No lung cancer (NSCLC: Non Small Cell Lung Cancer) - Gen EGFR.
There are two main types of lung cancer: small-cell carcinoma -microcítico- (SCLC: Small Cell Lung Cancer) and small cell lung cancer (NSCLC: Non-Samall Cell Lung Cancer). When a tumor has cells of both types is called "combined cell and non - small cell cancer , " but these are very rare. The distinction between SCLC and NSCLC is important because both are treated differently.
Cancer cell lung (NSCLC: Non-Small Cell Lung Cancer), is a cancer in which certain cells of the lungs become abnormal and multiply uncontrollably leading to the development of a tumor. This cancer represents between 85% and 90% of all cases of lung cancers and is divided into three main subtypes that differ in size, shape and cellular origin, but are grouped together because treatment and prognosis are very similar:
- Adenocarcinoma. Adenocarcinoma arises from the cells that normally secrete mucus and lining the alveoli located in the lungs. This type of lung cancer mainly occurs in current or former smokers, but it is also the most common type found in non - smokers lung cancer. It is more common in women than in men, and is more likely to occur in younger people compared to other types of lung cancer. This type of cancer tends to develop more slowly than other types of lung cancer, and is more likely to be detected before it has spread outside the lung. Overall, about 40% of lung cancers are adenocarcinomas.
- Squamous cell carcinoma (SCC: Squamous Cell Carcinoma). Squamous cell carcinoma arises from the squamous cells lining the bronchial tubes, so they appear in their vicinity. This type of cancer is more common in men than in women, and is usually associated with a history of smoking. About 25% to 30% of all lung cancers are squamous cell carcinomas.
- Lung carcinoma large cell (LCLC: Lung Cancer Cells Large). The large cell carcinoma describes cancers nonsmall cell lung adenocarcinomas appear to be not or squamous cell carcinomas. As the name suggests, the tumor cells are large when viewed under a microscope. This type of cancer develops from epithelial cells, so it appears anywhere in the lung. It tends to grow and spread quickly, which can make it more difficult to treat. Lung carcinoma large cell represents approximately between 10% and 15% of all lung cancers.
They may be combinations of the three types. There are also other types of lung cancers such as adenocarcinoma and adenosquamous carcinoma sarcomatoid, but are much less frequent.
Lung cancer non - small cell can trigger symptoms or not at its early stages. In some affected individuals, signs and symptoms include chest pain, frequent coughing, breathing problems, trouble swallowing or talking, mucosal bleeding, anorexia, weight loss, fatigue, and facial or neck edema. Most people who develop lung cancer have a history of consumption of snuff, so in smokers all types of lung cancers may appear, but the habit of smoking is more related cancers small cell lung (RBCs, SCLC). However, the disease can develop in people who have never smoked. Adenocarcinoma is the most common lung cancer in nonsmokers. The survival rate at 5 years for people with small cell lung cancer, it is usually between 11% and 17% of cases, but may be higher or lower depending on the subtype and stage when diagnosed .
There are many genes whose mutations have been associated with the development of lung cancer: p53, EGFR, MET, KRAS, BRAF, ERBB2, STK11, PIK3CA, NKX21, HMOX1, CDKN1A, GSTM1, FAS, FasL CASP8, CYP2A6, MPO , SOX2, DOK2, C10ORF97, ALK / EML4 ... of these, from the therapeutic point of view, it is interesting to study the EGFR gene, arranged inhibitors tyrosine kinase (gefitinib, erlotinib and afatinib), whose action is related with the presence of certain mutations in this gene. Genetic alterations in ALK / EML4 gene are relating to the activity of some newer drugs, inhibitors anaplastic linfomaquinasa ALK (crizotinib).
Cancer cell lung may be due to somatic mutations in the EGFR gene, located on the short arm of chromosome 7 (7p12). This gene encodes a protein called "epidermal growth factor receptor" (EGFR: Epidermal Growth Factor Receptor). This protein is found through the cell membrane, so that one end of the protein remains outside cell surface and the other end remains inside the cell surface. The inner end corresponds to the domain TK (tyrosine) protein (amino acids 688-875). When these proteins bind to other molecules (ligands), signaling pathways within cells that promote growth and cell division and cell survival are activated.
