Materiały źródłowe

• #1 Lung Cancer—Epidemiology, Pathogenesis, Treatment and Molecular Aspect (Review of Literature)

  https://www.mdpi.com/1422-0067/26/5/2049

  Lung cancer can develop as a consequence of several genetic factors and epigenetic changes (for example, point mutations, amplifications, insertions, deletions and translocations). This is particularly associated with the activation of a pathway that promotes growth and inhibition of the tumor suppressor pathways. […] The molecular basis of lung cancer should be understood as the accumulation of many genetic and epigenetic changes in the nucleus of the cell, which occur over a long period of time. The cancer process is initiated when a given cell breaks out of the control of the mechanisms that determine its division and location. Its cell cycle is similar to that of normal cells, with the difference that this cell does not submit to regulatory mechanisms and becomes insensitive to signals from other cells. Disorders in the expression of genes regulating the cell cycle play a key role in any neoplastic transformation. The initiation and progression of the neoplastic process is influenced by the following:

• #2 Lung cancer – Wikipedia

  https://en.wikipedia.org/wiki/Lung_cancer

  Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged airway cells gain the ability to multiply unchecked, causing the growth of a tumor. Without treatment, tumors spread throughout the lung, damaging lung function. Eventually lung tumors metastasize, spreading to other parts of the body. […] As with all cancers, lung cancer is triggered by mutations that allow tumor cells to endlessly multiply, stimulate blood vessel growth, avoid apoptosis (programmed cell death), generate pro-growth signalling molecules, ignore anti-growth signalling molecules, and eventually spread into surrounding tissue or metastasize throughout the body. Different tumors can acquire these abilities through different mutations, though generally cancer-contributing mutations activate oncogenes and inactivate tumor suppressors.

• #3 Pathogenesis of Lung Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2715312/

  Over the past 100 years, our understanding of the pathogenesis of lung cancer has advanced impressively. Environmental carcinogens and a gene locus determining susceptibility have been identified. The cellular and molecular genetic changes underlying lung cancer have become better understood over the past 25 years, but the stepwise progression of respiratory epithelium from normal to neoplastic is not yet well demarcated, limiting abilities to advance early detection and chemoprevention. The translation of improved understanding of dominant signal transduction pathways in lung cancer to rationally designed therapeutic strategies has had recent successes, demonstrating a proof of principle for targeted therapy in lung cancer. Improvement in overall patient outcomes has been stubbornly slow and will require concerted efforts.

• #4 Lung Cancer Pathophysiology, Etiology, and Risk Factors

  https://www.uspharmacist.com/article/lung-cancer-pathophysiology-etiology-and-risk-factors

  Both exposure (environmental or occupational) to particular agents and an individuals susceptibility to these agents are believed to contribute to a risk of developing lung cancer. In the United States, active smoking is the principal cause of lung cancer, accounting for an estimated 90% of lung cancer cases, whereas occupational exposures to carcinogens account for approximately 9% to 15% of lung cancer cases. The development of lung cancer is directly correlated to the number of cigarettes smoked, the extent of smoking history, and the tar and nicotine content of cigarettes. Risk is greatest among current smokers and lowest among nonsmokers. The risk of cancer declines after smoking cessation, but the level of risk is never restored to baseline in never-smokers, and an estimated 15% to 20% of individuals who develop lung cancer have never smoked or have smoked minimally. Other forms of tobacco smoke, including secondhand smoke, are also associated with significant increases in the risk of lung cancer. Secondhand tobacco smoke exposure at a younger age is linked to an elevated risk of lung cancer.

• #5 Lung Cancer Pathophysiology, Etiology, and Risk Factors

  https://www.uspharmacist.com/article/lung-cancer-pathophysiology-etiology-and-risk-factors1

  The pathophysiology of lung cancer is complex and not fully understood. […] Researchers hypothesize that repeated exposure to carcinogens, particularly cigarette smoke, leads to dysplasia of lung epithelium. Prolonged exposure can cause genetic mutations and affect protein synthesis. As a result, there is a disruption in the cell cycle, which promotes carcinogenesis. The genetic mutations MYC, BCL2, and p53 are the most common mutations responsible for the development of small cell lung cancer. Mutations in epidermal growth factor receptor, KRAS, and anaplastic lymphoma kinase are mutually exclusive in patients with nonsmall cell lung cancer. […] The development of lung cancer is directly correlated to the number of cigarettes smoked, the extent of smoking history, and the tar and nicotine content of cigarettes.

• #6 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Lung-Cancer-Pathogenesis.aspx

  Other genes that are thought to play a role in the pathogenesis of lung cancer include c-MET, NKX2-1, LKB1, PIK3CA and BRAF. […] Smoking is the primary risk factor for lung cancer and is intricately involved in the pathogenesis of many cases of the disease. […] Approximately 85% of cases of lung cancer are directly attributable to smoking habits, and it is also associated with 70-90% of deaths due the lung cancer. […] The smoke from cigarettes contains 73 identified carcinogens, with the possibility of others that are not yet known. […] Radon gas has the potential to ionize genetic material and cause genetic mutations that lead to lung cancer. […] Asbestos can also lead to an increased risk of lung cancer and exposure to both asbestos and tobacco smoke has a synergistic effect of the pathogenesis.

• #7 The Molecular Mechanisms of Tobacco in Cancer Pathogenesis

  https://brieflands.com/articles/ijcm-7902.html

  Studies have shown that cancer is a multi-factorial disease in its pathogenesis, in addition to genetic disorders, the effect of environmental factors can also be pointed. Among all environmental factors, tobacco that is considered as the leading cause of respiratory and cardiovascular disease plays a key role in cancer pathogenesis and progression. More than 5,000 chemicals and 62 carcinogenes have been detected in tobacco, which could contribute to tumorgenesis through activating oncogenes, inhibition of tumor suppressor genes, genetic and epigenetic changes, alteration of growth pathways, angiogenesis and metastasis. […] This review explains the association between tobacco smoking and the incidence of different human cancers; also it focuses on molecular mechanisms through which carcinogenic chemicals in tobacco smoke promote cancer progression. Among multiple components of tobacco smoke, three carcinogens, including polycyclic aromatic hydrocarbons (PAH), nictotine and nicotin-derived nitrosamine ketone (NNK) convincingly play major roles in the pathogenesis of a wide range of cancers. In fact, these toxic and carcinogenic agents alter the expression of oncogenes, tumor suppressors, DNA repair, and last but not least, apoptosis-related genes through several mechanisms, such as point mutations, deletions, translocations and gene recombination. Moreover, implication of different tumorgenic signal transduction pathways, such as PI3K/AKT, STAT3, ERK1/2 and COX-2 in tobacco-induced tumorgenesis should not be underestimated.

• #8 Lung Cancer Pathophysiology, Etiology, and Risk Factors

  https://www.uspharmacist.com/article/lung-cancer-pathophysiology-etiology-and-risk-factors

  Exposure to asbestos is the most common occupational risk factor for lung cancer. Studies have shown that radon exposure is associated with 10% of lung cancer cases, whereas outdoor air pollution accounts for perhaps 1% to 2% of cases. In addition, preexisting nonmalignant lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and tuberculosis, have all been shown to be associated with an expanded risk of lung cancer independent of smoking. Examples of other risk factors include radiation for nonlung cancer treatment, especially non-Hodgkin lymphoma and breast cancer. Exposure to metals such as chromium, nickel, and arsenic and exposure to polycyclic aromatic hydrocarbons are also correlated with an augmented risk of lung-cancer development.

• #9 Lung Cancer Pathophysiology, Etiology, and Risk Factors

  https://www.uspharmacist.com/article/lung-cancer-pathophysiology-etiology-and-risk-factors1

  Other forms of tobacco smoke, including secondhand smoke exposure, are also associated with a considerably higher risk of lung cancer. […] Exposure to asbestos is the most common occupational risk factor for lung cancer. Studies have shown that radon exposure is associated with 10% of lung cancer cases, whereas outdoor air pollution accounts for perhaps 1% to 2% of cases. In addition, preexisting nonmalignant lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and tuberculosis, have all been shown to be associated with an expanded risk of lung cancer independent of smoking. Examples of other risk factors include radiation for nonlung cancer treatment, especially non-Hodgkin lymphoma and breast cancer. An increased risk of lung cancer development is also linked to exposure to other carcinogens found in some work environments, such as chromium, nickel, silica, vinyl chloride, coal products, diesel exhaust, arsenic, and polycyclic aromatic hydrocarbons.

• #10 Lung Cancer Pathophysiology, Etiology, and Risk Factors

  https://www.uspharmacist.com/article/lung-cancer-pathophysiology-etiology-and-risk-factors

  Exposure to asbestos is the most common occupational risk factor for lung cancer. Studies have shown that radon exposure is associated with 10% of lung cancer cases, whereas outdoor air pollution accounts for perhaps 1% to 2% of cases. In addition, preexisting nonmalignant lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and tuberculosis, have all been shown to be associated with an expanded risk of lung cancer independent of smoking. Examples of other risk factors include radiation for nonlung cancer treatment, especially non-Hodgkin lymphoma and breast cancer. Exposure to metals such as chromium, nickel, and arsenic and exposure to polycyclic aromatic hydrocarbons are also correlated with an augmented risk of lung-cancer development.

