scholarly journals Divergent molecular profile of PIK3CA gene in arsenic-associated bladder carcinoma

Mutagenesis ◽  
2021 ◽  
Author(s):  
Mukta Basu ◽  
Balarko Chakraborty ◽  
Sabnam Ghosh ◽  
Sudip Samadder ◽  
Sankhadeep Dutta ◽  
...  
Keyword(s):  
Bladder Carcinoma ◽  
Expression Profiles ◽  
Genetic Alterations ◽  
Molecular Profile ◽  
Strong Impact ◽  
Pik3ca Gene ◽  
Recurrent Mutations ◽  
Number Variation ◽  
Exon 9 ◽  
Impact Of Arsenic

Abstract The activation of PIK3CA in bladder carcinoma (BlCa) with its recurrent mutations in exon 9 and 20 were well reported. But the association of arsenic on the activation of the pathway is not well elucidated. Therefore, we aimed to analyse the effect of arsenic on the genetic (copy number variation/mutation) and expression profiles of PIK3CA in primary BlCa samples. Infrequent amplification (16%) of the PIK3CA locus was observed, with higher frequency among the arsenic-high (AsH) than arsenic-low (AsL) samples. Frequent (54%) tumour-specific mutations in exon 9 and 20 of PIK3CA were observed in the BlCa samples with prevalent (47%) C>T transition mutations. Exon 9 and 20 harboured 48% and 73% of the total mutations, respectively, with 37% in E542K/E545K and 25% of the mutation in H1047Y/R. Though mutation frequency in AsH and AsL was found to be comparable, we observed some arsenic-specific mutation at c.1633G>A, c.1634A>C (E545K) and c.2985C>T and c.3130G>T mutations, as well as prevalent transverse mutations of A>C and G>T in AsH group. Furthermore, 73% of the BlCa samples showed overexpression (mRNA/protein) of PIK3CA with genetic alterations (amplification/mutation), significantly (P = 0.01) higher in AsH group. However, 36% of the samples showed overexpressed PIK3CA, independent of mutation or amplification, signifying a transcriptional upregulation of PIK3CA gene. Therefore, the expression status of NFκB, a transcription factor of PIK3CA, was assessed and found to be significantly correlated with the overexpression of PIK3CA (mRNA/protein) in AsH group. Similarly, the expression pattern of pAKT1 (Thr 308) was also found to be significantly correlated with PIK3CA overexpression. Finally, AsH patients with the overexpression of PIK3CA or NFκB had the worst overall survival, signifying a strong impact of arsenic on this pathway and outcome of the patients. Thus, our study showed that the arsenic-associated differential molecular profile of PIK3CA/AKT1/NFkB in BlCa has an important role in the molecular pathogenesis of the disease.

scholarly journals Molecular profile of Hürthle cell carcinomas: recurrent mutations in the Wnt/β-catenin pathway

2020 ◽  
Vol 183 (6) ◽  
pp. 647-656
Author(s):  
Nathalie Oliveira Santana ◽  
Antonio Marcondes Lerario ◽  
Cláudia Kliemann Schmerling ◽  
Suemi Marui ◽  
Venancio Avancini Ferreira Alves ◽  
...  
Keyword(s):  
Critical Role ◽  
Distant Metastases ◽  
Genetic Alterations ◽  
Molecular Profile ◽  
Single Nucleotide Variants ◽  
Hürthle Cell ◽  
Recurrent Mutations ◽  
Wide Range ◽  
Notch Pathways ◽  
Widely Invasive

Objective Genomic alterations in Hürthle cell carcinomas (HCC) include chromosomal losses, mitochondrial DNA mutations, and changes in the expression profile of the PI3K-AKT-mTOR and Wnt/β-catenin pathways. This study aimed at characterizing the mutational profile of HCC. Methods Next-generation sequencing (NGS) of 40 HCC using a 102-gene panel including, among others, the MAPK, PI3K-AKT-mTOR, Wnt/β-catenin, and Notch pathways. HCC was widely invasive in 57.5%, and lymph node and distant metastases were diagnosed in 5% and 7.5% of cases. During follow-up, 10% of patients presented with persistent/recurrent disease, but there were no cancer-related deaths. Results Genetic alterations were identified in 47.5% of HCC and comprised 190 single-nucleotide variants and 5 insertions/deletions. The Wnt/β-catenin pathway was most frequently affected (30%), followed by MAPK (27.5%) and PI3K-AKT-mTOR (25%). FAT1 and APC were the most frequently mutated genes and present in 17.5%. RAS mutations were present in 12.5% but no BRAF mutation was found. There was no association between the mutational profile and clinicopathological features. Conclusions This series of HCC presents a wide range of mutations in the Wnt/β-catenin, MAPK and PI3K-AKT-mTOR pathways. The recurrent involvement of Wnt/β-catenin pathway, particularly mutations in APC and FAT1, are of particular interest. The data suggest that mutated FAT1 may represent a potential novel driver in HCC tumorigenesis and that the Wnt/β-catenin pathway plays a critical role in this distinct thyroid malignancy.

