scholarly journals MYC amplification at diagnosis drives therapy-induced hypermutation of recurrent glioma

2021 ◽  
Author(s):  
Jiguang Wang ◽  
Quanhua Mu ◽  
Ruichao Chai ◽  
Hanjie Liu ◽  
Yingxi Yang ◽  
...  
Keyword(s):  
Machine Learning ◽  
Cancer Progression ◽  
Target Genes ◽  
Clonal Evolution ◽  
Active Regions ◽  
Open Chromatin ◽  
Diffuse Glioma ◽  
Cancer Evolution ◽  
Loss Of Function ◽  
Learning Platform

Abstract Clonal evolution drives cancer progression and therapeutic resistance1-2. Recent longitudinal analyses revealed divergent clonal dynamics in adult diffuse gliomas3–11. However, the early genomic and epigenomic factors that steer post-treatment molecular trajectories remain unknown. To track evolutionary predictors, we analyzed sequencing and clinical data of matched initial-recurrent tumor pairs from 511 adult diffuse glioma patients. Using machine learning we developed methods capable of predicting grade progression and hypermutation from tumor characteristics at diagnosis. Strikingly, MYC copy number gain in initial tumors emerged as a key factor predicting development of hypermutation under temozolomide (TMZ) treatment. The driving role of MYC in TMZ-associated hypermutagenesis has been experimentally validated in a model of TMZ-induced hypermutator using both patient-derived gliomaspheres and established glioma cell lines. Subsequent studies showed that c-Myc binding to open chromatin and transcriptionally active regions increases the vulnerability of genomic regions to TMZ-induced mutagenesis. Consequently, MYC target genes, including the key mismatch repair genes, develop loss-of-function mutations, thus triggering the hypermutation process. This study reveals MYC as an early predictor of cancer evolution and provides a machine learning platform for predicting cancer dynamics to improve patient management.

scholarly journals Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma

2020 ◽  
Vol 318 (3) ◽  
pp. G419-G427 ◽  
Author(s):  
Tatsuhide Nabeshima ◽  
Shin Hamada ◽  
Keiko Taguchi ◽  
Yu Tanaka ◽  
Ryotaro Matsumoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cancer Progression ◽  
Stress Responses ◽  
Target Genes ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Related Factor ◽  
Loss Of Function ◽  
P53 Expression ◽  
Nrf2 Activation

The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/ p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/ p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/ p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma. NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.

Measuring parameters of the cancer ecosystem for cancer ecological staging.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14684-e14684
Author(s):  
James R. Cunningham ◽  
Jon Rittenbach ◽  
Mitch Clemens ◽  
Cheryl Dodd ◽  
Ashley Wilson ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Clonal Evolution ◽  
Genetic Selection ◽  
Staging System ◽  
Patient Questionnaire ◽  
Tumor Evolution ◽  
Cancer Evolution ◽  
Level Of Selection ◽  
Ecological Profiles ◽  
Active Cancer

e14684 Background: Cancer progression through clonal evolution and emergent phenotypic heterogeneity is thought to reflect stochastic events such as genetic drift. This divergence over time in the character of a neoplasm might also reflect genetic selection, analogous to other populations in nature, to maximize niche resource utilization. We hypothesized that selection pressures operate in patients with cancer to drive cancer evolution, are clinically identifiable, their influence measurable. Methods: To develop a system for cancer ecology staging, a feasibility study recruited 15 patients with active cancer from any site, with expected survival of more than 6 months and providing informed consent. A set of clinical parameters obtained from a patient questionnaire, physical exam and laboratory testing was used to generate eight separate ecological profiles of tumor microenvironment, chronic inflammation, energy balance, psychosocial stress, GI microbiome, endocrine environment, skeletal remodeling and environmental mutagenesis. A scoring system, based on evidence of positive selection was designed to quantitate the individual profiles. Profile scores were then aggregated using a 2-D radar plot to generate a polygon, an ‘ecogram’, whose area, it is hypothesized, corresponds to the net level of selection pressure influencing tumor evolution. Results: Ecological profiles were obtained from each of 15 patients allowing determination of the ecogram area (EA) bounded by the polygon. EA determinations ranged widely among the 15 patient, from 0-12.7 arbitrary units (au, mean 5.01± 0.80). Ecograms from individual patients demonstrated unique shapes suggesting specificity for individual patient ecology. EA measurements were then used to inform an ecological staging system based on a simplified dichotomization, low/high, of ecosystem resources and threats. Of 15 patients, 6 were considered to have high resources (EA > 5au) available to support tumor evolution. High anti-tumor threat, measured by CD3 lymphocyte immunohistochemical scoring, was detected in 11 patients. Conclusions: An ecological assessment of patients with active cancer appears feasible. Inter-patient variation in ecogram area and morphology suggests there are potential important differences in genetic selection found between patients and should be correlated with survival outcomes in future studies, validation offering a target for ecosystem ‘restoration’.