• #11 Role of chronic obstructive pulmonary disease in lung cancer pathogenesis

  https://www.wjgnet.com/2218-6255/full/v3/i3/WJR-3-67-g001.htm

  Figure 1 Pathogenic processes linking chronic obstructive pulmonary disease and lung cancer. The figure shows some of the key pathways leading to both chronic obstructive pulmonary disease (COPD) and cancer, and demonstrates the complexity of the interactions between the diseases. Cigarette smoke causes oxidative stress which can both drive inflammation and occur due to inflammation; both processes lead to COPD. Inflammation may in turn lead to activation of matrix metalloproteases (MMPs) and the transforming growth factor (TGF) pathway, which by way of epithelial mesenchymal transition can promote lung cancer growth. Oxidative stress may also directly activate the epidermal growth factor receptor pathway which is involved in lung cancer growth. Cigarette smoke also interacts with pre-existing genetic predisposition and causes changes in DNA and miRNA which lead to processes relevant to cancer growth, such as cell proliferation and apoptosis, as well as to COPD. Finally, COPD may cause hypoxia which may augment angiogenesis, thereby interacting with prostaglandin based pathways to influence cell proliferation further, with the potential to influence cancer risk. […] Role of chronic obstructive pulmonary disease in lung cancer pathogenesis.

• #12

  https://link.springer.com/article/10.1007/s12094-023-03139-z

  The microbiome of the lungs, although until recently neglected, is now emerging as a potential contributor to chronic lung diseases, including cancer. […] Preclinical evidence suggests that the microbial burden of the lungs shapes the host immunity mechanisms and affects local antitumor immune responses. […] Studies of cohorts of patients with lung cancer reveal that different microbiome profiles are detected in patients with lung cancer compared to controls. […] In addition, an association between differential lung microbiome composition and distinct responses to immunotherapy has been suggested, yet, with limited data. […] Scarce evidence exists on the role of the lung microbiome in the development of metastases in the lungs. […] Interestingly, the lung microbiome is not isolated and interacts with the gut microbiome through a dynamic axis. […] Future research on the involvement of the lung microbiome in lung cancer pathogenesis and potential therapeutic implications is greatly anticipated.

• #13 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Lung-Cancer-Pathogenesis.aspx

  The pathogenesis of lung cancer is initiated the either by the activation of oncogenes or the inactivation of tumor suppressor genes, which leads to uncontrolled replication and growth of the cells in the lungs. […] There are several factors that may lead to these genetic mutations and they may be inherited from parents or acquired by exposure to carcinogens. […] Each of the different types of lung cancer has certain gene mutations that are associated with its pathogenesis. […] For example, a mutation in K-ras proto-oncogenes accounts for 10-30% of lung adenocarcinomas, whereas a mutation in EML4-ALK tyrosine kinase accounts for 4% of non-small-cell lung carcinomas. […] Genetic mutations that lead to the upregulation of EGFR are commonly observed in non-small cell lung carcinoma, which explains the use of EGFR-inhibitors in the treatment of the disease.

• #14 Lung Cancer—Epidemiology, Pathogenesis, Treatment and Molecular Aspect (Review of Literature)

  https://www.mdpi.com/1422-0067/26/5/2049

  Abnormalities in the regulation of the cell cycle; […] Mutations in proto-oncogenes and tumor suppressor genes; […] Disorders of the DNA repair process; […] Increased expression of growth factors and angiogenesis; […] Avoidance of apoptosis (mutations of anti- and pro-apoptotic genes); […] Increased telomerase activity; […] Tissue invasion and metastasis. […] The instability of the entire cell genome, which occurs at the beginning of the carcinogenesis process, also plays an important role. It is the result of the gradual accumulation of various genetic abnormalities. This leads to a weakening of the DNA structure and its greater susceptibility to further mutations. […] Disorders of cell cycle regulation concern mutations in proto-oncogenes and tumor suppressor genes. Lack of proliferation inhibition or accelerated proliferation so that the cell is not sensitive to inhibitory signals is the essence of any cancer process. The tumor suppressor genes in which mutations in lung cancer cells are most common include TP53, RB and p16. The proto-oncogenes that most often mutate in lung cancer are the MYC, RAS and HER gene families. The process of ALK gene rearrangement is also of great importance.

• #15

  https://www.healio.com/clinical-guidance/non-small-cell-lung-cancer/pathogenesis-and-pathophysiology-overview

  Theoretical modeling has suggested that progression from a normal cell to a malignant cell required a minimum of 3-12 critical mutations. The extent of the mutational load in a cancer genome is termed the tumor mutational burden (TMB), as is typically much greater than the theoretical minimum. In invasive lung carcinomas, including non-small cell lung cancer (NSCLC), the TMB ranges from 10 to nearly 1,000 mutations per million bases of exonic (i.e., protein-coding) DNA sequence; for reference, the human exonic genome is approximately 30 million base pairs in length, the absolute number of mutations in invasive lung carcinoma ranges from 300 to almost 30,000. […] Nevertheless, a high TMB is not necessarily advantageous for the tumor, as mutations may disable critical pathways required for proliferation and survival. Successful tumors contain mutations in oncogenes (i.e., genes that drive oncogenesis) that increase their activity and mutations in tumor suppressor genes (TSGs; genes that oppose oncogenesis such as those involved in programmed cell death) that decrease their activity or deactivate them.

• #16 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Lung-Cancer-Pathogenesis.aspx

  The pathogenesis of lung cancer is initiated the either by the activation of oncogenes or the inactivation of tumor suppressor genes, which leads to uncontrolled replication and growth of the cells in the lungs. […] There are several factors that may lead to these genetic mutations and they may be inherited from parents or acquired by exposure to carcinogens. […] Each of the different types of lung cancer has certain gene mutations that are associated with its pathogenesis. […] For example, a mutation in K-ras proto-oncogenes accounts for 10-30% of lung adenocarcinomas, whereas a mutation in EML4-ALK tyrosine kinase accounts for 4% of non-small-cell lung carcinomas. […] Genetic mutations that lead to the upregulation of EGFR are commonly observed in non-small cell lung carcinoma, which explains the use of EGFR-inhibitors in the treatment of the disease.

• #17 Molecular pathology of lung cancer: key to personalized medicine | Modern Pathology

  https://www.nature.com/articles/modpathol2011215

  EGFR alterations have been implicated in the pathogenesis and progression of many malignancies. […] Although the exact molecular mechanisms resulting from these somatic mutations are not completely understood, it seems clear that mutant EGFR has enhanced tyrosine kinase activity. […] Tyrosine kinase is an enzyme that transports phosphates from adenosine triphosphate (ATP) to a protein’s tyrosine residue. […] EGFR tyrosine kinase inhibitors (TKIs) competitively block the binding of ATP to the catalytic site in the tyrosine kinase domain of EGFR, subsequently inhibiting autophosphorylation. […] The process blocks downstream signaling and results in dramatic antitumor activity for a subset of lung adenocarcinoma patients. […] The most important mutation in exon 20 is T790M, which is associated with a small fraction of adenocarcinomas with primary resistance to EGFR TKI and over one-half of the patients with acquired resistance to EGFR TKI.

• #18 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Lung-Cancer-Pathogenesis.aspx

  The pathogenesis of lung cancer is initiated the either by the activation of oncogenes or the inactivation of tumor suppressor genes, which leads to uncontrolled replication and growth of the cells in the lungs. […] There are several factors that may lead to these genetic mutations and they may be inherited from parents or acquired by exposure to carcinogens. […] Each of the different types of lung cancer has certain gene mutations that are associated with its pathogenesis. […] For example, a mutation in K-ras proto-oncogenes accounts for 10-30% of lung adenocarcinomas, whereas a mutation in EML4-ALK tyrosine kinase accounts for 4% of non-small-cell lung carcinomas. […] Genetic mutations that lead to the upregulation of EGFR are commonly observed in non-small cell lung carcinoma, which explains the use of EGFR-inhibitors in the treatment of the disease.

• #19 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Lung-Cancer-Pathogenesis.aspx

  The pathogenesis of lung cancer is initiated the either by the activation of oncogenes or the inactivation of tumor suppressor genes, which leads to uncontrolled replication and growth of the cells in the lungs. […] There are several factors that may lead to these genetic mutations and they may be inherited from parents or acquired by exposure to carcinogens. […] Each of the different types of lung cancer has certain gene mutations that are associated with its pathogenesis. […] For example, a mutation in K-ras proto-oncogenes accounts for 10-30% of lung adenocarcinomas, whereas a mutation in EML4-ALK tyrosine kinase accounts for 4% of non-small-cell lung carcinomas. […] Genetic mutations that lead to the upregulation of EGFR are commonly observed in non-small cell lung carcinoma, which explains the use of EGFR-inhibitors in the treatment of the disease.

• #20 Molecular pathology of lung cancer: key to personalized medicine | Modern Pathology

  https://www.nature.com/articles/modpathol2011215

  The most commonly used method to detect EGFR mutations is direct sequencing. […] The ability to detect multiple driver mutations in lung adenocarcinoma has revolutionized the medical management of this disease and multiplexed testing for all common driver mutations will provide physicians with a more precise guide for therapy. […] The advent of targeted therapy based on driver mutations in lung adenocarcinoma has countered the notion that non-small cell lung cancer (NSCLC) is a distinct clinical entity. […] Current information indicates that distinguishing a tumor as NSCLC alone is no longer sufficient for patient management and the term non-small cell lung cancer (NSCLC) should be abandoned. […] The EML4ALK fusion is a rare abnormality detected in 3-13% of patients with adenocarcinomas.

