scholarly journals Integrative genomic analysis of mouse and human hepatocellular carcinoma

2018 ◽  
Vol 115 (42) ◽  
pp. E9879-E9888 ◽  
Author(s):  
Michelle Dow ◽  
Rachel M. Pyke ◽  
Brian Y. Tsui ◽  
Ludmil B. Alexandrov ◽  
Hayato Nakagawa ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mouse Models ◽  
Cancer Genomics ◽  
Genomic Analysis ◽  
Human Tumors ◽  
Low Grade ◽  
Mhc I ◽  
Molecular Features ◽  
Frequent Mutations

Cancer genomics has enabled the exhaustive molecular characterization of tumors and exposed hepatocellular carcinoma (HCC) as among the most complex cancers. This complexity is paralleled by dozens of mouse models that generate histologically similar tumors but have not been systematically validated at the molecular level. Accurate models of the molecular pathogenesis of HCC are essential for biomedical progress; therefore we compared genomic and transcriptomic profiles of four separate mouse models [MUP transgenic, TAK1-knockout, carcinogen-driven diethylnitrosamine (DEN), and Stelic Animal Model (STAM)] with those of 987 HCC patients with distinct etiologies. These four models differed substantially in their mutational load, mutational signatures, affected genes and pathways, and transcriptomes. STAM tumors were most molecularly similar to human HCC, with frequent mutations in Ctnnb1, similar pathway alterations, and high transcriptomic similarity to high-grade, proliferative human tumors with poor prognosis. In contrast, TAK1 tumors better reflected the mutational signature of human HCC and were transcriptionally similar to low-grade human tumors. DEN tumors were least similar to human disease and almost universally carried the Braf V637E mutation, which is rarely found in human HCC. Immune analysis revealed that strain-specific MHC-I genotype can influence the molecular makeup of murine tumors. Thus, different mouse models of HCC recapitulate distinct aspects of HCC biology, and their use should be adapted to specific questions based on the molecular features provided here.

scholarly journals Characterization of TGFβ-Associated Molecular Features and Drug Responses in Gastrointestinal Adenocarcinoma

2021 ◽  
Author(s):  
Qiaofeng Zhang ◽  
Furong Liu ◽  
Lu Qin ◽  
Zhibin Liao ◽  
Jia Song ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Genomic Analysis ◽  
Molecular Characteristics ◽  
Genomic Changes ◽  
Molecular Features ◽  
Highly Correlated ◽  
Worse Prognosis

Abstract Background: Gastrointestinal adenocarcinoma (GIAD) has caused a serious disease burden globally. Targeted therapy for the transforming growth factor beta (TGF-β) signaling pathway is becoming a reality. However, the molecular characterization of TGF-β in GIAD requires further exploration.Results: The TGF-β­­high group had a worse prognosis in overall GIAD patients, and had a worse prognosis trend in gastric cancer and colon cancer specifically. Signatures (including mRNA and proteins) of the TGF-β­­high group is highly correlated with EMT. According to miRNA analysis, miR-215-3p, miR-378a-5p, and miR-194-3p may block the effect of TGF-β. Further genomic analysis showed that TGF-β­­low group had more genomic changes in gastric cancer, such as TP53 mutation, EGFR amplification, and SMAD4 deletion. And drug response dataset revealed sensitive drugs or drug resistant drugs corresponding to TGF-β associated mRNAs. Finally, the DNN model showed an excellent predictive effect in predicting TGF-β status in different GIAD datasets.Conclusions: Our study provided a comprehensive analysis of the molecular characteristics associated with TGF-β and provides possible therapeutic targets in GIAD.

scholarly journals Cancer epigenome: A review

2005 ◽  
Vol 13 (3-4) ◽  
pp. 108-114 ◽  
Author(s):  
Bogomir Dimitrijevic
Keyword(s):  
Tumor Suppressor Genes ◽  
Genetic Basis ◽  
Cancer Genomics ◽  
Mutational Analysis ◽  
Large Database ◽  
Cpg Sites ◽  
Molecular Features ◽  
Cancer Phenotype ◽  
Cell Genome