scholarly journals Overexpression of NELFE contributes to gastric cancer progression via Wnt/β-catenin signaling-mediated activation of CSNK2B expression

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Shijun Yu ◽  
Li Li ◽  
Hui Cai ◽  
Bin He ◽  
Yong Gao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Target Genes ◽  
Mrna Level ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Mice Model ◽  
Qrt Pcr

Abstract Background Accumulating evidence has highlighted the importance of negative elongation factor complex member E (NELFE) in tumorigenesis. However, the relationship between NELFE and gastric cancer (GC) remains unclear. This study aimed to explore the expression pattern and specific function of NELFE in GC. Methods NELFE expression was evaluated by immunohistochemistry and qRT-PCR in GC tissues, respectively. Cell proliferation, migration and invasion were measured by CCK-8, colony formation, transwell assays, and nude mice model. Bioinformatics analysis was performed to search potential target genes of NELFE, and a Cignal Finder 10-Pathway Reporter Array was used to explore potential signaling pathways regulated by NELFE. Dual-luciferase reporter assays, qRT-PCR and western blotting were conducted to verify their regulatory relationship. The expression correlations among NELFE, β-catenin and CSNK2B were further explored by immunohistochemistry on consecutive resections. Results NELFE was significantly overexpressed in GC tissues both in protein and mRNA level and negatively correlated with the prognosis of GC patients. Gain- and loss-of-function experiments showed that NELFE potentiated GC cell proliferation and metastasis in vitro and in vivo. CSNK2B was identified as a downstream effector of NELFE. Wnt/β-catenin signaling may mediate the regulation of CSNK2B by NELFE. In addition, NELFE, β-catenin and CSNK2B were all remarkably upregulated in tumor tissues compared with adjacent normal tissues, and their expression levels in GC were positively correlated with each other. Conclusion Our findings reveal a new NELFE-Wnt/β-catenin-CSNK2B axis to promote GC progression and provide new candidate targets against this disease.

scholarly journals FOXM1 is a molecular determinant of the mitogenic and invasive phenotype of anaplastic thyroid carcinoma

2012 ◽  
Vol 19 (5) ◽  
pp. 695-710 ◽  
Author(s):  
Roberto Bellelli ◽  
Maria Domenica Castellone ◽  
Ginesa Garcia-Rostan ◽  
Clara Ugolini ◽  
Carmelo Nucera ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Cancer Progression ◽  
Target Genes ◽  
Cyclin B1 ◽  
Anaplastic Thyroid Carcinoma ◽  
Loss Of Function ◽  
Thyroid Carcinomas ◽  
Forkhead Box

Anaplastic thyroid carcinoma (ATC) is a very aggressive thyroid cancer. forkhead box protein M1 (FOXM1) is a member of the forkhead box family of transcription factors involved in control of cell proliferation, chromosomal stability, angiogenesis, and invasion. Here, we show that FOXM1 is significantly increased in ATCs compared with normal thyroid, well-differentiated thyroid carcinomas (papillary and/or follicular), and poorly differentiated thyroid carcinomas (P=0.000002). Upregulation of FOXM1 levels in ATC cells was mechanistically linked to loss-of-function of p53 and to the hyperactivation of the phosphatidylinositol-3-kinase/AKT/FOXO3a pathway. Knockdown of FOXM1 by RNA interference inhibited cell proliferation by arresting cells in G2/M and reduced cell invasion and motility. This phenotype was associated with decreased expression of FOXM1 target genes, like cyclin B1 (CCNB1), polo-like kinase 1 (PLK1), Aurora B (AURKB), S-phase kinase-associated protein 2 (SKP2), and plasminogen activator, urokinase: uPA (PLAU). Pharmacological inhibition of FOXM1 in an orthotopic mouse model of ATC reduced tumor burden and metastasization. All together, these findings suggest that FOXM1 represents an important player in thyroid cancer progression to the anaplastic phenotype and a potential therapeutic target for this fatal cancer.