• #21 NSCLC Targeted Therapy | Non-small Cell Lung Cancer Medication | American Cancer Society

  https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html

  About 5% of NSCLCs have a rearrangement in a gene called ALK. This change is often seen in people who don’t smoke (or who are light smokers), who are younger, and who have the adenocarcinoma subtype of NSCLC. The ALK gene rearrangement produces an abnormal ALK protein that causes the cells to grow and spread. […] About 1% to 2% of NSCLCs have a rearrangement in a gene called ROS1. This change is most often seen in people who have the adenocarcinoma subtype of NSCLC and whose tumors are also negative for ALK, KRAS and EGFR mutations. The ROS1 gene rearrangement is similar to the ALK gene rearrangement, and some drugs can work on cells with either ALK or ROS1 gene changes. […] In some NSCLCs, the cells have changes in the BRAF gene. Cells with these changes make an altered BRAF protein that helps them grow.

• #22 Lung adenocarcinoma: from molecular basis to genome-guided therapy and immunotherapy – Chalela – Journal of Thoracic Disease

  https://jtd.amegroups.org/article/view/14594/html

  BRAF mutations are present in 7-10% of patients with pulmonary ADC, and the vast majority of these mutations are characterized by the substitution of valine by glutamate (Val600Glu or V600E) in exon 15. […] NF1 is an oncogene encoding the neurofibromin protein. […] The presence of MET alterations has a negative impact on prognosis, since amplifications of this gene are related with resistance to EGFR-guided therapy in patients with advanced disease. […] Nearly 30 different ALK fusions have been described, including the EML4-ALK fusion, which is frequently observed in lung ADC. […] ROS1 is an oncogene that encodes tyrosine kinase receptor, being phylogenetically related to ALK.

• #23 MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregula | OTT

  https://www.dovepress.com/met-oncogene-in-non-small-cell-lung-cancer-mechanism-of-met-dysregulat-peer-reviewed-fulltext-article-OTT

  It is reported that the deregulation of the MET signaling in NSCLC can induce tumor invasion and metastasis, and can interact with other signaling pathways such as EGFR. […] MET amplification is the carcinogenic driver. […] The MET amplification was reported in 25% of NSCLC. […] The high MET gene amplification (MET/CEP7 5) is very rare, with an incidence of only 0.34%, and no other oncogenic driver genes were found in these patients compared to patients with low MET gene amplification (MET/CEP7 ratio 5), which also suggests that high MET gene amplification may act as a carcinogenic driver. […] In NSCLC, nearly all of the METex14 skipping can delete Y1003, c-Cbl binding site, in the juxtamembrane domain. […] This leads to MET ubiquitination abrogation, increased MET protein stability, and impaired MET degradation. This induces ligand-independent MET activation.

• #24 NSCLC Targeted Therapy | Non-small Cell Lung Cancer Medication | American Cancer Society

  https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html

  In a small percentage of NSCLCs, the tumor cells have rearrangement in the RET gene that cause them to make an abnormal form of the RET protein. This abnormal protein helps the tumor cells grow. […] In some NSCLCs, cancer cells have changes in the MET gene, called a MET exon 14 skipping mutation, that cause them to make an abnormal form of the MET protein. This abnormal protein helps the cancer cells grow and spread. […] In a small percentage of NSCLCs, the cancer cells have certain changes in the HER2 (ERBB2) gene that help them grow. […] A very small number of NSCLCs have changes in one of the NTRK genes, called NTRK gene fusions. Cells with these gene changes make abnormal TRK proteins, which can lead to abnormal cell growth and cancer.

• #25 NSCLC Targeted Therapy | Non-small Cell Lung Cancer Medication | American Cancer Society

  https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html

  In a small percentage of NSCLCs, the tumor cells have rearrangement in the RET gene that cause them to make an abnormal form of the RET protein. This abnormal protein helps the tumor cells grow. […] In some NSCLCs, cancer cells have changes in the MET gene, called a MET exon 14 skipping mutation, that cause them to make an abnormal form of the MET protein. This abnormal protein helps the cancer cells grow and spread. […] In a small percentage of NSCLCs, the cancer cells have certain changes in the HER2 (ERBB2) gene that help them grow. […] A very small number of NSCLCs have changes in one of the NTRK genes, called NTRK gene fusions. Cells with these gene changes make abnormal TRK proteins, which can lead to abnormal cell growth and cancer.

• #26 NSCLC Targeted Therapy | Non-small Cell Lung Cancer Medication | American Cancer Society

  https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html

  In a small percentage of NSCLCs, the tumor cells have rearrangement in the RET gene that cause them to make an abnormal form of the RET protein. This abnormal protein helps the tumor cells grow. […] In some NSCLCs, cancer cells have changes in the MET gene, called a MET exon 14 skipping mutation, that cause them to make an abnormal form of the MET protein. This abnormal protein helps the cancer cells grow and spread. […] In a small percentage of NSCLCs, the cancer cells have certain changes in the HER2 (ERBB2) gene that help them grow. […] A very small number of NSCLCs have changes in one of the NTRK genes, called NTRK gene fusions. Cells with these gene changes make abnormal TRK proteins, which can lead to abnormal cell growth and cancer.

• #27 Pathogenesis of lung cancer signaling pathways: roadmap for therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2762943/

  The p53 pathway includes several genes that belong to multiple upstream and downstream subpathways. […] p53 is the most frequently mutated gene in lung cancer. […] The mutation spectrum of p53 is tightly linked to carcinogen exposure, particularly smoking, which is related to GC to TA (GT) transversions at CpG sites. […] p14ARF is now considered to be a master tumour suppressor gene responding to both oncogenic stimuli (Ras, MYC, E2F1) and DNA damage. […] The downstream p53 pathway includes target genes of p53 transcription, which play key roles in the mitochondrial apoptotic pathway, as well as in the death receptor pathway: Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic) are up- and downregulated by p53, respectively; Fas and the tumour necrosis factor receptor-like apoptosis inducing ligand (TRAIL) receptor DR5 belong to the tumour necrosis factor receptor family.

• #28 The Molecular Mechanisms of Tobacco in Cancer Pathogenesis

  https://brieflands.com/articles/ijcm-7902.html

  Alteration in the expression of oncogenes, tumor suppressors, DNA repair mediators, and last but not least, apoptosis-related genes are the most important phenomena involved in the development and pathogenesis of all kinds of cancers. As a primary elucidation, tumorgenesis is usually associated with the activation of oncogenes and inactivation of tumor suppressor genes through several signaling pathways. Toxic and carcinogenic agents in cigarettes alter the expression of aforementioned genes through several mechanisms, such as point mutations, deletions, translocations and gene recombination. It is well-established that TP53, as the most important tumor suppressor gene, is commonly deregulated in many human cancers. Interestingly, TP53 mutations are detected in more than 50 % of lung cancer.

• #29 Pathogenesis of Lung Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2715312/

  The inherited susceptibility for developing addiction to nicotine is potentially the most important genetic determinant of lung cancer development. […] Chronic obstructive pulmonary disease (COPD) and lung cancer are highly associated, beyond what would be expected from smoking history alone. […] The Rb and p53 tumor suppressors were shown to be universally inactivated in SCLC and p53 is also frequently inactivated in NSCLC. […] The identification of a lung cancer-specific deletion initially seemed to be a providential clue to the identification of a lung cancer tumor suppressor gene. […] With the application of techniques more sensitive than traditional cytogenetics, such as comparative genomic hybridization and allelotyping, multiple additional chromosomal regions of genetic loss and amplification have been identified.

• #30 KoreaMed Synapse

  https://synapse.koreamed.org/articles/1050639

  The current working model of the sequential molecular abnormalities in the pathogenesis of SCC indicates that the genetic abnormalities commence in histologically normal epithelium and increase with increasing severity of histologic change, and that the genetic changes follow a sequence. […] The molecular abnormalities associated with the early pathogenesis of SCC include allelic losses at multiple regions of chromosome 3p and 9p21 (p16INK4a), subsequent losses of chromosome regions 8p21-23, 13q14 (RB), and 17p13 (TP53). […] Recent studies showed progressive amplification of 3q amplification in the evolution of squamous dysplasias and implicate SOX2 as a key target of this process. […] It has been suggested that adenocarcinomas may be preceded by AAH in peripheral airway cells; however, the respiratory structures and the specific epithelia cell types involved in the origin of most lung adenocarcinomas are unknown.

• #31 Pathogenesis of lung cancer signaling pathways: roadmap for therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2762943/

  Lung cancer is the major cancer killer worldwide, and 5-yr survival is extremely poor (15%), accentuating the need for more effective therapeutic strategies. […] Significant advances in lung cancer biology may lead to customised therapy based on targeting specific genes and pathways. The main signalling pathways that could provide roadmaps for therapy include the following: growth promoting pathways (Epidermal Growth Factor Receptor/Ras/PhosphatidylInositol 3-Kinase), growth inhibitory pathways (p53/Rb/P14ARF, STK11), apoptotic pathways (Bcl-2/Bax/Fas/FasL), DNA repair and immortalisation genes. […] The genetic and epigenetic pathways involved in lung tumorigenesis differ between smokers and nonsmokers, and are tools for cancer diagnosis, prognosis, clinical follow-up and targeted therapies.