PATH-34. MOLECULAR AND CLINICAL HETEROGENEITY WITHIN SPINAL EPENDYMOMAS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi122-vi122
Author(s):  
Sina Al-Kershi ◽  
Catena Kresbach ◽  
Lara Pohl ◽  
Mario M Dorostkar ◽  
Abigail K Suwala ◽  
...  
Keyword(s):  
Molecular Data ◽  
Genetic Alterations ◽  
Histological Evaluation ◽  
Molecular Profile ◽  
Clinical Heterogeneity ◽  
Intramedullary Tumors ◽  
Small Series ◽  
Number Variation ◽  
Tumor Types ◽  
Transcriptomic Changes

Abstract Ependymomas encompass multiple clinically relevant tumor types based on localization, genetic alterations, as well as epigenetic and transcriptomic profiles. Distinct global DNA methylation signatures serve as the most powerful diagnostic tool to distinguish these types. The methylation class of spinal ependymomas (SP-EPN) comprises mostly WHO°II tumors with slow progression and incomplete surgical resection rate. Molecular data of SP-EPN are scarce and clear treatment recommendations are lacking although these neoplasms represent the most common intramedullary tumors in children and adults. The only known recurrent genetic events in SP-EPN are the loss of chromosome 22q and mutations of the NF2 gene. However, data on the frequency of NF2 mutations range from 16 % to 71 % and originate from small series that lack epigenetic or transcriptomic characterization. Furthermore, it remains unclear whether SP-EPN with germline or sporadic NF2 mutation or with NF2 wild type status display clinical and other molecular differences. Finally, the underlying genomic and transcriptomic changes of SP-EPN without NF2 mutations are fully unclear. To provide a comprehensive molecular profile of SP-EPN, we integrated genomic and epigenetic analyses and clinical data of 170 cases. Unsupervised hierarchical clustering and t-SNE analyses of methylation data revealed three distinct molecular SP-EPN subtypes. Of the three subtypes, only subtype 1 and subtype 2 contained tumors with NF2 mutations, either as previously known germline mutations or as sporadic mutations without evidence for a syndromic disease (p< 0.0001). Besides the lack of NF2 mutations, subtype 3 tumors showed a higher frequency of MGMT promoter methylation (p= 0.0015) and occurred in significantly older patients compared to tumors of subtypes 1 and 2 (p= 0.0038). Further investigations such as whole-exome sequencing, copy number variation profiling, gene expression analysis, and histological evaluation are ongoing and will add to the picture of molecular and clinical heterogeneity within SP-EPN.

scholarly journals The genomic landscape of metastasis in treatment-naïve breast cancer models

2019 ◽  
Author(s):  
Christina Ross ◽  
Karol Szczepanek ◽  
Maxwell Lee ◽  
Howard Yang ◽  
Tinghu Qiu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Primary Tumour ◽  
Genetic Alterations ◽  
Breast Cancer Metastasis ◽  
Single Nucleotide Variants ◽  
Somatic Evolution ◽  
Recurrent Mutations ◽  
Number Variation ◽  
Treatment Naïve

AbstractMetastasis remains the principle cause of mortality for breast cancer and presents a critical challenge because secondary lesions are often refractory to conventional treatments. While specific genetic alterations are tightly linked to primary tumour development and progression, the role of genetic alteration in the metastatic process is not well-understood. To investigate how somatic evolution might contribute to breast cancer metastasis, we performed exome, whole genome, and RNA sequencing of matched metastatic and primary tumours from pre-clinical mouse models of breast cancer. Here we show that in a treatment-naïve setting, recurrent single nucleotide variants and copy number variation, but not gene fusion events, play key metastasis-driving roles in breast cancer. For instance, we identified recurrent mutations in Kras, a known driver of tumorigenesis that has not been previously implicated in breast cancer metastasis. The strategy presented here represents a novel framework to identify actionable metastasis-targeted therapies.

scholarly journals Copy Number Variation and Rearrangements Assessment in Cancer: Comparison of Droplet Digital PCR with the Current Approaches