So far, we have identified at least 10 mutations in the EGFR gene associated with lung cancer. The mutations described so far have been: missense mutations (7), regulatory mutations (1) and repeating variations (2). Almost all mutations of EGFR gene appear during the life of the person affected (somatic mutations) and are only present in cancer cells. However, there are germline, inherited mutations that predispose to this type of cancer found in all body cells. Somatic mutations in the EGFR gene occurs more frequently in adenocarcinoma. These mutations have been described more frequently in lung cancers nonsmall of the Asian population (30-40%), while in the Caucasian population occur less frequently (10 to 15%). Mutations are more common in people with the disease who have never smoked. Most somatic mutations of EGFR gene are associated with lung cancer removed genetic material (deletion) in exon 19 or change nucleotides in exon 21. These gene changes result in a protein active receptor constitutively, even when it is not bound to a ligand. As a result, cells constantly proliferate and survive, leading to tumor formation.
Cancers nonsmall cell lung cancer (NSCLC), are not very sensitive to chemotherapy and / or radiation, so that surgery is the treatment of choice, especially when diagnosed early. In cancers nonsmall there are two genetic markers useful: mutations in EGFR (Epidermal Growth Factor Receptor) and ALK (Anaplastic Lymphoma Kinase) genes. Mutations in the EGFR gene are of interest as they relate to treatment with inhibitors of tyrosine kinase (gefitinib, erlotinib and afatinib), whereas mutations in the ALK gene are related to treatment with inhibitors anaplastic linfomaquinasa (crizotinib ).
Currently available tyrosine kinase inhibitors -gefitinib, erlotinib and afatinib-, for treating non small cell lung cancer. These molecules act by selectively inhibiting the tyrosine kinase domain of the epidermal growth factor receptor in tumor cells. Several studies have shown that patients respond to tyrosine kinase inhibitors have some mutations in the gene encoding the EGFR tyrosine kinase domain. However, only 10 to 35% of lung cancers nonsmall (NSCLC) have sensitivity related mutations in the EGFR gene. Keep in mind that mutations in the EGFR gene are race-dependent, that is found in approximately 50% of patients of Asian race, while only found in 10% of Caucasian patients (White race). These mutations consist of small deletions in exon 19 (delL747-A750) or nucleotide substitutions that change the amino acid resulting in exons 18 (G719C) and 21 (L858R and L861Q). In over 90% of cases correspond to the mutations responsible delL747-A750 (exon 19) and L858R (exon 21).
In addition, there are single nucleotide polymorphisms (SNP: Single Nucleotide Polymorphism), which do not involve any change of amino acid in the structure of the EGFR protein but has been shown to increase susceptibility to cancer. This is the case G2607A polymorphism (nucleotide substitution guanine by adenine nucleotide position 2607). This polymorphism predisposes to this type of cancer, regardless of age, smoking habit, sex or family history of cancer.
Mutations expressed protein are clustered close ATP Cleavage of this domain, wherein the amino acids mediate the binding of the compounds 4-anilinoquinazoline such as gefitinib and erlotinib. Possibly repositioning of these critical residues occurs, stabilizing its interaction with ATP and its competitive inhibitor, gefitinib or erlotinib. This explains both increased activation of the receptor upon binding of the natural ligand (ATP), like most competitive inhibition caused by the drug (gefitinib, erlotinib or afatinib). Thus, the increased sensitivity to the tyrosine kinase inhibitors is associated with mutations of the EGFR gene and contribute to the clinical response in certain patients with carcinoma NSCLC having such mutations.
Most cases of lung cancer are not related to changes in the genes inherited (germline mutations). That majority are associated with somatic mutations that occur only in certain cells in the lung. When lung cancer is related to changes in inherited genes, the risk of developing cancer is inherited in an autosomal dominant, which means that a copy of the altered in every cell gene is sufficient to increase the likelihood of developing cancer. It is important to note that people do not inherit the disease but a higher risk of developing cancer and more or less sensitivity to tyrosine kinase inhibitors. Not all people who inherit mutations in these genes will develop lung cancer.
Tests in IVAMI: in IVAMI perform detection of mutations associated with small cell lung cancer by EGFR gene amplification by PCR, followed by sequencing. Because mutations that indicate predisposition to this type of cancer, and increase the therapeutic response to inhibitory drugs tyrosine kinase, are in four exons of EGFR (exons 18, 19, 20 and 21), we performed only the study of these exons.
Samples recommended: in many cases treated by somatic mutations, not inherited, tissue samples should be sent from the tumor previously obtained or preserved, even if they are embedded in paraffin. In the samples of peripheral blood, they can be found only, inherited germline mutations. To study germline mutations can refer EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).