scholarly journals Cancer Genetics and Epigenetics in Cancer Risk Assesment

2021 ◽  
Vol 5 (2) ◽  
pp. 41
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
Cancer Cells ◽  
Cancer Genetics ◽  
Point Mutations ◽  
Genetic Alterations ◽  
Genetic Mutations ◽  
Control Mechanisms ◽  
Normal Tissues ◽  
Knowing That ◽  
Whole Exome ◽  
Methylation Patterns

Compared to the normal tissues, cancer cells tend to have higher proliferation rate and often lost their ability to undergo apoptosis. In addition, cancer cells can separate themselves from their original tissue thus causing metastasis in other part of body. While undergoing program cell death, disordered cellular programming can happen. The main causes of this cellular programming anomaly are epigenetic and genetic alterations, which have been known as two separate mechanisms in carcinogenetic. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disturb the DNA methylation patterns, histone modifications, and nucleosome positioning, hence, the causing gene expression alternation. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. Epigenetic mechanisms changes could cause genetic mutations, and genetic mutations in epigenetic regulators could cause epigenome changes. Knowing that epigenome play a major role in the hierarchy of gene control mechanisms suggests that mutations might have impact on multiple pathways related to cancer phenotype. This pinpoint the fact that recently, the way the genes are organized and controlled are suggested to be a relevant factor for human carcinogenesis.Keywords: cancer genetic, cancer epigenetic, oncogens, tumor suppressor genes, driver mutation, passenger mutation

scholarly journals Genotypes and Phenotypes of MEF2C Haploinsufficiency Syndrome: New Cases and Novel Point Mutations

2021 ◽  
Vol 9 ◽  
Author(s):  
Lin Wan ◽  
Xinting Liu ◽  
Linyan Hu ◽  
Huimin Chen ◽  
Yulin Sun ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Poor Performance ◽  
Genetic Alterations ◽  
Mendelian Inheritance ◽  
Whole Exome ◽  
Patients With Epilepsy ◽  
Free Status

Aim: MEF2C haploinsufficiency syndrome (MCHS) is a severe neurodevelopmental disorder. We describe the clinical phenotypes and genotypes of seven patients with MCHS to enhance the understanding of clinical manifestations and genetic alterations associated with MCHS.Method: Seven patients (6 females and 1 male, aged between 2 years 5 months and 6 years) who had MEF2C mutations, and their parents underwent trio-based whole-exome sequencing; subsequently, their clinical features were assessed. A literature review of patients with MCHS was performed by searching the PubMed and Online Mendelian Inheritance in Man databases.Results: Seven mutations were identified, of which six were unreported in the past; of the reported cases, five patients had de novo mutations but two had an undefined inheritance pattern. All patients presented delays in developmental milestones, severe intellectual disabilities and lack of speech. Six patients exhibited infantile hypotonia, five patients experienced stereotypic movements and were unable to walk, four patients exhibited poor eye contact indicative of autism and two showed poor performance. While six patients experienced seizure, five among them became seizure free after receiving anti-seizure medicine. Three patients showed a regression in their development, whereas the mothers of two patients exhibited mosaicism but were healthy without any abovementioned symptoms.Interpretation: Regression was not a common phenomenon but occurred in MCHS. The prognosis of MCHS patients with epilepsy was good, but most patients can achieve a seizure-free status. Healthy people may have low-level mosaicism and carry a pathogenic MEF2C mutation.

scholarly journals Integrative Bioinformatics Study of Tangeretin Potential Targets for Preventing Metastatic Breast Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Adam Hermawan ◽  
Herwandhani Putri ◽  
Naufa Hanif ◽  
Muthi Ikawati
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Genetic Alterations ◽  
Pathway Enrichment ◽  
Normal Tissues ◽  
Kaplan Meier