• #32 Histological transformation in lung adenocarcinoma: Insights of mechanisms and therapeutic windows

  https://www.degruyter.com/document/doi/10.1515/jtim-2024-0019/html?lang=en

  Prior research has highlighted that baseline TP53 and RB1 mutations may differentiate ADC patients at risk for SCLC transformation. […] TP53 loss was observed in tumor biopsies from 37 patients with drug-resistant NSCLCs carrying EGFR mutations. […] An in vivo study utilized adenoviral vectors targeting Cre recombinase to three distinct cell types to investigate the effect of TP53 and RB1 inactivation. […] The findings indicated that AT2 cells, upon losing TP53 and RB1, exhibited neuroendocrine differentiation traits, akin to the progenitor cells of SCLC. […] This supports the notion that AT2 cells could be the cellular origin for both ADC and SCLC. […] Complete inactivation of both TP53 and RB1 is associated with an increased risk of SCLC transformation and can be detected by immunohistochemistry (IHC) in the early stages of ADC.

• #33 Lung adenocarcinoma: from molecular basis to genome-guided therapy and immunotherapy – Chalela – Journal of Thoracic Disease

  https://jtd.amegroups.org/article/view/14594/html

  BRAF mutations are present in 7-10% of patients with pulmonary ADC, and the vast majority of these mutations are characterized by the substitution of valine by glutamate (Val600Glu or V600E) in exon 15. […] NF1 is an oncogene encoding the neurofibromin protein. […] The presence of MET alterations has a negative impact on prognosis, since amplifications of this gene are related with resistance to EGFR-guided therapy in patients with advanced disease. […] Nearly 30 different ALK fusions have been described, including the EML4-ALK fusion, which is frequently observed in lung ADC. […] ROS1 is an oncogene that encodes tyrosine kinase receptor, being phylogenetically related to ALK.

• #34 Lung cancer – Wikipedia

  https://en.wikipedia.org/wiki/Lung_cancer

  Some mutations called „driver mutations” are particularly common in adenocarcinomas, and contribute disproportionately to tumor development. These typically occur in the receptor tyrosine kinases EGFR, BRAF, MET, KRAS, and PIK3CA. Similarly, some adenocarcinomas are driven by chromosomal rearrangements that result in overexpression of tyrosine kinases ALK, ROS1, NTRK, and RET. A given tumor will typically have just one driver mutation. […] In contrast, SCLCs rarely have these driver mutations, and instead often have mutations that have inactivated the tumor suppressors p53 and RB. A cluster of tumor suppressor genes on the short arm of chromosome 3 are often lost early in the development of all lung cancers.

• #35 Lung cancer – McMaster Pathophysiology Review

  https://www.pathophys.org/lung-cancer/

  SCLC and NSCLC are treated differently because they (i) originate from different cells, (ii) undergo different pathogenesis processes, and (iii) accumulate different genetic mutations. SCLC often harbours mutations in MYC, BCL2, c-KIT, p53, and RB, while NSCLC often has mutations in EGFR, KRAS, CD44, and p16. These are all either tumour suppressor genes or oncogenes.

• #36 Pathogenesis of lung cancer signaling pathways: roadmap for therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2762943/

  The genetic abnormalities linked to risk of lung cancer should be regarded in the context of signalling pathways having their main functions altered, rather than focusing on individual factors. Several pathways with major components have their functions altered in lung cancer, and these pathways are emerging as having considerable importance with regard to targeted therapy. […] Epidermal growth factor receptor is the prototypical member of a family of four RTKs, EGFR (ERBB1, HER1), ERBB2 (HER2, Neu), ERBB3 (HER3) and ERBB4 (HER4). […] EGFR deregulation has been observed in multiple tumour types, including NSCLCs. […] The Ras/mitogen-activated protein kinase and PI3K/Akt pathways are major signalling networks linking EGFR activation to cell proliferation and survival. […] As a consequence of the frequent deregulation of EGFR pathway genes in NSCLC, EGFR became one of the first rationally selected molecules for targeted therapy.

• #37 Mechanism of Action: Novel Mechanisms in Lung Cancer – The Oncology Pharmacist

  https://www.theoncologypharmacist.com/special-issue-archive/16686:mechanism-of-action-novel-mechanisms-in-lung-cancer

  Lung cancer is the leading cause of death from cancer worldwide, estimated to be responsible for nearly 1 in 5 cancer deaths in 2012 (1.59 million deaths, 19.4% of total cancer deaths). […] The activation of EGFR—a member of the ErbB family of type I receptor tyrosine kinases—has been implicated in the pathogenesis of several human malignancies. The binding of EGFR ligands to EGFR, including epidermal growth factor, transforming growth factor-, amphiregulin, and betacellulin, has profound effects on cellular proliferation, apoptosis, cell differentiation, and metastasis. This process occurs through the activation of several critical signaling cascades, including the reticular activating system and mitogen-activated protein kinase, phospholipase C-, phosphatidylinositol 3-kinase and protein kinase B, and the signal transducer and activator of transcription 3 pathways. EGFR expression and the EGFR-mediated activation of downstream signaling pathways are related to poor outcomes in several human malignancies. Lung cancer is known to coexpress EGFR and its ligands, setting the stage for autocrine activation of EGFR. Indeed, it has been shown that the coexpression of EGFR and its ligands is a poor prognostic indicator in lung cancer and in other tumors.

• #38 Pathogenesis of lung cancer signaling pathways: roadmap for therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2762943/

  The p53 pathway includes several genes that belong to multiple upstream and downstream subpathways. […] p53 is the most frequently mutated gene in lung cancer. […] The mutation spectrum of p53 is tightly linked to carcinogen exposure, particularly smoking, which is related to GC to TA (GT) transversions at CpG sites. […] p14ARF is now considered to be a master tumour suppressor gene responding to both oncogenic stimuli (Ras, MYC, E2F1) and DNA damage. […] The downstream p53 pathway includes target genes of p53 transcription, which play key roles in the mitochondrial apoptotic pathway, as well as in the death receptor pathway: Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic) are up- and downregulated by p53, respectively; Fas and the tumour necrosis factor receptor-like apoptosis inducing ligand (TRAIL) receptor DR5 belong to the tumour necrosis factor receptor family.

• #39 Pathogenesis of lung cancer signaling pathways: roadmap for therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2762943/

  The p53 pathway includes several genes that belong to multiple upstream and downstream subpathways. […] p53 is the most frequently mutated gene in lung cancer. […] The mutation spectrum of p53 is tightly linked to carcinogen exposure, particularly smoking, which is related to GC to TA (GT) transversions at CpG sites. […] p14ARF is now considered to be a master tumour suppressor gene responding to both oncogenic stimuli (Ras, MYC, E2F1) and DNA damage. […] The downstream p53 pathway includes target genes of p53 transcription, which play key roles in the mitochondrial apoptotic pathway, as well as in the death receptor pathway: Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic) are up- and downregulated by p53, respectively; Fas and the tumour necrosis factor receptor-like apoptosis inducing ligand (TRAIL) receptor DR5 belong to the tumour necrosis factor receptor family.

• #40 Mapping lung squamous cell carcinoma pathogenesis through in vitro and in vivo models | Communications Biology

  https://www.nature.com/articles/s42003-021-02470-x

  Enforced expression of SOX2 in human bronchial epithelial cells in ALI culture has been shown to induce the formation of squamous metaplasia and dysplasia, enhance mucinous differentiation and reduce ciliated differentiation. […] The ability of SOX2 to induce squamous metaplasia and dysplasia was found to require phosphatidylinositol 3-kinase (PI3K) activity, as either pharmacological inhibition of the PI3K/AKT pathway or knockdown of PIK3CA encoding the p110 catalytic subunit of PI3K suppressed squamous differentiation. […] Inactivation of Trp53 (the mouse orthologue of TP53) in bulk mouse tracheal epithelial cells has been shown to enhance organoid formation efficiency. […] Using lentiviral vectors to model amplification of different genes located within the 3q26 chromosomal region, it has been shown that SOX2, ECT2 and PRKCI exert cooperative interactions to induce neoplastic transformation of Trp53-depleted murine basal cells.

• #41 MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregula | OTT

  https://www.dovepress.com/met-oncogene-in-non-small-cell-lung-cancer-mechanism-of-met-dysregulat-peer-reviewed-fulltext-article-OTT

  C-MET alterations in NSCLC include point mutations, amplification, fusion, and protein overexpression, which are associated with poor prognosis. […] Therefore, agents targeting c-MET are a promising treatment strategy for NSCLC. […] The c-MET gene is located on chromosome 7 q21-31 belonging to the HGF receptor family, which encodes a protein tyrosine kinase, and regulates important cellular processes including cell differentiation, proliferation, cell cycle, movement, and apoptosis. […] The extracellular portion of c-MET consists of the immunoglobulin (Ig)-like, plexins, transcription factors (IPT) domain, the plexin-semaphorin-integrin (PSI) domain, and the Sema domain (homologous to semaphorin) responsible for binding to HGF. […] HGF/c-MET binding leads to receptor dimerization, tyrosine residues autophosphorylate, substrate docking, and activation of downstream signaling pathways such as PI3K/AKT, RAS/ERK/MAPK, Wnt/-catenin, SRC, and STAT3 thereby, inducing excessive cell proliferation, and is closely related to the occurrence and development of tumors.