Oligometastatic prostate cancer patients stratification: A molecular signature identified by liquid biopsy.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS400-TPS400 ◽  
Author(s):  
Luca Triggiani ◽  
Lilia Bardoscia ◽  
Antonella Colosini ◽  
Simona Bernardi ◽  
Roberto Bresciani ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Peripheral Blood ◽  
Liquid Biopsy ◽  
Target Genes ◽  
Clonal Evolution ◽  
Initial Step ◽  
Molecular Signature ◽  
Rapid Progression ◽  
Oligometastatic Prostate Cancer

TPS400 Background: Oligometastatic prostate cancer (OPC) may represent the initial step of an unavoidable, rapid progression to a polymetastatic state, or the expression of a real oligometastatic phenotype related to a condition of stable disease for a long time. In the last scenario, stereotactic body radiation therapy (SBRT) can be considered as a potentially curative treatment option for hormone-naïve OPC. We propose a prospective, explorative trail with the aim of identifying by liquid biopsy a molecular signature (genes or differential expression of miRNA), and related clonal evolution, underlying metastatic prostate cancer progression after a course of SBRT. Methods: Study population will be 30 adult, hormone-naïve OPC undergoing SBRT. Table 1 summarizes gene and miRNA panel for molecular analysis. For each patient, 15 ml of peripheral blood will be collected before and at the end of SBRT, every 3 months for the first year, then every 6 months until disease progression, when another blood sample will be collected in case of instrumental evidence of failure (using PET-Choline or CT-scan plus bone scintigraphy). 7.5 ml of peripheral blood will be centrifuged to separate sera and 7.5 ml of peripheral blood will be centrifuged to separate plasma from the other blood components, respectively. Sera and plasma will be stored at -20°C and centralized to CREA Laboratory at our Institution, then immediately processed for cell free DNA (cfDNA) and miRNA extraction for NGS of target genes (by Illumina platforms MiSeq and MiniSeq) and dPCR analysis. Study duration will be 36 months. This protocol has been written and will be conducted in agreement with either the Declaration of Helsinki and subsequent amendments and ICH Harmonized Tripartite Guideline for Good Clinical Practice, and has received approval of local Ethics Committee. Panel for analysis. [Table: see text]

scholarly journals The Role of p53 Signaling in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2125
Author(s):  
Magdalena C. Liebl ◽  
Thomas G. Hofmann
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Tp53 Gene ◽  
Cellular Responses ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Wild Type ◽  
P53 Signaling ◽  
Stress Signals

The transcription factor p53 functions as a critical tumor suppressor by orchestrating a plethora of cellular responses such as DNA repair, cell cycle arrest, cellular senescence, cell death, cell differentiation, and metabolism. In unstressed cells, p53 levels are kept low due to its polyubiquitination by the E3 ubiquitin ligase MDM2. In response to various stress signals, including DNA damage and aberrant growth signals, the interaction between p53 and MDM2 is blocked and p53 becomes stabilized, allowing p53 to regulate a diverse set of cellular responses mainly through the transactivation of its target genes. The outcome of p53 activation is controlled by its dynamics, its interactions with other proteins, and post-translational modifications. Due to its involvement in several tumor-suppressing pathways, p53 function is frequently impaired in human cancers. In colorectal cancer (CRC), the TP53 gene is mutated in 43% of tumors, and the remaining tumors often have compromised p53 functioning because of alterations in the genes encoding proteins involved in p53 regulation, such as ATM (13%) or DNA-PKcs (11%). TP53 mutations in CRC are usually missense mutations that impair wild-type p53 function (loss-of-function) and that even might provide neo-morphic (gain-of-function) activities such as promoting cancer cell stemness, cell proliferation, invasion, and metastasis, thereby promoting cancer progression. Although the first compounds targeting p53 are in clinical trials, a better understanding of wild-type and mutant p53 functions will likely pave the way for novel CRC therapies.