Agents that target metastasis are important to improve treatment efficacy in patients with breast cancer. Tangeretin, a citrus flavonoid, exhibits antimetastatic effects on breast cancer cells, but its molecular mechanism remains unclear. Tangeretin targets were retrieved from PubChem, whereas metastatic breast cancer regulatory genes were downloaded from PubMed. In total, 58 genes were identified as potential therapeutic target genes of tangeretin (PTs). GO and KEGG pathway enrichment analyses of PTs were performed using WebGestalt (WEB-based Gene SeT AnaLysis Toolkit). The PPI network was analyzed using STRING-DB v11.0 and visualized by Cytoscape software. Hub genes were selected on the basis of the highest degree score as calculated by the CytoHubba plugin. Genetic alterations of the PTs were analyzed using cBioPortal. The prognostic values of the PTs were evaluated with the Kaplan–Meier plot. The expression of PTs across breast cancer samples was confirmed using GEPIA. The reliability of the PTs in metastatic breast cancer cells was validated using ONCOMINE. Molecular docking was performed to foresee the binding sites of tangeretin with PIK3Cα, MMP9, PTGS2, COX-2, and IKK. GO analysis showed that PTs participate in the biological process of stimulus response, are the cellular components of the nucleus and the membrane, and play molecular roles in enzyme regulation. KEGG pathway enrichment analysis revealed that PTs regulate the PI3K/Akt pathway. Genetic alterations for each target gene were MTOR (3%), NOTCH1 (4%), TP53 (42%), MMP9 (4%), NFKB1 (3%), PIK3CA (32%), PTGS2 (15%), and RELA (5%). The Kaplan–Meier plot showed that patients with low mRNA expression levels of MTOR, TP53, MMP9, NFKB1, PTGS2, and RELA and high expression of PIK3CA had a significantly better prognosis than their counterparts. Further validation of gene expression by using GEPIA revealed that the mRNA expression of MMP9 was significantly higher in breast cancer tissues than in normal tissues, whereas the mRNA expression of PTGS2 showed the opposite. Analysis with ONCOMINE demonstrated that the mRNA expression levels of MMP9 and NFKB1 were significantly higher in metastatic breast cancer cells than in normal tissues. The results of molecular docking analyses revealed the advantage of tangeretin as an inhibitor of PIK3CA, MMP9, PTGS2, and IKK. Tangeretin inhibits metastasis in breast cancer cells by targeting TP53, PTGS2, MMP9, and PIK3CA and regulating the PI3K/Akt signaling pathway. Further investigation is needed to validate the results of this study.

scholarly journals Epigenetic Regulation of Angiogenesis in Development and Tumors Progression: Potential Implications for Cancer Treatment

2021 ◽  
Vol 9 ◽  
Author(s):  
Veronica Mãdãlina Aspriţoiu ◽  
Ileana Stoica ◽  
Coralia Bleotu ◽  
Carmen Cristina Diaconu
Keyword(s):  
Cancer Cells ◽  
Current Knowledge ◽  
Early Stage ◽  
Tumor Development ◽  
Adult Life ◽  
Genetic Alterations ◽  
Control Mechanisms ◽  
Placental Development ◽  
Cardiac Damage ◽  
Epigenetic Markers

Angiogenesis is a multi-stage process of new blood vessel development from pre-existing vessels toward an angiogenic stimulus. The process is essential for tissue maintenance and homeostasis during embryonic development and adult life as well as tumor growth. Under normal conditions, angiogenesis is involved in physiological processes, such as wound healing, cyclic regeneration of the endometrium, placental development and repairing certain cardiac damage, in pathological conditions, it is frequently associated with cancer development and metastasis. The control mechanisms of angiogenesis in carcinogenesis are tightly regulated at the genetic and epigenetic level. While genetic alterations are the critical part of gene silencing in cancer cells, epigenetic dysregulation can lead to repression of tumor suppressor genes or oncogene activation, becoming an important event in early development and the late stages of tumor development, as well. The global alteration of the epigenetic spectrum, which includes DNA methylation, histone modification, chromatin remodeling, microRNAs, and other chromatin components, is considered one of the hallmarks of cancer, and the efforts are concentrated on the discovery of molecular epigenetic markers that identify cancerous precursor lesions or early stage cancer. This review aims to highlight recent findings on the genetic and epigenetic changes that can occur in physiological and pathological angiogenesis and analyze current knowledge on how deregulation of epigenetic modifiers contributes to tumorigenesis and tumor maintenance. Also, we will evaluate the clinical relevance of epigenetic markers of angiogenesis and the potential use of “epi-drugs” in modulating the responsiveness of cancer cells to anticancer therapy through chemotherapy, radiotherapy, immunotherapy and hormone therapy as anti-angiogenic strategies in cancer.

scholarly journals Integrative Bioinformatics Study Reveals Tangeretin Targets and Molecular Mechanisms Against Metastatic Breast Cancer

2020 ◽  
Author(s):  
Adam Hermawan ◽  
Herwandhani Putri ◽  
Naufa Hanif ◽  
Muthi Ikawati
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Genetic Alterations ◽  
Expression Levels ◽  
Normal Tissues ◽  
Mrna Expression Levels