Cancer genomics that normally relies on mutational analysis of oncogenes and tumor suppressor genes has approached its inherent limits. This was not much of a surprise having in mind the genome dynamics and the resulting complexity of cancer phenotype and genotype. In response to this challenge, molecular genetics offered a new armory for the analysis of the genetic basis of cancer. This refers to the analysis of molecular features that regulate gene activity and the analysis of products of this activity. In the focus of tuning transcription is the methylation surveillance of the genome of the cell. Modification of proteins associated with chromatin and methylation of CpG sites in DNA was found to affect profoundly gene expression and is commonly termed epigenomics. Quantitative and qualitative characterization of the methylation profile of the cancer cell genome is formidable but necessary task with great potential for molecular pathology of cancer. There is little doubt that this line of research will add a great deal to the clinical practice and the basic science of oncology. The only question is how to make a large database large enough and how select the most reliable and sensitive technological approach with the highest throughput.

Solid-Pseudopapillary Neoplasm: A Pancreatic Enigma

2009 ◽  
Vol 133 (12) ◽  
pp. 1989-1993 ◽  
Author(s):  
Zaher I. Chakhachiro ◽  
Ghazi Zaatari
Keyword(s):  
Surgical Excision ◽  
Needle Aspiration ◽  
Low Grade ◽  
Cell Of Origin ◽  
Solid Pseudopapillary Neoplasm ◽  
Molecular Features ◽  
Complete Surgical Excision ◽  
Histopathologic Evaluation ◽  
Almost All

Abstract Solid-pseudopapillary neoplasm of the pancreas is a relatively uncommon tumor. It typically affects young women, has nonspecific clinical and radiologic manifestations, and can be readily diagnosed by ultrasound-guided fine-needle aspiration and histopathologic evaluation. Histologic features characteristically show loosely cohesive, relatively uniform polygonal cells surrounding delicate capillary-sized blood vessels. Other features include cytoplasmic vacuolization, finely stippled chromatin, nuclear grooving, eosinophilic hyaline globules, and degenerative changes. Almost all solid-pseudopapillary neoplasms harbor mutations in the β-catenin gene. They stain with β-catenin, CD10, and focally with neuroendocrine markers. Although previously considered benign, this tumor is currently considered a low-grade malignant epithelial neoplasm with low metastatic rate and high overall survival. Most patients are cured by complete surgical excision. Despite the characterization of the morphologic and molecular features of this enigmatic neoplasm, more work is needed to uncover its cell of origin and true histogenesis.

scholarly journals Neuroendocrine Lung Cancer Mouse Models: An Overview

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 14
Author(s):  
Corina Lorz ◽  
Marta Oteo ◽  
Mirentxu Santos
Keyword(s):  
Lung Cancer ◽  
Molecular Imaging ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Somatostatin Receptors ◽  
Unmet Need ◽  
Human Tumors ◽  
Low Grade ◽  
Cell Lung Carcinoma

Neuroendocrine lung tumors comprise a range of malignancies that extend from benign tumorlets to the most prevalent and aggressive Small Cell Lung Carcinoma (SCLC). They also include low-grade Typical Carcinoids (TC), intermediate-grade Atypical Carcinoids (AC) and high-grade Large Cell Neuroendocrine Carcinoma (LCNEC). Optimal treatment options have not been adequately established: surgical resection when possible is the choice for AC and TC, and for SCLC chemotherapy and very recently, immune checkpoint inhibitors. Some mouse models have been generated based on the molecular alterations identified in genomic analyses of human tumors. With the exception of SCLC, there is a limited availability of (preclinical) models making their development an unmet need for the understanding of the molecular mechanisms underlying these diseases. For SCLC, these models are crucial for translational research and novel drug testing, given the paucity of human material from surgery. The lack of early detection systems for lung cancer point them out as suitable frameworks for the identification of biomarkers at the initial stages of tumor development and for testing molecular imaging methods based on somatostatin receptors. Here, we review the relevant models reported to date, their impact on the understanding of the biology of the tumor subtypes and their relationships, as well as the effect of the analyses of the genetic landscape of the human tumors and molecular imaging tools in their development.

