Bilevel integer programming on a Boolean network for discovering critical genetic alterations in cancer development and therapy

2021 ◽  
Author(s):  
Kyungduk Moon ◽  
Kangbok Lee ◽  
Sunil Chopra ◽  
Steve Kwon
Keyword(s):  
Integer Programming ◽  
Boolean Network ◽  
Genetic Alterations ◽  
Cancer Development ◽  
Bilevel Integer Programming

scholarly journals Clinical Significance of MicroRNA Expression Profiles and Polymorphisms in Lung Cancer Development and Management

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Francesca Megiorni ◽  
Antonio Pizzuti ◽  
Luigi Frati
Keyword(s):  
Lung Cancer ◽  
Expression Profiles ◽  
Genetic Alterations ◽  
Cancer Development ◽  
Industrialized Countries ◽  
Lung Cancers ◽  
Novel Treatments ◽  
Novel Mirna ◽  
Clinical Biomarkers ◽  
Development And Management

Lung cancers account for a huge percentage of death in industrialized countries, and hence there is an increasing call for the development of novel treatments. These malignancies are caused by a combination of environmental factors, principally cigarette smoking and genetic alterations. MicroRNAs (miRNAs) are a recently discovered class of regulatory noncoding small RNAs with a significance in numerous biological processes. Strong evidence links miRNA impaired expression profiles and pathways to the etiology of several diseases, including neoplasia. This paper focuses on the emerging role of miRNA function in lung cancer development with particular highlighting on the use of miRNA profiles and polymorphisms for the molecular and biological characterization of tumor pulmonary growth and progression. Furthermore, we underline the potential utility of lung cancer-associated miRNAs as clinical biomarkers with a diagnostic, prognostic, and therapeutic significance and give emphasis to the promising novel miRNA-based curative strategies.

scholarly journals Tyrosine Kinase Receptors in Oncology

2020 ◽  
Vol 21 (22) ◽  
pp. 8529
Author(s):  
Jorge Esteban-Villarrubia ◽  
Juan José Soto-Castillo ◽  
Javier Pozas ◽  
María San Román-Gil ◽  
Inmaculada Orejana-Martín ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Essential Role ◽  
Kinase Inhibitors ◽  
Genetic Alterations ◽  
Cancer Development ◽  
Tyrosine Kinase Receptors ◽  
Precision Oncology ◽  
Comprehensive Review ◽  
Molecular Alterations ◽  
Tumor Types

Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.

scholarly journals Regulation of antitumor immunity by inflammation-induced epigenetic alterations

2021 ◽  
Author(s):  
Michael Karin ◽  
Shabnam Shalapour
Keyword(s):  
Cancer Cells ◽  
Chronic Inflammation ◽  
Antitumor Immunity ◽  
Immune Escape ◽  
Tumor Development ◽  
Treatment Resistance ◽  
Genetic Alterations ◽  
Cancer Development ◽  
Epigenetic Alterations ◽  
Regulatory Processes

AbstractChronic inflammation promotes tumor development, progression, and metastatic dissemination and causes treatment resistance. The accumulation of genetic alterations and loss of normal cellular regulatory processes are not only associated with cancer growth and progression but also result in the expression of tumor-specific and tumor-associated antigens that may activate antitumor immunity. This antagonism between inflammation and immunity and the ability of cancer cells to avoid immune detection affect the course of cancer development and treatment outcomes. While inflammation, particularly acute inflammation, supports T-cell priming, activation, and infiltration into infected tissues, chronic inflammation is mostly immunosuppressive. However, the main mechanisms that dictate the outcome of the inflammation-immunity interplay are not well understood. Recent data suggest that inflammation triggers epigenetic alterations in cancer cells and components of the tumor microenvironment. These alterations can affect and modulate numerous aspects of cancer development, including tumor growth, the metabolic state, metastatic spread, immune escape, and immunosuppressive or immunosupportive leukocyte generation. In this review, we discuss the role of inflammation in initiating epigenetic alterations in immune cells, cancer-associated fibroblasts, and cancer cells and suggest how and when epigenetic interventions can be combined with immunotherapies to improve therapeutic outcomes.