Abstract Background: Agents that target metastasis are important to improve treatment efficacy in patients with breast cancer. Tangeretin, a citrus flavonoid, exhibits antimetastatic effects on breast cancer cells, but its molecular mechanism remains unclear.Results: Tangeretin targets were retrieved from PubChem, whereas metastatic breast cancer regulatory genes were downloaded from PubMed. In total, 58 genes were identified as potential therapeutic target genes of tangeretin (PTs). Gene ontology analysis with Webgestalt showed that the PTs participate in the biological process of stimulus response, are the cellular components of the nucleus and the membrane, and play molecular roles in enzyme regulation. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the PTs regulate the PI3K/Akt pathway. Genetic alterations for each target gene were MTOR (3%), NOTCH1 (4%), TP53 (42%), MMP9 (4%), NFKB1 (3%), PIK3CA (32%), PTGS2 (15%), and RELA (5%). The Kaplan–Meier plot displayed that patients with low mRNA expression levels of MTOR, TP53, MMP9, NFKB1, PTGS2, and RELA and high expression of PIK3CA had a significantly better prognosis than their counterparts. Further validation of gene expression by using GEPIA revealed that the mRNA expression of MMP9 was significantly lower in breast cancer tissues than in normal tissues, whereas the mRNA expression of PTGS2 showed the opposite. Analysis with ONCOMINE demonstrated that the mRNA expression levels of MMP9 and NFKB1 were significantly higher in metastatic breast cancer cells than in normal tissues. The results of molecular docking analyses revealed the advantage of tangeretin as an inhibitor of PIK3CA, MMP9, PTGS2, and IKK.Conclusion: Tangeretin inhibits metastasis in breast cancer cells by targeting TP53, PTGS2, MMP9, and PIK3CA and regulating the PI3K/Akt signaling pathway. Further investigation is needed to validate the results of this study.

scholarly journals Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing

2016 ◽  
Vol 113 (35) ◽  
pp. 9846-9851 ◽  
Author(s):  
Margaret L. Hoang ◽  
Isaac Kinde ◽  
Cristian Tomasetti ◽  
K. Wyatt McMahon ◽  
Thomas A. Rosenquist ◽  
...  
Keyword(s):  
Massively Parallel Sequencing ◽  
Point Mutations ◽  
Genetic Alterations ◽  
Human Tissues ◽  
Molecular Barcoding ◽  
Normal Tissues ◽  
Rare Mutations ◽  
Normal Human ◽  
Nuclear Genomes ◽  
Mutation Spectra

We present the bottleneck sequencing system (BotSeqS), a next-generation sequencing method that simultaneously quantifies rare somatic point mutations across the mitochondrial and nuclear genomes. BotSeqS combines molecular barcoding with a simple dilution step immediately before library amplification. We use BotSeqS to show age- and tissue-dependent accumulations of rare mutations and demonstrate that somatic mutational burden in normal human tissues can vary by several orders of magnitude, depending on biologic and environmental factors. We further show major differences between the mutational patterns of the mitochondrial and nuclear genomes in normal tissues. Lastly, the mutation spectra of normal tissues were different from each other, but similar to those of the cancers that arose in them. This technology can provide insights into the number and nature of genetic alterations in normal tissues and can be used to address a variety of fundamental questions about the genomes of diseased tissues.

Resveratrol as an Adjuvant for Normal Tissues Protection and Tumor Sensitization

2020 ◽  
Vol 20 (2) ◽  
pp. 130-145 ◽  
Author(s):  
Keywan Mortezaee ◽  
Masoud Najafi ◽  
Bagher Farhood ◽  
Amirhossein Ahmadi ◽  
Dheyauldeen Shabeeb ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Clinical Studies ◽  
Normal Tissue ◽  
Medical Science ◽  
Treatment Modalities ◽  
Radiation Toxicity ◽  
Normal Tissues ◽  
Normal Tissue Toxicity

Cancer is one of the most complicated diseases in present-day medical science. Yearly, several studies suggest various strategies for preventing carcinogenesis. Furthermore, experiments for the treatment of cancer with low side effects are ongoing. Chemotherapy, targeted therapy, radiotherapy and immunotherapy are the most common non-invasive strategies for cancer treatment. One of the most challenging issues encountered with these modalities is low effectiveness, as well as normal tissue toxicity for chemo-radiation therapy. The use of some agents as adjuvants has been suggested to improve tumor responses and also alleviate normal tissue toxicity. Resveratrol, a natural flavonoid, has attracted a lot of attention for the management of both tumor and normal tissue responses to various modalities of cancer therapy. As an antioxidant and anti-inflammatory agent, in vitro and in vivo studies show that it is able to mitigate chemo-radiation toxicity in normal tissues. However, clinical studies to confirm the usage of resveratrol as a chemo-radioprotector are lacking. In addition, it can sensitize various types of cancer cells to both chemotherapy drugs and radiation. In recent years, some clinical studies suggested that resveratrol may have an effect on inducing cancer cell killing. Yet, clinical translation of resveratrol has not yielded desirable results for the combination of resveratrol with radiotherapy, targeted therapy or immunotherapy. In this paper, we review the potential role of resveratrol for preserving normal tissues and sensitization of cancer cells in combination with different cancer treatment modalities.

