced NSCLC between March 2015 and January 2018. Technical failure occurred in only 3% of cases. Three hundred and fifty-six targetable mutations were detected. At least one targetable mutation was found in 209 patients. For all these patients, the MTB was able to recommend treatment with a targeted agent based on the evaluation of the tumour's genetic profile and treatment history. Twenty-nine patients (13.9%) were subsequently treated with an MTB-recommended targeted therapy. We did not observe any improvement in terms of clinical benefit for these patients. CONCLUSIONS: In this case series, we show that including LNGS into routine clinical management was feasible but does not appear to provide clinical benefit in the management of patients with advanced NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Oncogenes
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