2021 ◽  
Vol 22 (9) ◽  
pp. 4732
Author(s):  
Vincenza Ylenia Cusenza ◽  
Alessandra Bisagni ◽  
Monia Rinaldini ◽  
Chiara Cattani ◽  
Raffaele Frazzi
Keyword(s):  
Digital Pcr ◽  
Genetic Alterations ◽  
Droplet Digital Pcr ◽  
Molecular Oncology ◽  
Therapeutic Choice ◽  
Golden Standard ◽  
Number Variation ◽  
Key Aspects

The cytogenetic and molecular assessment of deletions, amplifications and rearrangements are key aspects in the diagnosis and therapy of cancer. Not only the initial evaluation and classification of the disease, but also the follow-up of the tumor rely on these laboratory approaches. The therapeutic choice can be guided by the results of the laboratory testing. Genetic deletions and/or amplifications directly affect the susceptibility or the resistance to specific therapies. In an era of personalized medicine, the correct and reliable molecular characterization of the disease, also during the therapeutic path, acquires a pivotal role. Molecular assays like multiplex ligation-dependent probe amplification and droplet digital PCR represent exceptional tools for a sensitive and reliable detection of genetic alterations and deserve a role in molecular oncology. In this manuscript we provide a technical comparison of these two approaches with the golden standard represented by fluorescence in situ hybridization. We also describe some relevant targets currently evaluated with these techniques in solid and hematologic tumors.

scholarly journals The role of epigenetic modifications, long-range contacts, enhancers and topologically associating domains in the regulation of glioma grade-specific genes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ilona E. Grabowicz ◽  
Bartek Wilczyński ◽  
Bożena Kamińska ◽  
Adria-Jaume Roura ◽  
Bartosz Wojtaś ◽  
...  
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Genetic Alterations ◽  
Chromatin Organization ◽  
Open Chromatin ◽  
Low Grade ◽  
Strong Impact ◽  
Cell Matrix ◽  
Topologically Associating Domains ◽  
Genome Wide

AbstractGenome-wide studies have uncovered specific genetic alterations, transcriptomic patterns and epigenetic profiles associated with different glioma types. We have recently created a unique atlas encompassing genome-wide profiles of open chromatin, histone H3K27ac and H3Kme3 modifications, DNA methylation and transcriptomes of 33 glioma samples of different grades. Here, we intersected genome-wide atlas data with topologically associating domains (TADs) and demonstrated that the chromatin organization and epigenetic landscape of enhancers have a strong impact on genes differentially expressed in WHO low grade versus high grade gliomas. We identified TADs enriched in glioma grade-specific genes and/or epigenetic marks. We found the set of transcription factors, including REST, E2F1 and NFKB1, that are most likely to regulate gene expression in multiple TADs, containing specific glioma-related genes. Moreover, many genes associated with the cell–matrix adhesion Gene Ontology group, in particular 14 PROTOCADHERINs, were found to be regulated by long-range contacts with enhancers. Presented results demonstrate the existence of epigenetic differences associated with chromatin organization driving differential gene expression in gliomas of different malignancy.

scholarly journals A computational method for prioritizing targeted therapies in precision oncology: performance analysis in the SHIVA01 trial

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Istvan Petak ◽  
Maud Kamal ◽  
Anna Dirner ◽  
Ivan Bieche ◽  
Robert Doczi ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Progressive Disease ◽  
Genetic Alterations ◽  
Outcome Data ◽  
Computational Method ◽  
Molecular Profile ◽  
Precision Oncology ◽  
Driver Genes ◽  
Oncology Clinical Trial ◽  
Molecularly Targeted Agents

AbstractPrecision oncology is currently based on pairing molecularly targeted agents (MTA) to predefined single driver genes or biomarkers. Each tumor harbors a combination of a large number of potential genetic alterations of multiple driver genes in a complex system that limits the potential of this approach. We have developed an artificial intelligence (AI)-assisted computational method, the digital drug-assignment (DDA) system, to prioritize potential MTAs for each cancer patient based on the complex individual molecular profile of their tumor. We analyzed the clinical benefit of the DDA system on the molecular and clinical outcome data of patients treated in the SHIVA01 precision oncology clinical trial with MTAs matched to individual genetic alterations or biomarkers of their tumor. We found that the DDA score assigned to MTAs was significantly higher in patients experiencing disease control than in patients with progressive disease (1523 versus 580, P = 0.037). The median PFS was also significantly longer in patients receiving MTAs with high (1000+ <) than with low (<0) DDA scores (3.95 versus 1.95 months, P = 0.044). Our results indicate that AI-based systems, like DDA, are promising new tools for oncologists to improve the clinical benefit of precision oncology.