scholarly journals Characterization of TGFβ-associated molecular features and drug responses in gastrointestinal adenocarcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qiaofeng Zhang ◽  
Furong Liu ◽  
Lu Qin ◽  
Zhibin Liao ◽  
Jia Song ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Transforming Growth Factor Beta ◽  
Drug Response ◽  
Transforming Growth Factor ◽  
Genomic Analysis ◽  
Copy Number Variations ◽  
Molecular Features ◽  
Different Levels ◽  
Worse Prognosis

Abstract Background Gastrointestinal adenocarcinoma (GIAD) has caused a serious disease burden globally. Targeted therapy for the transforming growth factor beta (TGF-β) signaling pathway is becoming a reality. However, the molecular characterization of TGF-β associated signatures in GIAD requires further exploration. Methods Multi-omics data were collected from TCGA and GEO database. A pivotal unsupervised clustering for TGF-β level was performed by distinguish status of TGF-β associated genes. We analyzed differential mRNAs, miRNAs, proteins gene mutations and copy number variations in both clusters for comparison. Enrichment of pathways and gene sets were identified in each type of GIAD. Then we performed differential mRNA related drug response by collecting data from GDSC. At last, a summarized deep neural network for TGF-β status and GIADs was constracted. Results The TGF-βhigh group had a worse prognosis in overall GIAD patients, and had a worse prognosis trend in gastric cancer and colon cancer specifically. Signatures (including mRNA and proteins) of the TGF-βhigh group is highly correlated with EMT. According to miRNA analysis, miR-215-3p, miR-378a-5p, and miR-194-3p may block the effect of TGF-β. Further genomic analysis showed that TGF-βlow group had more genomic changes in gastric cancer, such as TP53 mutation, EGFR amplification, and SMAD4 deletion. And drug response dataset revealed tumor-sensitive or tumor-resistant drugs corresponding to TGF-β associated mRNAs. Finally, the DNN model showed an excellent predictive effect in predicting TGF-β status in different GIAD datasets. Conclusions We provide molecular signatures associated with different levels of TGF-β to deepen the understanding of the role of TGF-β in GIAD and provide potential drug possibilities for therapeutic targets in different levels of TGF-β in GIAD.

Molecular characterization of NSCLC-like and SCLC-like subsets in Chinese pulmonary large cell neuroendocrine carcinoma (LCNEC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13125-e13125
Author(s):  
Lin Wu ◽  
Liming Cao ◽  
Likun Chen ◽  
Bo Zhu ◽  
Xiaohua HU ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Large Cell ◽  
Molecular Characteristics ◽  
Molecular Features ◽  
Cancer Related Gene ◽  
Ffpe Samples ◽  
Chinese Cohort ◽  
Frequent Mutations ◽  
Tcga Dataset

e13125 Background: LCNEC is an aggressive, biologically heterogenous carcinoma which can be molecularly characterized as SCLC-like and NSCLC-like. Accurate distinction of molecular subset is of major clinical relevance since it may guide treatment choices in LCNEC. Here we determined the genomic characteristics of the two LCNEC subsets in a Chinese cohort to clarify their correlations with traditional lung cancer histologies. Methods: FFPE samples from 31 LCNECs were sequenced using a 520-cancer-related gene panel, with an average sequencing depth of 1353X. Comparative mutational analysis was conducted between NSCLC-like LCNECs from our cohort and adenocarcinomas from TCGA dataset. Results: Despite similar clinical features in terms of stage and age at diagnosis, NSCLC-like (42%, 13/31) and SCLC-like (32%, 10/31) subsets from LCNEC displayed distinct molecular characteristics. NSCLC-like subset harbored significant higher mutation frequencies of STK11, KEAP1 and FAT3 (53.8%, 38.5% and 38.5%, p = .007, .046 and .046), while SCLC-like subset was characterized by highly mutated RB1 (100%, p < .001) and PTEN (50%, p = .007). Compared with TCGA adenocarcinomas, NSCLC-like LCNEC displayed more frequent mutations in TP53, STK11, APC, KMT2D and SMARCA4 (76.9%, 53.8%, 30.8%, 30.8% and 23.1%; p = .043, .004, .045, .005 and .049). In addition, potential targetable alterations were present in 46.2% (6/13) pts of NSCLC-like subset. For those advanced stage pts, 2/5 NSCLC-like and 5/5 SCLC-like pts received relevant chemotherapy according to their molecular characteristics. The clinical outcomes of these pts are still under follow-up. Conclusions: This study demonstrates the distinct molecular features between NSCLC-like and SCLC-like subsets, and highlights the predominant genomic similarity and separate entities between NSCLC-like LCNEC with adenocarcinoma. Given the evidence that genomic profiling may aid in informing treatment decisions for pts with LCNEC, our study indicates that, based on accurate molecular typing, 46.2% NSCLC-like pts may benefit from potential targeted therapy and the rest of them may be more suitable to receive NSCLC-chemotherapy.

