scholarly journals Multiple Molecular Targets Associated with Genomic Instability in Lung Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Giovanny Soca-Chafre ◽  
Angelica Montiel-Dávalos ◽  
Inti Alberto De La Rosa-Velázquez ◽  
Claudia Haydeé Saraí Caro-Sánchez ◽  
Adriana Peña-Nieves ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Genomic Instability ◽  
Targeted Therapies ◽  
Molecular Mechanisms ◽  
Cell Cycle Control ◽  
Point Mutations ◽  
Number Variation ◽  
Never Smokers ◽  
Diagnosis Therapy ◽  
Tobacco Carcinogens

Lung cancer (LC) is the first cause of cancer-related deaths worldwide. Elucidating the pathogenesis of LC will give information on key elements of tumor initiation and development while helping to design novel targeted therapies. LC is an heterogeneous disease that has the second highest mutation rate surpassed only by melanoma, since 90% of LC occurs in tobacco smokers. However, only a small percent of smokers develops LC, indicating an inherent genomic instability. Additionally, LC in never smokers suggests other molecular mechanisms not causally linked to tobacco carcinogens. This review presents a current outlook of the connection between LC and genomic instability at the molecular and clinical level summarizing its implications for diagnosis, therapy, and prognosis. The genomic landscape of LC shows widespread alterations such as DNA methylation, point mutations, copy number variation, chromosomal translocations, and aneuploidy. Genome maintenance mechanisms including cell cycle control, DNA repair, and mitotic checkpoints open a window to translational research for finding novel diagnostic biomarkers and targeted therapies in LC.

Molecular profiling of 502 patient cohort with NSCLC using a 27 somatic gene panel.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23193-e23193
Author(s):  
Nikolaos Tsoulos ◽  
Eirini Papadopoulou ◽  
Vasiliki Metaxa-Mariatou ◽  
Georgios Tsaousis ◽  
Chrisoula Efstathiadou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Dna Analysis ◽  
Hot Spot ◽  
Point Mutations ◽  
Molecular Profile ◽  
Driver Gene ◽  
Multiplex Amplification ◽  
Nsclc Patients ◽  
Tumor Dna

e23193 Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and a tumor with broad spectrum of targeted therapies already available or in clinical trials. Thus, molecular characterization of the tumor using the Next Generation Sequencing (NGS) technology, has become a key tool for NSCLC patients’ treatment decision and clinical management. Methods: The performance of a custom 23 gene multiplex amplification hot spot panel, based on Ion AmpliSeq Technology, was evaluated for the analysis of tumor DNA extracted from FFPE (Formalin Fixed Parraffin Embedded) tissue. Furthermore the Ion AmpliSeq™ RNA Fusion Lung Cancer Research Panel was used for fusion RNA transcript analysis. Tumors’ mutation spectrum was determined in a cohort of 502 patients with NSCLC using the aforementioned targeted gene panels. Results: The panel used for tumor DNA analysis in this study exhibit high rates (100%) of sensitivity, specificity and reproducibility at a mutation frequency of 3%. At least one DNA mutation was detected in 374 patients (74.5%) and an RNA fusion was identified in 16 patients, (3.2%). In total, alterations in a cancer driver gene were identified (including point mutations, gene rearrangements and MET amplifications) in 77.6% of the tumors tested. Among the NSCLC patients, 13.5% (68/502) presented a mutation in a gene with approved targeted therapy (EGFR, ALK ROS1) and 9.4% had an alteration in a gene related to emerging targeted therapies according the NCCN guidelines. These alterations include ERBB2, BRAF and MET mutations, MET amplification and RET rearrangements. The remaining 51.6% of the patients had a mutation in a gene that could be related to an off label therapy or give them access to a clinical trial. Conclusions: Thus the NGS panel validated is a reliable approach of clinical applicability for tumor molecular profile detection in NSCLC patients.

scholarly journals Copy number variation, increased gene expression, and molecular mechanisms of neurofascin in lung cancer

2017 ◽  
Vol 56 (9) ◽  
pp. 2076-2085 ◽  
Author(s):  
Johanna Samulin Erdem ◽  
Yke Jildouw Arnoldussen ◽  
Vidar Skaug ◽  
Aage Haugen ◽  
Shanbeh Zienolddiny
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Copy Number Variation ◽  
Copy Number ◽  
Molecular Mechanisms ◽  
Number Variation

scholarly journals Congenital Diseases of DNA Replication: Clinical Phenotypes and Molecular Mechanisms

2021 ◽  
Vol 22 (2) ◽  
pp. 911
Author(s):  
Megan Schmit ◽  
Anja-Katrin Bielinsky
Keyword(s):  
Dna Replication ◽  
Genomic Instability ◽  
Molecular Mechanisms ◽  
Point Mutations ◽  
Chromosomal Anomalies ◽  
Congenital Diseases ◽  
Clinical Phenotypes ◽  
Pathogenic Variants ◽  
Dna Alterations ◽  
Functional Mechanisms

Deoxyribonucleic acid (DNA) replication can be divided into three major steps: initiation, elongation and termination. Each time a human cell divides, these steps must be reiteratively carried out. Disruption of DNA replication can lead to genomic instability, with the accumulation of point mutations or larger chromosomal anomalies such as rearrangements. While cancer is the most common class of disease associated with genomic instability, several congenital diseases with dysfunctional DNA replication give rise to similar DNA alterations. In this review, we discuss all congenital diseases that arise from pathogenic variants in essential replication genes across the spectrum of aberrant replisome assembly, origin activation and DNA synthesis. For each of these conditions, we describe their clinical phenotypes as well as molecular studies aimed at determining the functional mechanisms of disease, including the assessment of genomic stability. By comparing and contrasting these diseases, we hope to illuminate how the disruption of DNA replication at distinct steps affects human health in a surprisingly cell-type-specific manner.