• #42 Pathogenesis of lung cancer signaling pathways: roadmap for therapies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2762943/

  The genetic abnormalities linked to risk of lung cancer should be regarded in the context of signalling pathways having their main functions altered, rather than focusing on individual factors. Several pathways with major components have their functions altered in lung cancer, and these pathways are emerging as having considerable importance with regard to targeted therapy. […] Epidermal growth factor receptor is the prototypical member of a family of four RTKs, EGFR (ERBB1, HER1), ERBB2 (HER2, Neu), ERBB3 (HER3) and ERBB4 (HER4). […] EGFR deregulation has been observed in multiple tumour types, including NSCLCs. […] The Ras/mitogen-activated protein kinase and PI3K/Akt pathways are major signalling networks linking EGFR activation to cell proliferation and survival. […] As a consequence of the frequent deregulation of EGFR pathway genes in NSCLC, EGFR became one of the first rationally selected molecules for targeted therapy.

• #43 Mechanism of Action: Novel Mechanisms in Lung Cancer – The Oncology Pharmacist

  https://theoncologypharmacist.com/special-issue-archive/mechanism-of-action-novel-mechanisms-in-lung-cancer

  Lung cancer is the leading cause of death from cancer worldwide, estimated to be responsible for nearly 1 in 5 cancer deaths in 2012 (1.59 million deaths, 19.4% of total cancer deaths). […] The activation of EGFR—a member of the ErbB family of type I receptor tyrosine kinases—has been implicated in the pathogenesis of several human malignancies. The binding of EGFR ligands to EGFR, including epidermal growth factor, transforming growth factor-α, amphiregulin, and betacellulin, has profound effects on cellular proliferation, apoptosis, cell differentiation, and metastasis. This process occurs through the activation of several critical signaling cascades, including the reticular activating system and mitogen-activated protein kinase, phospholipase C-γ, phosphatidylinositol 3-kinase and protein kinase B, and the signal transducer and activator of transcription 3 pathways. EGFR expression and the EGFR-mediated activation of downstream signaling pathways are related to poor outcomes in several human malignancies. Lung cancer is known to coexpress EGFR and its ligands, setting the stage for autocrine activation of EGFR. Indeed, it has been shown that the coexpression of EGFR and its ligands is a poor prognostic indicator in lung cancer and in other tumors. […] Although the SQUIRE trial shows only modest benefit in OS with the addition of necitumumab, it is clear that the EGFR pathway is important in the pathogenesis of squamous-cell carcinoma; hence the use of an EGFR inhibitor, such as necitumumab, offers an important advantage.

• #44 Mechanism of Action: Novel Mechanisms in Lung Cancer – The Oncology Pharmacist

  https://theoncologypharmacist.com/special-issue-archive/mechanism-of-action-novel-mechanisms-in-lung-cancer

  Lung cancer is the leading cause of death from cancer worldwide, estimated to be responsible for nearly 1 in 5 cancer deaths in 2012 (1.59 million deaths, 19.4% of total cancer deaths). […] The activation of EGFR—a member of the ErbB family of type I receptor tyrosine kinases—has been implicated in the pathogenesis of several human malignancies. The binding of EGFR ligands to EGFR, including epidermal growth factor, transforming growth factor-α, amphiregulin, and betacellulin, has profound effects on cellular proliferation, apoptosis, cell differentiation, and metastasis. This process occurs through the activation of several critical signaling cascades, including the reticular activating system and mitogen-activated protein kinase, phospholipase C-γ, phosphatidylinositol 3-kinase and protein kinase B, and the signal transducer and activator of transcription 3 pathways. EGFR expression and the EGFR-mediated activation of downstream signaling pathways are related to poor outcomes in several human malignancies. Lung cancer is known to coexpress EGFR and its ligands, setting the stage for autocrine activation of EGFR. Indeed, it has been shown that the coexpression of EGFR and its ligands is a poor prognostic indicator in lung cancer and in other tumors. […] Although the SQUIRE trial shows only modest benefit in OS with the addition of necitumumab, it is clear that the EGFR pathway is important in the pathogenesis of squamous-cell carcinoma; hence the use of an EGFR inhibitor, such as necitumumab, offers an important advantage.

• #45 Mapping lung squamous cell carcinoma pathogenesis through in vitro and in vivo models | Communications Biology

  https://www.nature.com/articles/s42003-021-02470-x

  Lung cancer is the main cause of cancer death worldwide, with lung squamous cell carcinoma (LUSC) being the second most frequent subtype. Preclinical LUSC models recapitulating human disease pathogenesis are key for the development of early intervention approaches and improved therapies. […] Over the last decade, sequencing studies have not only identified recurrent genomic alterations across large cohorts of LUSC samples, but also highlighted the great inter- and intra-tumour heterogeneity and their complex evolutionary histories, which cannot be recapitulated in traditional cancer cell line cultures. Additionally, it is clear that the tumour microenvironment plays an essential role in lung cancer progression. Together, these observations stress the importance of developing alternative LUSC models that allow dissection of the molecular pathogenesis of LUSC, analyses of complex cell-cell and cell-microenvironment interactions, and assessment of tailored therapies at different stages of disease progression.

• #46

  https://discovery.ucl.ac.uk/id/eprint/10142043

  Lung cancer remains the leading cause of cancer related deaths worldwide. The tumour microenvironment of the lung plays an important role in cancer initiation and progression. The complex interplay between cancer cells and their stroma is directed by several biochemical and biophysical cues. Increased matrix stiffness is a biophysical element, which has been shown to affect several proteins associated with tumour progression. Lung cancer tissues are much stiffer than the surrounding normal tissues. Collagens are important constituents of the ECM and contribute to lung mechanics, as increased collagen levels are associated with increased tumour stiffness. Collagens are associated with other ECM proteins, such as Secreted Protein Acidic and Rich in Cysteine (SPARC). SPARC is a calcium binding matricellular glycoprotein that binds collagens in the ECM and mediates cell-matrix interaction. Published evidence, suggests SPARC is also associated with YAP/TAZ, members of the Hippo pathway and important mechanosensing proteins. YAP/TAZ sense the stiffening of the ECM and promote transcriptional activation of targeted genes. These data support the hypothesis that SPARC might be a candidate in mechanotransduction pathways.

• #47

  https://discovery.ucl.ac.uk/id/eprint/10142043

  Lung cancer remains the leading cause of cancer related deaths worldwide. The tumour microenvironment of the lung plays an important role in cancer initiation and progression. The complex interplay between cancer cells and their stroma is directed by several biochemical and biophysical cues. Increased matrix stiffness is a biophysical element, which has been shown to affect several proteins associated with tumour progression. Lung cancer tissues are much stiffer than the surrounding normal tissues. Collagens are important constituents of the ECM and contribute to lung mechanics, as increased collagen levels are associated with increased tumour stiffness. Collagens are associated with other ECM proteins, such as Secreted Protein Acidic and Rich in Cysteine (SPARC). SPARC is a calcium binding matricellular glycoprotein that binds collagens in the ECM and mediates cell-matrix interaction. Published evidence, suggests SPARC is also associated with YAP/TAZ, members of the Hippo pathway and important mechanosensing proteins. YAP/TAZ sense the stiffening of the ECM and promote transcriptional activation of targeted genes. These data support the hypothesis that SPARC might be a candidate in mechanotransduction pathways.

• #48 Lung Cancer Immunotherapy | American Lung Association

  https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/treatment/types-of-treatment/immunotherapy

  Mary Jo Fidler: Immunotherapy is a cancer treatment that is designed to help the patient’s own body fight the cancer cells. The immune system is constantly surveying our body to see what doesn’t belong. In particular, the immune system uses T cells to find and destroy cancer cells and viruses. The genes of the cancer cells are unstable and constantly changing, and that allows cancer cells to acquire new skills to avoid the immune system. One way it does this is through the development of the PDL1 protein, which can silence T cells that have been activated against the cancer. […] The immunotherapy drugs that we have for lung cancer are given through the vein, usually through an I.V. What they are doing is blocking the interaction between the PDL1 protein and the activated T cells. This is supposed to release the brakes on the immune system and let the immune system do its job and kill the cancer cells.

• #49 Scientists Detail Major Mechanism Lung Cancers Use to Evade Immune Attack | Newsroom | Weill Cornell Medicine

  https://news.weill.cornell.edu/news/2023/01/scientists-detail-major-mechanism-lung-cancers-use-to-evade-immune-attack

  A protein commonly found at high levels in lung cancer cells controls a major immunosuppressive pathway that allows lung tumors to evade immune attack, according to a study led by researchers at Weill Cornell Medicine. […] The researchers analyzed human lung cancer datasets and performed experiments in preclinical models of lung cancer to show that the transcription factor XBP1s enhances tumor survival by suppressing the anti-cancer activity of neighboring immune cells. […] They discovered that XBP1s exerts this effect by driving the production of a powerful immunosuppressive molecule, prostaglandin E2. […] We found that XBP1s is part of an important pathway in cancer cells that regulates the local immune environment in lung tumors, and can be disabled to increase anticancer immunity, said study co-senior author Dr. Vivek Mittal.