Resveratrol as an Enhancer of Apoptosis in Cancer: A Mechanistic Review

2020 ◽  
Vol 20 ◽  
Author(s):  
Milad Ashrafizadeh ◽  
Shahram Taeb ◽  
Hamed Haghi-Aminjan ◽  
Shima Afrashi ◽  
Kave Moloudi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Fas Ligand ◽  
Inhibitory Effect ◽  
Mitochondrial Pathway ◽  
Multi Drug Resistance ◽  
Chemotherapy Drugs ◽  
Normal Tissues ◽  
Anti Cancer

: Resistance of cancer cells to therapy is a challenge for achieving an appropriate therapeutic outcome. Cancer (stem) cells possess several mechanisms for increasing their survival following exposure to toxic agents such as chemotherapy drugs, radiation as well as immunotherapy. Evidences show that apoptosis plays a key role in response of cancer (stem) cells and their multi drug resistance. Modulation of both intrinsic and extrinsic pathways of apoptosis can increase efficiency of tumor response and amplify the therapeutic effect of radiotherapy, chemotherapy, targeted therapy and also immunotherapy. To date, several agents as adjuvant have been proposed to overcome resistance of cancer cells to apoptosis. Natural products are interesting because of low toxicity on normal tissues. Resveratrol is a natural herbal agent that has shown interesting anti-cancer properties. It has been shown to kill cancer cells selectively, while protecting normal cells. Resveratrol can augment reduction/oxidation (redox) reactions, thus increases the production of ceramide and the expression of apoptosis receptors such as Fas ligand (FasL). Resveratrol also triggers some pathways which induce mitochondrial pathway of apoptosis. On the other hand, resveratrol has an inhibitory effect on anti-apoptotic mediators such as nuclear factor κ B (NFκB), cyclooxygenase-2 (COX-2), phosphatidylinositol 3–kinase (PI3K) and mTOR. In this review, we explain the modulatory effects of resveratrol on apoptosis, which can augment the therapeutic efficiency of anti-cancer drugs or radiotherapy.

scholarly journals Cross-presentation of a TAP-independent signal peptide induces CD8 T immunity to escaped cancers but necessitates anchor replacement

2021 ◽  
Author(s):  
Koen A. Marijt ◽  
Lisa Griffioen ◽  
Laura Blijleven ◽  
Sjoerd. H. van der Burg ◽  
Thorbald van Hall
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Signal Sequence ◽  
Cell Repertoire ◽  
Cross Presentation ◽  
Normal Tissues ◽  
Cell Immunity

AbstractCancer cells frequently display defects in their antigen-processing pathway and thereby evade CD8 T cell immunity. We described a novel category of cancer antigens, named TEIPP, that emerge on cancers with functional loss of the peptide pump TAP. TEIPPs are non-mutated neoantigens despite their ‘self’ origin by virtue of their absence on normal tissues. Here, we describe the development of a synthetic long peptide (SLP) vaccine for the most immunogenic TEIPP antigen identified thus far, derived from the TAP-independent LRPAP1 signal sequence. LRPAP121–30-specific CD8 T cells were present in blood of all tested healthy donors as well as patients with non-small cell lung adenocarcinoma. SLPs with natural flanking, however, failed to be cross-presented by monocyte-derived dendritic cells. Since the C-terminus of LRPAP121–30 is an unconventional and weakly binding serine (S), we investigated if replacement of this anchor would result in efficient cross-presentation. Exchange into a valine (V) resulted in higher HLA-A2 binding affinity and enhanced T cell stimulation. Importantly, CD8 T cells isolated using the V-variant were able to bind tetramers with the natural S-variant and respond to TAP-deficient cancer cells. A functional screen with an array of N-terminal and C-terminal extended SLPs pointed at the 24-mer V-SLP, elongated at the N-terminus, as most optimal vaccine candidate. This SLP was efficiently cross-presented and consistently induced a strong polyclonal LRPAP121–30-specific CD8 T cells from the endogenous T cell repertoire. Thus, we designed a TEIPP SLP vaccine from the LRPAP1 signal sequence ready for validation in clinical trials.