Molecular mechanisms of lung cancer

2021 ◽  
pp. 124-132
Author(s):  
О.Э. Лосев ◽  
В.Б. Бородулин ◽  
Н.Ю. Русецкая ◽  
Е.В. Бобылева ◽  
Я.В. Бородулин
Keyword(s):  
Lung Cancer ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Point Mutations ◽  
Cell Cycle Gene ◽  
Kras Mutations ◽  
Nrf2 Signaling Pathway ◽  
Multistep Process ◽  
Important Approach ◽  
Regulation Of Cell Cycle

Рак легкого является многоэтапным процессом с участием генетических факторов и изменений в эпигенетическом регулировании клеточного цикла. Амплификация генов, сверхэкспрессия, точечные мутациии или перестройки ДНК могут привести к постоянной позитивной регуляции митогенных сигналов роста, вследствие чего усиливается онкогенная сигнализация в клетках. В данном обзоре рассматриваются нарушения в 3 сигнальных путях (RAS-RAF-MEK-ERK, PI3K-Akt-mTOR и Keap1-Nrf2) при раке легкого. Причинами неконтролируемого роста и пролиферации клеток являются мутации EGFR, KRAS и аномальное слияние EML4-ALK, вследствие чего активируются 2 основных пути внутриклеточной сигнализации RAS-RAF-MEK-ERK и PI3K-Akt-mTOR. Канцерогенез при раке легкого может быть вызван генетическими аберрациями в любых компонентах пути PI3K-Akt-mTOR, его отрицательных регуляторах, взаимосвязанных путях и передаче сигналов через рецепторы RTK. Нарушения сигнального пути Keap1-Nrf2, обнаруженные при раке легкого, вызваны соматическими мутациями, потерей гетерозиготности или метилированием ДНК в промоторной области Keap1 и мутациями Nrf2, что приводит к увеличению накопления Nrf2. Опухоли с высоким уровнем Nrf2 связаны с плохим прогнозом из-за радио- и химиорезистентности и агрессивной пролиферации раковых клеток. Гиперактивность Nrf2 помогает автономным злокачественным клеткам выдерживать высокие уровни эндогенных активных форм кислорода (АФК) и избегать апоптоза. В этой связи важным подходом для профилактики рака является усиление активности Nrf2, тогда как для лечения рака желательно ингибирование Nrf2. Lung cancer is a multistep process involving genetic factors and changes in the epigenetic regulation of cell cycle. Gene amplification, overexpression, point mutations or DNA rearrangements may lead to continuous positive regulation of mitogenic growth signals resulting in enhancement of oncogenic cell signaling. This review focuses on disorders of three signaling pathways (RAS-RAF-MEK-ERK, PI3K-Akt-mTOR, and Keap1-Nrf2) in lung cancer. The causes for the uncontrolled cell growth and proliferation are EGFR and KRAS mutations and the abnormal EML4-ALK merging, which activate two major pathways of intracellular signaling, RAS-RAF-MEK-ERK and PI3K-Akt-mTOR. Carcinogenesis in lung cancer may result from genetic aberrations in any component of the PI3K-Akt-mTOR pathway, its negative regulators, interconnected pathways, and the signal transduction through RTK receptors. The disorders of the Keap1-Nrf2 signaling pathway found in lung cancer are caused by somatic mutations, loss of heterozygosity or DNA methylation in the Keap1 promoter region and Nrf2 mutations, which lead to an increase in the accumulation of Nrf2. Tumors with high Nrf2 levels are associated with a poor prognosis due to their radio- and chemoresistance and aggressive proliferation of cancer cells. The Nrf2 hyperactivity helps autonomous malignant cells withstand high levels of endogenous reactive oxygen species (ROS) and evade apoptosis. In this regard, enhancing the Nrf2 activity is an important approach to prevention of cancer while Nrf2 inhibition is desirable for its treatment.

scholarly journals CDK/CCN and CDKI Alterations for Cancer Prognosis and Therapeutic Predictivity

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Patrizia Bonelli ◽  
Franca Maria Tuccillo ◽  
Antonella Borrelli ◽  
Antonietta Schiattarella ◽  
Franco Maria Buonaguro
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Molecular Mechanisms ◽  
Cell Cycle Control ◽  
Chemotherapy Resistance ◽  
Point Mutations ◽  
Cancer Prognosis ◽  
Cell Cycle Regulators ◽  
Human Cancers ◽  
Cell Alterations

The regulation of cell growth and division occurs in an accurate sequential manner. It is dictated by the accumulation of cyclins (CCNs) and cyclin-dependent kinases (CDKs) complexes and degradation of CCNs. In human tumors, instead, the cell cycle is deregulated, causing absence of differentiation and aberrant cell growth. Oncogenic alterations of CCNs, CDKs, and CDKIs have been reported in more than 90% of human cancers, and the most frequent are those related to the G1 phase. Several molecular mechanisms, including gene overexpression, chromosomal translocations, point mutations, insertions and deletions, missense and frame shift mutation, splicing, or methylation, may be responsible for these alterations. The cell cycle regulators are involved in tumor progression given their association with cancers characterized by higher incidence of relapses and chemotherapy resistance. In the last decade anticancer drug researches focused on new compounds, able to target molecules related to changes in genes associated with tumor status. Recently, the studies have focused on the restoration of cell cycle control modulating molecular targets involved in cancer-cell alterations. This paper aims to correlate alterations of cell cycle regulators with human cancers and therapeutic responsivity.

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