• #50 Lung cancer – McMaster Pathophysiology Review

  https://www.pathophys.org/lung-cancer/

  The pathogenesis of lung cancer is like other cancers, beginning with carcinogen-induced initiation events, followed by a long period of promotion and progression in a multistep process. Cigarette smoke both initiates and promotes carcinogenesis. The initiation event happens early on, as evidenced by similar genetic mutations between current and former smokers (e.g. 3p deletion, p53 mutations). Smoking thus causes a field effect on the lung epithelium, providing a large population of initiated cells and increasing the chance of transformation. Continued smoke exposure allows additional mutations to accumulate due to promotion by chronic irritation and promoters in cigarette smoke (e.g. nicotine, phenol, formaldehyde). The time delay between smoking onset and cancer onset is typically long, requiring 20-25 years for cancer formation. Cancer risk decreases after smoking cessation, but existing initiated cells may progress if another carcinogen carries on the process.

• #51 Squamous cell carcinoma of the lung pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Squamous_cell_carcinoma_of_the_lung_pathophysiology

  Squamous cell carcinoma of the lung arises from the epithelial cells of the lung of the central bronchi to terminal alveoli, which are normally involved in the protection of the airways. The pathological irritation caused by cigarette smoke causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells that line the airways to be replaced by stratified squamous epithelium. […] Genes involved in the pathogenesis of squamous cell carcinoma include several oncogenes, such as: EGFR, EML-4, KRAS, HER2, and ALK. […] Lung cancer pathogenesis can be understood with the help of following hypothesis. Familial lung cancer: 6q2325 locus has been identified as a susceptibility gene for familial lung cancer. […] Multistep tumorigenesis: Tumors of organs such as skin, lung and colon are developed through a process called multistep tumorigenesis. As with other epithelial malignancies, lung cancers are believed to arise from preneoplastic or precursor lesions in the respiratory mucosa. Multistep tumorigenesis is development of tumor through a series of progressive pathologic events such as preneoplastic or precursor lesions with corresponding genetic and epigenetic aberrations. Hyperplasia, squamous metaplasia, squamous dysplasia, and carcinoma in situ (CIS) comprise changes in the large airways that precede or accompany invasive squamous cell carcinoma of the lung.

• #52

  https://www.healio.com/clinical-guidance/non-small-cell-lung-cancer/pathogenesis-and-pathophysiology-overview

  The general mechanisms described above all contribute to NSCLC carcinogenesis. The two most common types of NSCLC both develop from initially normal epithelial cells, progressing through several distinct stages to become malignant tumors. […] Adenocarcinoma typically develops from the peripheral bronchioloalveolar epithelium, first turning into atypical adenomatous hyperplasia, then adenocarcinoma in situ, and finally invasive carcinoma. Similarly, squamous cell carcinoma (SqCC) usually begins as normal central bronchial epithelium, sequentially developing into squamous dysplasia, carcinoma in situ and finally invasive carcinoma. […] Adenocarcinoma may also partially or entirely transform into SqCC as the tumor develops. It is important to note that NSCLC progenitor lesions (i.e., pre-invasive growths) are much more common than invasive carcinoma; a lung that contains a single invasive lesion typically also contains multiple non-invasive lesions in the process of evolution into malignancy. This phenomenon, known as field change or field cancerization, is thought to result from broad (field) exposure of the airway region to carcinogens.

• #53

  https://www.healio.com/clinical-guidance/non-small-cell-lung-cancer/pathogenesis-and-pathophysiology-overview

  The general mechanisms described above all contribute to NSCLC carcinogenesis. The two most common types of NSCLC both develop from initially normal epithelial cells, progressing through several distinct stages to become malignant tumors. […] Adenocarcinoma typically develops from the peripheral bronchioloalveolar epithelium, first turning into atypical adenomatous hyperplasia, then adenocarcinoma in situ, and finally invasive carcinoma. Similarly, squamous cell carcinoma (SqCC) usually begins as normal central bronchial epithelium, sequentially developing into squamous dysplasia, carcinoma in situ and finally invasive carcinoma. […] Adenocarcinoma may also partially or entirely transform into SqCC as the tumor develops. It is important to note that NSCLC progenitor lesions (i.e., pre-invasive growths) are much more common than invasive carcinoma; a lung that contains a single invasive lesion typically also contains multiple non-invasive lesions in the process of evolution into malignancy. This phenomenon, known as field change or field cancerization, is thought to result from broad (field) exposure of the airway region to carcinogens.

• #54 Mapping lung squamous cell carcinoma pathogenesis through in vitro and in vivo models | Communications Biology

  https://www.nature.com/articles/s42003-021-02470-x

  Lung cancer is the main cause of cancer death worldwide, with lung squamous cell carcinoma (LUSC) being the second most frequent subtype. Preclinical LUSC models recapitulating human disease pathogenesis are key for the development of early intervention approaches and improved therapies. […] Over the last decade, sequencing studies have not only identified recurrent genomic alterations across large cohorts of LUSC samples, but also highlighted the great inter- and intra-tumour heterogeneity and their complex evolutionary histories, which cannot be recapitulated in traditional cancer cell line cultures. Additionally, it is clear that the tumour microenvironment plays an essential role in lung cancer progression. Together, these observations stress the importance of developing alternative LUSC models that allow dissection of the molecular pathogenesis of LUSC, analyses of complex cell-cell and cell-microenvironment interactions, and assessment of tailored therapies at different stages of disease progression.

• #55

  https://www.healio.com/clinical-guidance/non-small-cell-lung-cancer/pathogenesis-and-pathophysiology-overview

  Lesion evolution does not stop once the tumor becomes malignant; additional genomic alterations often continue to arise within the mass, leading to distinct sub-clones defined by their own mutations, and a generally increased TMB. […] Mutations that happen early in NSCLC development, often at the precursor lesion stage, involve TSG inactivation, which can also occur through epigenetic silencing (e.g., promoter methylation leading to loss of expression). Precursor lesions also often contain adaptive mutations that allow them to escape detection and destruction by the immune system. […] Interestingly, the genomic complexity of invasive tumors is a function of whether they associated with the patients smoking history or not. Tumors related to tobacco consumption (e.g., SqCC and some subtypes of adenocarcinoma) commonly exhibit strong mosaicism reflective of their clonal evolution, with distinct mutational profiles in different parts of the tumor mass. In adenocarcinomas not related to tobacco use, a single driving oncogenic mutation is usually present throughout the tumor mass. This is referred to as oncogene addiction because the tumor cannot survive without its driver oncogene. This makes oncogene-addicted tumors susceptible to drugs that target the driver oncogene. […] However, while oncogene-addicted NSCLC generally exhibits lower genomic complexity than oncogene non-addicted NSCLC, it still exhibits a degree of mosaicism reflective of its developmental history.

• #56

  https://www.healio.com/clinical-guidance/non-small-cell-lung-cancer/pathogenesis-and-pathophysiology-overview

  Lesion evolution does not stop once the tumor becomes malignant; additional genomic alterations often continue to arise within the mass, leading to distinct sub-clones defined by their own mutations, and a generally increased TMB. […] Mutations that happen early in NSCLC development, often at the precursor lesion stage, involve TSG inactivation, which can also occur through epigenetic silencing (e.g., promoter methylation leading to loss of expression). Precursor lesions also often contain adaptive mutations that allow them to escape detection and destruction by the immune system. […] Interestingly, the genomic complexity of invasive tumors is a function of whether they associated with the patients smoking history or not. Tumors related to tobacco consumption (e.g., SqCC and some subtypes of adenocarcinoma) commonly exhibit strong mosaicism reflective of their clonal evolution, with distinct mutational profiles in different parts of the tumor mass. In adenocarcinomas not related to tobacco use, a single driving oncogenic mutation is usually present throughout the tumor mass. This is referred to as oncogene addiction because the tumor cannot survive without its driver oncogene. This makes oncogene-addicted tumors susceptible to drugs that target the driver oncogene. […] However, while oncogene-addicted NSCLC generally exhibits lower genomic complexity than oncogene non-addicted NSCLC, it still exhibits a degree of mosaicism reflective of its developmental history.

• #57 Non-small cell lung cancer-small cell lung cancer transformation as mechanism of resistance to tyrosine kinase inhibitors in lung cancer

  https://www.oaepublish.com/articles/cdr.2019.85

  Mutated or rearranged driver kinases in non-small cell lung cancer (NSCLC) cells are clinically amenable to treatment with tyrosine kinase inhibitors (TKIs) resulting in prolonged survival and significant benefit compared to cytotoxic chemotherapy. […] A special feature of NSCLC is the occurrence of histological transformation to small cell lung cancer (SCLC) in up to 14% of cases, which, in general, is accompanied by resistance to the original TKIs. […] NSCLCs become resistant to first-line EGFR-TKIs, within a median progression-free survival (PFS) of 9-13 months. […] Despite the prominent anticancer activities of the TKIs, resistance develops invariably within approximately 12-18 months and the tumors relapse. […] Although formerly regarded to be rare with 1%-3% of cases, it became clear that NSCLC-SCLC transformation is more frequent with an incidence of up to 14% of cases and the resulting SCLC tumors exhibit varying characteristics and chemosensitivities.