scholarly journals Generation of diffuse intrinsic pontine glioma mouse models by brainstem targeted in utero electroporation

2019 ◽  
Author(s):  
Smruti K Patel ◽  
Rachel M Hartley ◽  
Xin Wei ◽  
Robin Furnish ◽  
Fernanda Escobar-Riquelme ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Mouse Models ◽  
Rapid Development ◽  
In Utero ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Dominant Negative ◽  
Low Grade ◽  
In Utero Electroporation ◽  
Molecular Features

Abstract Background Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal childhood brain tumors. Their unique genetic makeup, pathological heterogeneity, and brainstem location all present challenges to treatment. Developing mouse models that accurately reflect each of these distinct features will be critical to advance our understanding of DIPG development, progression, and therapeutic resistance. The aim of this study was to generate new mouse models of DIPG, and characterize the role of specific oncogenic combinations in DIPG pathogenesis. Methods We used in utero electroporation (IUE) to transfect neural stem cells in the developing brainstem with PiggyBac DNA transposon plasmids. Combinations of PDGFB, PdgfraD842V, or PdgfraWT, combined with dominant negative Trp53 (DNp53) and H3.3K27M expression induced fully penetrant brainstem gliomas. Results IUE enabled the targeted transfection of brainstem neural stem cells. PDGFB + DNp53 + H3.3K27M induced the rapid development of grade-IV gliomas. PdgfraD842V + DNp53 + H3.3K27M produced slower forming grade-III gliomas. PdgfraWT + DNp53 + H3.3K27M produced high and low-grade gliomas with extended latencies. PDGFB, PdgfraD842V, and PdgfraWT DIPG models display unique histopathological and molecular features found in human DIPGs. Conclusion Brainstem targeted in utero electroporation provides a rapid and flexible system to generate diverse DIPG mouse models. Using IUE to investigate mutation and pathohistological heterogeneity of DIPG will provide a valuable tool for future genetic and preclinical studies.

scholarly journals Genomic Perspective on Mouse Liver Cancer Models

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1648
Author(s):  
Sun Young Yim ◽  
Ju-Seog Lee
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mouse Models ◽  
Mouse Liver ◽  
Cancer Genomics ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Genomic Data ◽  
Preclinical Research ◽  
Cancer Models ◽  
Distinct Aspect

Selecting the most appropriate mouse model that best recapitulates human hepatocellular carcinoma (HCC) allows translation of preclinical mouse studies into clinical studies. In the era of cancer genomics, comprehensive and integrative analysis of the human HCC genome has allowed categorization of HCC according to molecular subtypes. Despite the variety of mouse models that are available for preclinical research, there is a lack of evidence for mouse models that closely resemble human HCC. Therefore, it is necessary to identify the accurate mouse models that represent human HCC based on molecular subtype as well as histologic aggressiveness. In this review, we summarize the mouse models integrated with human HCC genomic data to provide information regarding the models that recapitulates the distinct aspect of HCC biology and prognosis based on molecular subtypes.

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