Correlation Epidermal Growth Factor Receptor Mutation with Non-small Cell Lung Cancer in Passive Smokers: A Review

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with an extracellular epidermal growth factor binding domain and an intracellular tyrosine kinase domain through signaling pathways to regulate cellular proliferation. Epidermal growth factor receptor binding to its ligand will result in autophosphorylation by intrinsic tyrosine kinase activity, thereby triggering multiple signal transduction cascades. Constant or sustained activation of these downstream target sequences is thought to result in a more aggressive tumor phenotype. Mutations in EGFR are associated with non-small cell lung cancer in passive smokers.


Introduction
Indonesia is one of the countries with the thirdhighest number of smokers in the world, after China and India. 1 A 2015 study by the Research and Development Agency reported that Indonesia accounts for more than 230,000 deaths due to the consumption of tobacco products each year. 2 Smoking prevalence in Indonesia is 29.3% and 13 out of 33 provinces have smoking prevalence above the national average. 2 As a result, more people are exposed to or inhaled cigarette smoke exhaled by active smokers. Several studies explain that passive smokers are more susceptible to respiratory tract diseases than active smokers. 3 Riskesdas reported in 2018 the prevalence of passive smoking in a closed room, which was 32.4% exposed every day and 43.1% exposed only occasionally. 2 Cancer is an abnormal cell that divides without control, is invasive, and can invade surrounding tissues. 3 Cancer cells can spread to other parts of the body through the blood and lymph system. 3 Lung cancer is one of the most important causes of cancer In the early stages, lung cancer does not cause specific symptoms. 5 Generally more than 60% of patients are diagnosed in an advanced state due to the rapid growth of cancer cells. About 80-85% of all lung cancers are non-small cell lung cancer (NSCLC) and 15% are small cell lung cancer (SCLC). 5,6 The most common type of NSCLC is adenocarcinoma, which accounts for 40% of all lung cancer cases. These cells are derived from type II alveolar cells that secrete mucus and other substances. 6 Adenocarcinoma is the most common type of lung cancer that occurs in all people. 5.6 Cancers located in the central bronchi will cause symptoms of cough, hemoptysis, wheezing, stridor, shortness of breath, and pneumonitis, while cancers located in the periphery cause chest pain, cough, shortness of breath, and symptoms of lung abscess due to cavitation of the cancer mass. 6,7 Clinical diagnosis can be identified by sputum cytology examination as a histological examination. 7 If the nodule is centrally located bronchoscopy for biopsy and the mass is peripherally located transthoracal biopsy or

Types of molecules inhaled by passive smokers
Second-hand smoke, also known as environmental tobacco smoke, is a mixture of two clouds of smoke that come from burning tobacco, namely mainstream tobacco smoke and side stream tobacco smoke. 14.15 A non-smoker who inhales second-hand smoke consumes nicotine and other toxic chemicals in the same way as a smoker, so the more second-hand smoke is inhaled, the higher the levels of harmful substances that settle in the respiratory system. 15 Active smokers will inhale the main smoke (mainstream tobacco smoke) during inhalation, while passive smokers inhale the smoke produced from the end of a lit cigarette (side stream tobacco smoke) and smoke exhaled by active smokers (exhaled mainstream tobacco smoke). 15 16,18 The dose of smoke constituents received depends not only on the cigarette itself, but also on the duration and intensity of inhalation, the presence and competence of the filter, and the duration of cooling of the smoke before inhalation. 20 the main factor that determines the intensity of cigarette use is nicotine dependence on smokers to smoke more intensively with higher inhalations per minute and deeper inhalations to meet their nicotine needs so that the peripheral bronchi in the lungs will be exposed to smoke containing carcinogens compared to the major bronchi. 20  The influence of other carcinogens related to occupational exposures may also be responsible for the development of lung cancer. Workers exposed to asbestos and inhalation of dust containing arsenic, chromium, nickel or vinyl chloride and radon that interact synergistically with tobacco cigarettes in active smokers will increase the risk of developing lung cancer by about 55 times, while passive smokers who are exposed to asbestos exposure can increase the risk of lung cancer by 5 times. 21

Non-small cell lung cancer
In general, lung cancer is grouped into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC will be grouped into squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, while SCLC is classified histologically into a pure small cell, mixed small cell, and large cell carcinoma. 6

EGFR gene
The EGFR gene provides instructions for making a receptor protein called epidermal growth factor receptor (EGFR). The protein encoded by the EGFR gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. 25 EGFR is a cell surface protein that binds to epidermal growth factor. 26 Binding of proteins to ligands induces receptor dimerization and autophosphorylation of tyrosine by intrinsic tyrosine kinase activity leading to cellular proliferation. Mutations in EGFR are associated with several types of lung cancer. 26

Structure of the EGFR gene
The human EGFR gene is located on

Conclusion
The EGFR gene is expressed by 60% in NSCLC and represented 87% of all EGFR mutations observed in NSCLC patients from secondhand smoke which were also associated with lung cancer stage, gender, sample type, and treatment modality. EGFR mutation analysis by direct sequencing is the most studied and reliable method for predicting response to therapy. However, an increase in the number of copies of the EGFR gene can be seen because the mutation is the initial event of lung cancer carcinogenesis followed by gene amplification.
Thus, EGFR mutations and gene amplification status are important in determining the type of lung cancer that will respond to EGFR-TKI therapy.