• #58 Small Cell Transformation: An Increasingly Common Mechanism of Resistance in EGFR-Mutated Lung Cancer

  https://www.targetedonc.com/view/small-cell-transformation-an-increasingly-common-mechanism-of-resistance-in-egfrmutated-lung-cancer

  Lung cancer is the main cause of cancer deaths in both men and women in the United States. The disease has 2 major histological subtypes: Non-small cell lung cancer accounts for 85% of cases, with small cell lung cancer comprising the remaining 15%. […] SCLC transformation is a relatively rare acquired drug resistance mechanism in EGFR-mutant LADC that has been treated with TKI therapy. Identification of this resistance is important because SCLC-specific treatment with platinum-based therapy and etoposide has shown to provide a clinical benefit. […] Resistance to these therapies remains a persistent clinical problem. The most common resistance mechanism is the T790M mutation, reported to account for 50% to 60% of cases. A less common form of resistance is transformation to SCLC, with various case reports observing this histologic transformation in 5% to 14% of patient biopsies at the time of TKI resistance.

• #59 Non-small cell lung cancer-small cell lung cancer transformation as mechanism of resistance to tyrosine kinase inhibitors in lung cancer

  https://www.oaepublish.com/articles/cdr.2019.85

  Resistance to EGFR inhibitors through histological transformation of lung EGFR-mutant adenocarcinoma to SCLC has been reported in 3%-14% of cases in repeated biopsies series. […] Transformation of NSCLC into SCLC may be due to a combined histology or a true switch of the histotype. […] The underlying mechanism of this histological NSCLC-SCLC transition is not clear. […] However, loss of RB1 was proven in a series of 11 cases of transformed EGFR mutant NSCLC specimens. […] The combination of EGFR TKI treatment and genetic and epigenetic modifications, such as RB1 loss and EGFR down-regulation, could switch NSCLCs towards a SCLC histotype. […] The most efficient therapy for SCLC-transformed NSCLC cells is not clear. […] The example of BH15 demonstrates that tumors more similar to NSCLC after a partial change of the histotype may exhibit high resistance to cisplatin and are expected to respond poorly to the cisplatin/etoposide SCLC standard therapy. […] However, functional testing of tumor cells may be essential to provide the best available chemotherapy for the NSCLC-SCLC transformed TKI-resistant tumors.

• #60 Small Cell Transformation: An Increasingly Common Mechanism of Resistance in EGFR-Mutated Lung Cancer

  https://www.targetedonc.com/view/small-cell-transformation-an-increasingly-common-mechanism-of-resistance-in-egfrmutated-lung-cancer

  A major cause for transformation is thought to be genomic alteration. LADC with EGFR mutations that transform to SCLC after an initial response to EGFR TKI have been shown to retain EGFR mutation but develop additional loss or mutation in TP53 and RB1 genes, which are frequently seen in SCLC. […] The transformed SCLC is thought to have the same cells of origin as the adenocarcinoma. Historically, the cells of origin of SCLC and NSCLC are different. SCLC is thought to arise from neuroendocrine cells in the distal part of the airways, while adenocarcinoma is believed to arise from the alveolar type II cells located in the periphery. […] Once the tumor has transformed to SCLC, treatment with platinum and etoposide is commonly employed. This regimen is considered as the standard induction regimen for SCLC with reported response rates of 70% to 90% for limited-stage disease and 60% to 70% for extensive-stage disease.

• #61 Histological transformation in lung adenocarcinoma: Insights of mechanisms and therapeutic windows

  https://www.degruyter.com/document/doi/10.1515/jtim-2024-0019/html?lang=en

  Prior research has highlighted that baseline TP53 and RB1 mutations may differentiate ADC patients at risk for SCLC transformation. […] TP53 loss was observed in tumor biopsies from 37 patients with drug-resistant NSCLCs carrying EGFR mutations. […] An in vivo study utilized adenoviral vectors targeting Cre recombinase to three distinct cell types to investigate the effect of TP53 and RB1 inactivation. […] The findings indicated that AT2 cells, upon losing TP53 and RB1, exhibited neuroendocrine differentiation traits, akin to the progenitor cells of SCLC. […] This supports the notion that AT2 cells could be the cellular origin for both ADC and SCLC. […] Complete inactivation of both TP53 and RB1 is associated with an increased risk of SCLC transformation and can be detected by immunohistochemistry (IHC) in the early stages of ADC.

• #62 Histological transformation in lung adenocarcinoma: Insights of mechanisms and therapeutic windows

  https://www.degruyter.com/document/doi/10.1515/jtim-2024-0019/html?lang=en

  Deletion of LKB1 not only promotes the occurrence and progression of lung cancer but also specifically leads to tumor heterogeneity, resulting in the development of ADC, SCC, and adenosquamous carcinoma and leading to drug resistance. […] Overall, ADC histological transformation after treatments may be influenced by both genomic and transcriptomic alterations. […] SCLC transformation has been identified as a resistance mechanism in 4%14% of cases of EGFR-TKIs relapsed ADC. […] Genomic sequencing of EGFR in transformed SCLC tumor samples revealed the preservation of the original EGFR-activating mutation, indicating that these transformed tumors were not de-novo cancers but rather a phenotypic change in response to treatment. […] This suggested that the SCLC component becomes dominant after successful treatment with EGFR TKIs targeting the ADC component.

• #63 Lung adenocarcinoma-to-squamous transdifferentiation mechanism

  https://dailyreporter.esmo.org/map-2021-virtual/article-section-1/study-sheds-light-on-lung-adenocarcinoma-to-squamous-transdifferentiation-mechanism

  A Mini Oral session at the Molecular Analysis for Precision Oncology Virtual Congress 2021 provides the first comprehensive molecular characterisation of phenotypic transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (LUSC), a phenomenon that often leads to acquired resistance to targeted treatments. […] However, in order to identify potential therapeutic approaches for squamous transdifferentiation, we first need to understand the biology behind it. […] The study identified that mutations in TBX3, MET and RBM10 were enriched specifically in transforming adenocarcinoma, suggesting they may help identify adenocarcinoma tumours at high risk of transitioning to a squamous phenotype. Additionally, three potential drivers or mediators of squamous transdifferentiation were identified: the stemness-related transcription factor MYC, the AKT signalling pathway, and the epigenetic remodelling complex PRC2, previously involved in lineage plasticity.

• #64 KoreaMed Synapse

  https://synapse.koreamed.org/articles/1050639

  Non-small cell lung carcinoma (NSCLC) from histological and biological perspectives is a complex neoplasm. […] The advances in molecular methodologies are providing new insights into the biology involved in the pathogenesis of NSCLC. […] It has been shown that clinically evident lung cancers are the results of the accumulation of a number of genetic and epigenetic changes, including abnormalities for the inactivation of tumor suppressor genes and the activation of oncogenes. […] The recent molecular advances in our understanding of the pathogenesis of NSCLC will provide a unique opportunity to improve the prevention and treatment of lung cancer. […] Two important concepts of the pathogenesis of lung cancer (field of cancerization) and the development of novel chemoprevention strategies (reverse migration) will be discussed.

• #65 Lung Cancer Immunotherapy | American Lung Association

  https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/treatment/types-of-treatment/immunotherapy

  Checkpoint inhibitor immunotherapy drugs work by disrupting the interaction between the PD-L1 protein on cancer cells and the PD-1 receptor on T-cells. When this connection is broken, T-cells are better able to recognize the cancer cells and respond to them. Drugs either target the PD-L1 protein (durvalumab, atezolizumab) or the PD-1 receptor (nivolumab, pembrolizumab). No matter which they target, they have the same goal of blocking or „inhibiting” the contact between the PD-L1 protein and the PD-1 receptor on the T cell. This re-activates the T cells and turns the immune system back on, helping it fight the cancer.

• #66 Molecular pathology of lung cancer: key to personalized medicine | Modern Pathology

  https://www.nature.com/articles/modpathol2011215

  EGFR alterations have been implicated in the pathogenesis and progression of many malignancies. […] Although the exact molecular mechanisms resulting from these somatic mutations are not completely understood, it seems clear that mutant EGFR has enhanced tyrosine kinase activity. […] Tyrosine kinase is an enzyme that transports phosphates from adenosine triphosphate (ATP) to a protein’s tyrosine residue. […] EGFR tyrosine kinase inhibitors (TKIs) competitively block the binding of ATP to the catalytic site in the tyrosine kinase domain of EGFR, subsequently inhibiting autophosphorylation. […] The process blocks downstream signaling and results in dramatic antitumor activity for a subset of lung adenocarcinoma patients. […] The most important mutation in exon 20 is T790M, which is associated with a small fraction of adenocarcinomas with primary resistance to EGFR TKI and over one-half of the patients with acquired resistance to EGFR TKI.

• #67 NSCLC Targeted Therapy | Non-small Cell Lung Cancer Medication | American Cancer Society

  https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html

  About 5% of NSCLCs have a rearrangement in a gene called ALK. This change is often seen in people who don’t smoke (or who are light smokers), who are younger, and who have the adenocarcinoma subtype of NSCLC. The ALK gene rearrangement produces an abnormal ALK protein that causes the cells to grow and spread. […] About 1% to 2% of NSCLCs have a rearrangement in a gene called ROS1. This change is most often seen in people who have the adenocarcinoma subtype of NSCLC and whose tumors are also negative for ALK, KRAS and EGFR mutations. The ROS1 gene rearrangement is similar to the ALK gene rearrangement, and some drugs can work on cells with either ALK or ROS1 gene changes. […] In some NSCLCs, the cells have changes in the BRAF gene. Cells with these changes make an altered BRAF protein that helps them grow.