scholarly journals Distinctive Prognostic Value and Cellular Functions of Osteopontin Splice Variants in Human Gastric Cancer

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1820
Author(s):  
Chengcheng Hao ◽  
Yuxin Cui ◽  
Jane Lane ◽  
Shuqin Jia ◽  
Jiafu Ji ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Prognostic Value ◽  
Splice Variants ◽  
Tnm Staging ◽  
Migration And Invasion ◽  
Ros Production ◽  
Gastric Cancer Cells ◽  
Normal Tissues

Background: Osteopontin (OPN) splice variants are identified as predictors of tumour progression and therapeutic resistance in certain types of solid tumours. However, their roles in gastric cancer (GC) remain poorly characterized. The current study sought to assess the prognostic value of the three OPN splice variants (namely OPN-a, OPN-b, and OPN-c) in gastric cancer and their potential functions within gastric cancer cells. Methods: RNA extraction and reverse transcription were performed using our clinical cohort of gastric carcinomas and matched normal tissues (n = 324 matched pairs). Transcript levels were determined using real-time quantitative PCR. Three OPN splice variants overexpressed cell lines were created from the gastric cancer cell line HGC-27. Subsequently, biological functions, including cell growth, adhesion, migration, and invasion, were studied. The potential effects of OPN isoforms on cisplatin and 5-Fu were evaluated by detecting cellular reactive oxygen species (ROS) levels in the HGC-27-derived cell lines. Results: Compared with normal tissues, the expression levels of three splice variants were all elevated in gastric cancer tissues in an order of OPN-a > OPN-b > OPN-c. The OPN-a level significantly increased with increasing TNM staging and worse clinical outcome. There appeared to be a downregulation for OPN-c in increasing lymph node status (p < 0.05), increasing TNM staging, and poor differentiation. High levels of OPN-a and OPN-b were correlated with short overall survival and disease-free survival of gastric cancer patients. However, the low expression of OPN-c was significantly associated with a poor prognosis. Functional analyses further showed that ectopic expression of OPN-c suppressed in vitro proliferation, adhesiveness, migration, and invasion properties of HGC-27 cells, while the opposite role was seen for OPN-a. Cellular ROS detection indicated that OPN-a and OPN-c significantly promoted ROS production after treatment with 5-Fu comparing to OPN-vector, while only OPN-a markedly induced ROS production after treatment with cisplatin. Conclusion: Our results suggest that OPN splice variants have distinguished potential to predict the prognosis of gastric cancer. Three OPN variants exert distinctive functions in gastric cancer cells. Focusing on specific OPN isoforms could be a novel direction for developing diagnostic and therapeutic approaches in gastric cancer.

scholarly journals Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alejandro Schcolnik-Cabrera ◽  
Alma Chavez-Blanco ◽  
Guadalupe Dominguez-Gomez ◽  
Mandy Juarez ◽  
Ariana Vargas-Castillo ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Drug Combination ◽  
Cell Cycle Progression ◽  
De Novo ◽  
In Vivo Evaluation ◽  
Fat Loss ◽  
Normal Tissues ◽  
Animal Metabolism ◽  
Energetic Expenditure

AbstractThe malignant energetic demands are satisfied through glycolysis, glutaminolysis and de novo synthesis of fatty acids, while the host curses with a state of catabolism and systemic inflammation. The concurrent inhibition of both, tumor anabolism and host catabolism, and their effect upon tumor growth and whole animal metabolism, have not been evaluated. We aimed to evaluate in colon cancer cells a combination of six agents directed to block the tumor anabolism (orlistat + lonidamine + DON) and the host catabolism (growth hormone + insulin + indomethacin). Treatment reduced cellular viability, clonogenic capacity and cell cycle progression. These effects were associated with decreased glycolysis and oxidative phosphorylation, leading to a quiescent energetic phenotype, and with an aberrant transcriptomic landscape showing dysregulation in multiple metabolic pathways. The in vivo evaluation revealed a significant tumor volume inhibition, without damage to normal tissues. The six-drug combination preserved lean tissue and decreased fat loss, while the energy expenditure got decreased. Finally, a reduction in gene expression associated with thermogenesis was observed. Our findings demonstrate that the simultaneous use of this six-drug combination has anticancer effects by inducing a quiescent energetic phenotype of cultured cancer cells. Besides, the treatment is well-tolerated in mice and reduces whole animal energetic expenditure and fat loss.

Sign in / Sign up

Export Citation Format

Share Document