scholarly journals Insight into Molecular Profile Changes after Skeletal Muscle Contusion Using Microarray and Bioinformatics Analyses

2020 ◽  
Author(s):  
Na Li ◽  
Ru-feng Bai ◽  
Chun Li ◽  
Li-hong Dang ◽  
Qiu-xiang Du ◽  
...  
Keyword(s):  
Gene Expression ◽  
Network Analysis ◽  
Differentially Expressed Genes ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Healing Process ◽  
Differentially Expressed ◽  
Molecular Profile ◽  
Wound Age ◽  
Functional Modules

Abstract Background: Muscle trauma frequently occurs in daily life. However, the molecular mechanisms of muscle healing, which partly depend on the extent of the damage, are not well understood. This study aimed to investigate gene expression profiles following mild and severe muscle contusion, and to provide more information about the molecular mechanisms underlying the repair process.Methods: A total of 33 rats were divided randomly into control (n = 3), mild contusion (n = 15), and severe contusion (n = 15) groups; the contusion groups were further divided into five subgroups (1, 3, 24, 48, and 168 h post-injury; n = 3 per subgroup). Then full genome microarray of RNA isolated from muscle tissue was performed to access the gene expression changes during healing process.Results: A total of 2,844 and 2,298 differentially expressed genes were identified in the mild and severe contusion groups, respectively. The analysis of the overlapping differentially expressed genes showed that there are common mechanisms of transcriptomic repair of mild and severe contusion within 48 h post-contusion. This was supported by the results of principal component analysis, hierarchical clustering, and weighted gene co‐expression network analysis of the 1,620 coexpressed genes in mildly and severely contused muscle. From these analyses, we discovered that the gene profiles in functional modules and temporal clusters were similar between the mild and severe contusion groups; moreover, the genes showed time-dependent patterns of expression, which allowed us to identify useful markers of wound age. We then performed an analysis of the functions of genes (including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway annotation, and protein–protein interaction network analysis) in the functional modules and temporal clusters, and the hub genes in each module–cluster pair were identified. Interestingly, we found that genes downregulated within 24−48 h of the healing process were largely associated with metabolic processes, especially oxidative phosphorylation of reduced nicotinamide adenine dinucleotide phosphate, which has been rarely reported. Conclusions: These results improve our understanding of the molecular mechanisms underlying muscle repair, and provide a basis for further studies of wound age estimation.

scholarly journals Analyzing cancer gene expression data through the lens of normal tissue-specificity

2021 ◽  
Author(s):  
H. Robert Frost
Keyword(s):  
Gene Expression ◽  
Normal Tissue ◽  
Tissue Specificity ◽  
Cancer Genomics ◽  
Expression Profiles ◽  
Genetic Alterations ◽  
Cancer Type ◽  
Tissue Specific ◽  
Normal Tissues ◽  
Cancer Types

AbstractThe genetic alterations that underlie cancer development are highly tissue-specific with the majority of driving alterations occurring in only a few cancer types and with alterations common to multiple cancer types often showing a tissue-specific functional impact. This tissue-specificity means that the biology of normal tissues carries important information regarding the pathophysiology of the associated cancers, information that can be leveraged to improve the power and accuracy of cancer genomic analyses. Research exploring the use of normal tissue data for the analysis of cancer genomics has primarily focused on the paired analysis of tumor and adjacent normal samples. Efforts to leverage the general characteristics of normal tissue for cancer analysis has received less attention with most investigations focusing on understanding the tissue-specific factors that lead to individual genomic alterations or dysregulated pathways within a single cancer type. To address this gap and support scenarios where adjacent normal tissue samples are not available, we explored the genome-wide association between the transcriptomes of 21 solid human cancers and their associated normal tissues as profiled in healthy individuals. While the average gene expression profiles of normal and cancerous tissue may appear distinct, with normal tissues more similar to other normal tissues than to the associated cancer types, when transformed into relative expression values, i.e., the ratio of expression in one tissue or cancer relative to the mean in other tissues or cancers, the close association between gene activity in normal tissues and related cancers is revealed. As we demonstrate through an analysis of tumor data from The Cancer Genome Atlas and normal tissue data from the Human Protein Atlas, this association between tissue-specific and cancer-specific expression values can be leveraged to improve the prognostic modeling of cancer, the comparative analysis of different cancer types, and the analysis of cancer and normal tissue pairs.