scholarly journals Mutational likeliness and entropy help to identify driver mutations and their functional role in cancer

2018 ◽  
Author(s):  
Giorgio Mattiuz ◽  
Salvatore Di Giorgio ◽  
Lorenzo Tofani ◽  
Antonio Frandi ◽  
Francesco Donati ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Somatic Mutations ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Loss Of Function ◽  
Driver Genes ◽  
Cancer Driver ◽  
Cancer Genomes ◽  
Passenger Mutations ◽  
Mutational Processes

AbstractAlterations in cancer genomes originate from mutational processes taking place throughout oncogenesis and cancer progression. We show that likeliness and entropy are two properties of somatic mutations crucial in cancer evolution, as cancer-driver mutations stand out, with respect to both of these properties, as being distinct from the bulk of passenger mutations. Our analysis can identify novel cancer driver genes and differentiate between gain and loss of function mutations.

scholarly journals Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by PU.1

2018 ◽  
Author(s):  
Jonas Ungerbäck ◽  
Hiroyuki Hosokawa ◽  
Xun Wang ◽  
Tobias Strid ◽  
Brian A. Williams ◽  
...  
Keyword(s):  
T Cell ◽  
Dna Binding ◽  
Target Genes ◽  
Dynamic Properties ◽  
Chromatin Accessibility ◽  
Site Quality ◽  
Open Chromatin ◽  
Loss Of Function ◽  
Dna Binding Domains ◽  
Binding Domains

AbstractPU.1 is a dominant but transient regulator in early T-cell precursors and a potent transcriptional controller of developmentally important pro-T cell genes. Before T-lineage commitment, open chromatin is frequently occupied by PU.1, and many PU.1 sites lose accessibility when PU.1 is later downregulated. Pioneering activity of PU.1 was tested in in this developmentally dynamic context, by quantitating the relationships between PU.1 occupancy and site quality and accessibility as PU.1 levels naturally declined in pro-T cell development, and by using stage-specific gain and loss of function perturbations to relate binding to effects on target genes. PU.1 could bind closed genomic sites, but rapidly opened many of them, despite the absence of its frequent collaborators, C/EBP factors. The dynamic properties of PU.1 engagements implied that PU.1 binding affinity and concentration determine its occupancy choices, but with quantitative tradeoffs for occupancy between site sequence quality and stage-dependent site accessibility in chromatin. At non-promoter sites PU.1 binding criteria were more stringent than at promoters, and PU.1 was also much more effective as a transcriptional regulator at non-promoter sites where local chromatin accessibility depended on the presence of PU.1. Runx motifs and Runx1 binding were often linked to PU.1 at open sites, but highly expressed PU.1 could bind its sites without Runx1. Notably, closed chromatin presented a qualitative barrier to occupancy by the PU.1 DNA binding domain alone. Thus, effective pioneering at closed chromatin sites also depends on requirements beyond site recognition served by non-DNA binding domains of PU.1.

Role of MicroRNAs in Colon Cancer Progression and Metastasis

2020 ◽  
Vol 20 ◽  
Author(s):  
Shruthi Sanjitha Sampath ◽  
Sivaramakrishnan Venkatabalsubramanian ◽  
Satish Ramalingam
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Tumour Progression ◽  
Intestinal Barrier ◽  
Colon Cancer Progression ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Novel Therapeutic Strategies

: MicroRNAs regulate gene expression at the posttranscriptional level by binding to the mRNA of their target genes. The dysfunction of miRNAs is strongly associated with the inflammation of the colon. Besides, some microRNAs are shown to suppress tumours while others promote tumour progression and metastasis. Inflammatory bowel diseases include Crohn’s disease and Ulcerative colitis which increase the risk factor for inflammation-associated colon cancer. MicroRNAs are shown to be involved in gastrointestinal pathologies, by targeting the transcripts encoding proteins of the intestinal barrier and their regulators that are associated with inflammation and colon cancer. Detection of these microRNAs in the blood, serum, tissues, faecal matter, etc will enable us to use these microRNAs as biomarkers for early detection of the associated malignancies and design novel therapeutic strategies to overcome the same. Information on MicroRNAs can be applied for the development of targeted therapies against inflammation-mediated colon cancer.

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