• #68 NSCLC Targeted Therapy | Non-small Cell Lung Cancer Medication | American Cancer Society

  https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html

  About 5% of NSCLCs have a rearrangement in a gene called ALK. This change is often seen in people who don’t smoke (or who are light smokers), who are younger, and who have the adenocarcinoma subtype of NSCLC. The ALK gene rearrangement produces an abnormal ALK protein that causes the cells to grow and spread. […] About 1% to 2% of NSCLCs have a rearrangement in a gene called ROS1. This change is most often seen in people who have the adenocarcinoma subtype of NSCLC and whose tumors are also negative for ALK, KRAS and EGFR mutations. The ROS1 gene rearrangement is similar to the ALK gene rearrangement, and some drugs can work on cells with either ALK or ROS1 gene changes. […] In some NSCLCs, the cells have changes in the BRAF gene. Cells with these changes make an altered BRAF protein that helps them grow.

• #69 NSCLC Targeted Therapy | Non-small Cell Lung Cancer Medication | American Cancer Society

  https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html

  About 5% of NSCLCs have a rearrangement in a gene called ALK. This change is often seen in people who don’t smoke (or who are light smokers), who are younger, and who have the adenocarcinoma subtype of NSCLC. The ALK gene rearrangement produces an abnormal ALK protein that causes the cells to grow and spread. […] About 1% to 2% of NSCLCs have a rearrangement in a gene called ROS1. This change is most often seen in people who have the adenocarcinoma subtype of NSCLC and whose tumors are also negative for ALK, KRAS and EGFR mutations. The ROS1 gene rearrangement is similar to the ALK gene rearrangement, and some drugs can work on cells with either ALK or ROS1 gene changes. […] In some NSCLCs, the cells have changes in the BRAF gene. Cells with these changes make an altered BRAF protein that helps them grow.

• #70 NSCLC Targeted Therapy | Non-small Cell Lung Cancer Medication | American Cancer Society

  https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html

  In a small percentage of NSCLCs, the tumor cells have rearrangement in the RET gene that cause them to make an abnormal form of the RET protein. This abnormal protein helps the tumor cells grow. […] In some NSCLCs, cancer cells have changes in the MET gene, called a MET exon 14 skipping mutation, that cause them to make an abnormal form of the MET protein. This abnormal protein helps the cancer cells grow and spread. […] In a small percentage of NSCLCs, the cancer cells have certain changes in the HER2 (ERBB2) gene that help them grow. […] A very small number of NSCLCs have changes in one of the NTRK genes, called NTRK gene fusions. Cells with these gene changes make abnormal TRK proteins, which can lead to abnormal cell growth and cancer.

• #71 NSCLC Targeted Therapy | Non-small Cell Lung Cancer Medication | American Cancer Society

  https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html

  In a small percentage of NSCLCs, the tumor cells have rearrangement in the RET gene that cause them to make an abnormal form of the RET protein. This abnormal protein helps the tumor cells grow. […] In some NSCLCs, cancer cells have changes in the MET gene, called a MET exon 14 skipping mutation, that cause them to make an abnormal form of the MET protein. This abnormal protein helps the cancer cells grow and spread. […] In a small percentage of NSCLCs, the cancer cells have certain changes in the HER2 (ERBB2) gene that help them grow. […] A very small number of NSCLCs have changes in one of the NTRK genes, called NTRK gene fusions. Cells with these gene changes make abnormal TRK proteins, which can lead to abnormal cell growth and cancer.

• #72 Non-small cell lung cancer-small cell lung cancer transformation as mechanism of resistance to tyrosine kinase inhibitors in lung cancer

  https://www.oaepublish.com/articles/cdr.2019.85

  Mutated or rearranged driver kinases in non-small cell lung cancer (NSCLC) cells are clinically amenable to treatment with tyrosine kinase inhibitors (TKIs) resulting in prolonged survival and significant benefit compared to cytotoxic chemotherapy. […] A special feature of NSCLC is the occurrence of histological transformation to small cell lung cancer (SCLC) in up to 14% of cases, which, in general, is accompanied by resistance to the original TKIs. […] NSCLCs become resistant to first-line EGFR-TKIs, within a median progression-free survival (PFS) of 9-13 months. […] Despite the prominent anticancer activities of the TKIs, resistance develops invariably within approximately 12-18 months and the tumors relapse. […] Although formerly regarded to be rare with 1%-3% of cases, it became clear that NSCLC-SCLC transformation is more frequent with an incidence of up to 14% of cases and the resulting SCLC tumors exhibit varying characteristics and chemosensitivities.

• #73 Molecular pathology of lung cancer: key to personalized medicine | Modern Pathology

  https://www.nature.com/articles/modpathol2011215

  The EML4ALK fusion protein activates canonical signaling pathways, including STAT3, RAS/MAP2K1, and PIK3CA/AKT1 cascades, which further affect cell cycle regulation, cell proliferation, neovascularization, and cell survival. […] The most important mutation associated with acquired EGFR TKI resistance is T790M, a point mutation located at exon 20, resulting in the substitution of methionine for threonine. […] This secondary mutation is quite prevalent, being found in up to 50% of EGFR-mutant tumors treated with first-generation EGFR TKIs.

• #74 Pathogenesis of Lung Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2715312/

  The expectation is that further understanding and exploitation of growth factor or oncogene addiction in specific tumors will take us beyond the therapeutic plateau we have now reached with cytotoxic chemotherapy. […] Tremendous progress in understanding the pathogenesis of lung cancer has occurred over the past century.

• #75 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Lung-Cancer-Pathogenesis.aspx

  We currently have a relatively good understanding of lung cancer pathogenesis, including the cellular and molecular genetic changes that are associated with the disease. […] However, there remain several aspects of the condition that have not been clearly evaluated, including the progression from normal to neoplastic cells.

• #76 Cell-by-Cell: Unlocking Lung Cancer Pathogenesis

  https://www.mdpi.com/2072-6694/14/14/3424

  Cell-by-Cell: Unlocking Lung Cancer Pathogenesis […] Advances in lung cancer screening have led to a growing need for early intervention strategies for the expanding cohort of patients being diagnosed with the number one cancer killer. Such efforts heavily rely on an in-depth understanding of the pathogenic processes affecting normal lung epithelium and its surrounding microenvironment at the cellular level. […] The advent of single-cell sequencing technologies has revolutionized our ability to interrogate these same models, tissues, and cohorts at an unprecedented resolution. Single-cell tracking of lung cancer pathogenesis is now transforming our understanding of the roles and consequences of epithelial-microenvironmental cues and crosstalk during disease evolution. […] By taking a step back and interrogating lung premalignant lesions (PMLs), scientists were able to construct a timeline for the initiation and progression of certain lung cancer subtypes. […] More recently, the advent of single-cell sequencing technologies has uncovered new prospects for in-depth analysis of the transcriptomes, genomes, and proteomes of single cells. […] Given the many parallels between the pathobiology of cancer and that of some of these aforementioned diseases (e.g., COPD, fibrosis), or with unique transcriptional states (e.g., stem cell-like potential, inflammatory responses), it is not unlikely that some of these single-cell mechanisms described in normal lung development, regeneration, and homeostatic regulation are also implicated and/or deregulated in lung cancer pathogenesis. […] By providing a more detailed account of the natural history of lung tumor cells and the molecular and cellular underpinnings of how these aggressive cancers evolve with time, single-cell studies are providing in-depth knowledge into the tumor cells-of-origin, role of tumor–immune interactions, niche factors that can modulate epithelial lineage plasticity and the susceptibility to form tumors, and the facets of heterogeneity within and across tumors. […] The histopathology of NSCLCs is not fixed over time, and this can be due to the deviation of tumor-initiating populations from their original lineages by dedifferentiating or transdifferentiating. […] Specifically for LUADs, a gene module of normal alveolar differentiation stratifies tumors with distinct grades, biological properties, and clinical outcome. […] Studying LUAD pathogenesis at the single-cell level is elucidating a growing role for aberrant cellular plasticity programs (e.g., in alveolar subsets) in space or time, throughout LUAD inception and evolution. […] Overall, these cells show increased DNA damage and can be caught up and increase in number in cases where the damage is not cleared, thereby leading to homeostatic imbalance and diseased lung states such as fibrosis. Therefore, it is tempting to suppose that in the presence of tissue damaging and tumor-promoting insults (e.g., carcinogenic, chronic inflammation), emerging intermediary cell states could also be the missing link along the transition of normal alveolar cells to premalignancy. […] The findings from these single-cell approaches to decode NSCLCs and particularly LUADs uncovered novel players in tumor development, progression, and/or response to therapy that contribute to a high level of ITH, which has been, for the most part, elusive.

• #77 Molecular pathology of lung cancer: key to personalized medicine | Modern Pathology

  https://www.nature.com/articles/modpathol2011215

  The most commonly used method to detect EGFR mutations is direct sequencing. […] The ability to detect multiple driver mutations in lung adenocarcinoma has revolutionized the medical management of this disease and multiplexed testing for all common driver mutations will provide physicians with a more precise guide for therapy. […] The advent of targeted therapy based on driver mutations in lung adenocarcinoma has countered the notion that non-small cell lung cancer (NSCLC) is a distinct clinical entity. […] Current information indicates that distinguishing a tumor as NSCLC alone is no longer sufficient for patient management and the term non-small cell lung cancer (NSCLC) should be abandoned. […] The EML4ALK fusion is a rare abnormality detected in 3-13% of patients with adenocarcinomas.

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