Identification of hub genes specific to pulmonary metastasis in osteosarcoma through integrated bioinformatics analysis

2021 ◽  
pp. 1-11
Author(s):  
Yinan Chai ◽  
Lihan Xu ◽  
Rui He ◽  
Liangjun Zhong ◽  
Yuying Wang
Keyword(s):  
Pulmonary Metastasis ◽  
Kegg Pathway ◽  
Expression Profiles ◽  
Experimental Studies ◽  
Genetic Alterations ◽  
Mapk Signaling ◽  
Receptor Interaction ◽  
Hub Genes ◽  
Pathway Analyses ◽  
Geo Database

BACKGROUND: Pulmonary metastasis is the most frequent cause of death in osteosarcoma (OS) patients. Recently, several bioinformatics studies specific to pulmonary metastatic osteosarcoma (PMOS) have been applied to identify genetic alterations. However, the interpretation and reliability of the results obtained were limited for the independent database analysis. OBJECTIVE: The expression profiles and key pathways specific to PMOS remain to be comprehensively explored. Therefore, in our study, three original datasets of GEO database were selected. METHODS: Initially, three microarray datasets (GSE14359, GSE14827, and GSE85537) were downloaded from the GEO database. Differentially expressed genes (DEGs) between PMOS and nonmetastatic osteosarcoma (NMOS) were identified and mined using DAVID. Subsequently, GO and KEGG pathway analyses were carried out for DEGs. Corresponding PPI network of DEGs was constructed based on the data collected from STRING datasets. The network was visualized with Cytoscape software, and ten hub genes were selected from the network. Finally, survival analysis of these hub genes also used the TARGET database. RESULTS: In total, 569 upregulated and 1238 downregulated genes were filtered as DEGs between PMOS and NMOS. Based on the GO analysis result, these DEGs were significantly enriched in the anatomical structure development, extracellular matrix, biological adhesion, and cell adhesion terms. Based on the KEGG pathway analysis result, these DEGs were mainly enriched in the pathways in cancer, PI3K-Akt signaling, MAPK signaling, focal adhesion, cytokine-cytokine receptor interaction, and IL-17 signaling. Hub genes (ANXA1 and CXCL12) were significantly associated with overall survival time in OS patient. CONCLUSION: Our results may provide new insight into pulmonary metastasis of OS. However, experimental studies remain necessary to elucidate the biological function and mechanism underlying PMOS.

Molecular Genetics of Cancer

2012 ◽  
Author(s):  
Leif W. Ellisen
Keyword(s):  
Risk Assessment ◽  
Tumor Suppressor ◽  
Environmental Factors ◽  
Cancer Risk ◽  
Tumor Progression ◽  
Cancer Genomics ◽  
Precancerous Lesions ◽  
Expression Profiles ◽  
Genetic Alterations ◽  
Cancer Risk Assessment

The uncontrolled clonal expansion of a cell, which often leads to invasion of surrounding tissues and metastatic spread, produces cancer. A clear histologic and molecular genetic evolution from precancerous lesions to frankly malignant and invasive cancer has been defined for some tumors (e.g., colon and bladder cancers). In rare cases, mutations may occur and be passed on in the germline, resulting in genetic predisposition to cancer (i.e., familial cancer syndromes). Environmental factors are also thought to contribute to the development of cancer. Interactions between environmental factors and subtle germline genetic variations that distinguish individuals may in some cases constitute an important determinant of cancer risk within the general population. Finally, viral infection has been linked to the development of specific cancers. Oncogenes and proto-oncogenes, and germline genetic analysis and cancer risk assessment are covered. Also discussed are genetic alterations and abnormalities, tumor suppressor genes, tumor progression, genetic mechanisms of treatment sensitivity and resistance, and emerging trends in cancer genomics and risk assessment. Figures illustrate activation of proto-oncogenes, the Knudsen two-hit model of tumor initiation, allelic losses in tumors, the retinoblastoma gene (RB1) cell cycle pathway, the p53 cellular stress and DNA damage response pathway, microsatellite instability and DNA mismatch repair, multiple oncogenes and tumor suppressors, tumor progression, cellular senescence and telomerase activation, tumor angiogenesis, chemotherapy drug resistance, targeting of oncogenic proteins by imatinib mesylate, analysis of expression profiles using high-density microarrays, and the spectrum of risk alleles for breast cancer predisposition. Tables outline oncogene and tumor suppressor gene mutations. This chapter contains 119 references.

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