scholarly journals Comprehensive Genomic Analysis Reveals the Prognostic Role of LRRK2 Copy-Number Variations in Human Malignancies

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 846
Author(s):  
Gianluca Lopez ◽  
Giulia Lazzeri ◽  
Alessandra Rappa ◽  
Giuseppe Isimbaldi ◽  
Fulvia Milena Cribiù ◽  
...  
Keyword(s):  
Copy Number ◽  
Prognostic Significance ◽  
Point Mutations ◽  
Genomic Analysis ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Cancer Development ◽  
Future Research ◽  
Gene Deletions ◽  
Significant Difference

Genetic alterations of leucine-rich repeat kinase 2 (LRRK2), one of the most important contributors to familial Parkinson’s disease (PD), have been hypothesized to play a role in cancer development due to demographical and preclinical data. Here, we sought to define the prevalence and prognostic significance of LRRK2 somatic mutations across all types of human malignancies by querying the publicly available online genomic database cBioPortal. Ninety-six different studies with 14,041 cases were included in the analysis, and 761/14,041 (5.4%) showed genetic alterations in LRRK2. Among these, 585 (76.9%) were point mutations, indels or fusions, 168 (22.1%) were copy number variations (CNVs), and 8 (1.0%) showed both types of alterations. One case showed the somatic mutation R1441C. A significant difference in terms of overall survival (OS) was noted between cases harboring somatic LRRK2 whole deletions, amplifications, and CNV-unaltered cases (median OS: 20.09, 57.40, and 106.57 months, respectively; p = 0.0008). These results suggest that both LRRK2 amplifications and whole gene deletions could play a role in cancer development, paving the way for future research in terms of potential treatment with LRRK2 small molecule inhibitors for LRRK2-amplified cases.

scholarly journals NF-κB in Gastric Cancer Development and Therapy

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 870
Author(s):  
Supattra Chaithongyot ◽  
Phatcharida Jantaree ◽  
Olga Sokolova ◽  
Michael Naumann
Keyword(s):  
Gastric Cancer ◽  
Immune Cell ◽  
Genetic Alterations ◽  
Cancer Development ◽  
Cell Cycle Regulators ◽  
Major Health Problem ◽  
Major Health ◽  
Common Causes ◽  
Physical And Chemical ◽  
Transcription Factor Nuclear Factor

Gastric cancer is considered one of the most common causes of cancer-related death worldwide and, thus, a major health problem. A variety of environmental factors including physical and chemical noxae, as well as pathogen infections could contribute to the development of gastric cancer. The transcription factor nuclear factor kappa B (NF-κB) and its dysregulation has a major impact on gastric carcinogenesis due to the regulation of cytokines/chemokines, growth factors, anti-apoptotic factors, cell cycle regulators, and metalloproteinases. Changes in NF-κB signaling are directed by genetic alterations in the transcription factors themselves, but also in NF-κB signaling molecules. NF-κB actively participates in the crosstalk of the cells in the tumor micromilieu with divergent effects on the heterogeneous tumor cell and immune cell populations. Thus, the benefits/consequences of therapeutic targeting of NF-κB have to be carefully evaluated. In this review, we address recent knowledge about the mechanisms and consequences of NF-κB dysregulation in gastric cancer development and therapy.

scholarly journals Single-cell DNA and RNA sequencing reveals the dynamics of intra-tumor heterogeneity in a colorectal cancer model

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hanako Ono ◽  
Yasuhito Arai ◽  
Eisaku Furukawa ◽  
Daichi Narushima ◽  
Tetsuya Matsuura ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Cell ◽  
Tumor Heterogeneity ◽  
Genetic Alterations ◽  
Cancer Development ◽  
Intestinal Cell ◽  
Cancer Model ◽  
Cell Level ◽  
Cancer Data ◽  
Tumor Stages

Abstract Background Intra-tumor heterogeneity (ITH) encompasses cellular differences in tumors and is related to clinical outcomes such as drug resistance. However, little is known about the dynamics of ITH, owing to the lack of time-series analysis at the single-cell level. Mouse models that recapitulate cancer development are useful for controlled serial time sampling. Results We performed single-cell exome and transcriptome sequencing of 200 cells to investigate how ITH is generated in a mouse colorectal cancer model. In the model, a single normal intestinal cell is grown into organoids that mimic the intestinal crypt structure. Upon RNAi-mediated downregulation of a tumor suppressor gene APC, the transduced organoids were serially transplanted into mice to allow exposure to in vivo microenvironments, which play relevant roles in cancer development. The ITH of the transcriptome increased after the transplantation, while that of the exome decreased. Mutations generated during organoid culture did not greatly change at the bulk-cell level upon the transplantation. The RNA ITH increase was due to the emergence of new transcriptional subpopulations. In contrast to the initial cells expressing mesenchymal-marker genes, new subpopulations repressed these genes after the transplantation. Analyses of colorectal cancer data from The Cancer Genome Atlas revealed a high proportion of metastatic cases in human subjects with expression patterns similar to the new cell subpopulations in mouse. These results suggest that the birth of transcriptional subpopulations may be a key for adaptation to drastic micro-environmental changes when cancer cells have sufficient genetic alterations at later tumor stages. Conclusions This study revealed an evolutionary dynamics of single-cell RNA and DNA heterogeneity in tumor progression, giving insights into the mesenchymal-epithelial transformation of tumor cells at metastasis in colorectal cancer.

Genetic diversity during the development of Barrett's oesophagus-associated adenocarcinoma: how, when and why?

2010 ◽  
Vol 38 (2) ◽  
pp. 374-379 ◽  
Author(s):  
Trevor A. Graham ◽  
Stuart A.C. McDonald
Keyword(s):  
Genetic Diversity ◽  
Epithelial Cell ◽  
Present Article ◽  
Genetic Heterogeneity ◽  
Genetic Alterations ◽  
Cancer Development ◽  
Barrett’S Oesophagus ◽  
Future Research ◽  
Barrett's Oesophagus ◽  
Single Lesion

Recent investigations into Barrett's oesophagus at the level of individual crypts have found significant genetic heterogeneity within a single lesion. Furthermore, this genetic diversity has been shown to predict cancer development. In the present article, we review the genetic alterations implicated in disease progression in Barrett's oesophagus and discuss how genetic diversity could arise during tumorigenesis. Three arguments are discussed: a high mutation rate coupled with strong selection, clonal interaction driving progression, and a hitherto unidentified alteration that disrupts epithelial cell homoeostasis. Suggestions are made for future research to distinguish which of these theories is the predominant mechanism in Barrett's oesophagus-associated tumorigenesis.

scholarly journals Pathobiology and Chemoprevention of Bladder Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-23 ◽  
Author(s):  
Takuji Tanaka ◽  
Katsuhito Miyazawa ◽  
Tetsuya Tsukamoto ◽  
Toshiya Kuno ◽  
Koji Suzuki
Keyword(s):  
Bladder Cancer ◽  
Tumor Suppressor Genes ◽  
Urothelial Cancer ◽  
Biological Significance ◽  
Genetic Alterations ◽  
Cancer Development ◽  
Primary Cancer ◽  
Preneoplastic Lesions ◽  
The Past ◽  
Novel Targets

Our understanding of the pathogenesis of bladder cancer has improved considerably over the past decade. Translating these novel pathobiological discoveries into therapies, prevention, or strategies to manage patients who are suspected to have or who have been diagnosed with bladder cancer is the ultimate goal. In particular, the chemoprevention of bladder cancer development is important, since urothelial cancer frequently recurs, even if the primary cancer is completely removed. The numerous alterations of both oncogenes and tumor suppressor genes that have been implicated in bladder carcinogenesis represent novel targets for therapy and prevention. In addition, knowledge about these genetic alterations will help provide a better understanding of the biological significance of preneoplastic lesions of bladder cancer. Animal models for investigating bladder cancer development and prevention can also be developed based on these alterations. This paper summarizes the results of recent preclinical and clinical chemoprevention studies and discusses screening for bladder cancer.

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