SNP Browser for Human [Homo sapiens] Genetic Disorders

DiseaseID	HGD57
Genetic Disorder	Lung Cancer
Gene Name	Ras association (RalGDS/AF-6) domain family member 1
Description	Lung cancer is a disease of uncontrolled cell growth in tissues of the lung. This growth may lead to metastasis, invasion of adjacent tissue and infiltration beyond the lungs. The vast majority of primary lung cancers are carcinomas of the lung, derived from epithelial cells. Lung cancer, the most common cause of cancer-related death in men and the second most common in women, is responsible for 1.3 million deaths worldwide annually. The most common symptoms are shortness of breath, coughing (including coughing up blood), and weight loss. The main types of lung cancer are small cell lung carcinoma and non-small cell lung carcinoma. This distinction is important because the treatment varies; non-small cell lung carcinoma (NSCLC) is sometimes treated with surgery, while small cell lung carcinoma (SCLC) usually responds better to chemotherapy and radiation. The most common cause of lung cancer is long term exposure to tobacco smoke. The occurrence of lung cancer in non-smokers, who account for fewer than 10% of cases, appears to be due to a combination of genetic factors, radon gas, asbestos, and air pollution,including second-hand smoke. Lung cancer may be seen on chest x-ray and computed tomography (CT scan). The diagnosis is confirmed with a biopsy. This is usually performed via bronchoscopy or CT-guided biopsy. Treatment and prognosis depend upon the histological type of cancer, the stage (degree of spread), and the patient's performance status. Possible treatments include surgery, chemotherapy, and radiotherapy. With treatment, the five-year survival rate is 14%.
Symptoms	Symptoms that suggest lung cancer include: dyspnea (shortness of breath) hemoptysis (coughing up blood) chronic coughing or change in regular coughing pattern wheezing chest pain or pain in the abdomen cachexia (weight loss), fatigue and loss of appetite dysphonia (hoarse voice) clubbing of the fingernails (uncommon) dysphagia (difficulty swallowing). If the cancer grows in the airway, it may obstruct airflow, causing breathing difficulties. This can lead to accumulation of secretions behind the blockage, predisposing the patient to pneumonia. Many lung cancers have a rich blood supply. The surface of the cancer may be fragile, leading to bleeding from the cancer into the airway. This blood may subsequently be coughed up. Depending on the type of tumor, so-called paraneoplastic phenomena may initially attract attention to the disease. In lung cancer, these phenomena may include Lambert-Eaton myasthenic syndrome (muscle weakness due to auto-antibodies), hypercalcemia or syndrome of inappropriate antidiuretic hormone (SIADH). Tumors in the top (apex) of the lung, known as Pancoast tumors, may invade the local part of the sympathetic nervous system, leading to changed sweating patterns and eye muscle problems (a combination known as Horner's syndrome), as well as muscle weakness in the hands due to invasion of the brachial plexus. Many of the symptoms of lung cancer (bone pain, fever, weight loss) are nonspecific; in the elderly, these may be attributed to comorbid illness. In many patients, the cancer has already spread beyond the original site by the time they have symptoms and seek medical attention. Common sites of metastasis include the bone, such as the spine (causing back pain and occasionally spinal cord compression), the liver and the brain. About 10% of people with lung cancer do not have symptoms at diagnosis; these cancers are incidentally found on routine chest x-rays
Causes	Lung cancer most commonly begins in the cells that line your lungs. Smoking causes the majority of lung cancers — both in smokers and in people exposed to secondhand smoke. But lung cancer also occurs in people who never smoked. In these cases, there may be no clear cause of lung cancer. Doctors have identified factors that may increase the risk. How smoking causes lung cancer Doctors believe smoking causes lung cancer by damaging the cells that line the lungs. When you inhale cigarette smoke, which is full of cancer-causing substances (carcinogens), changes in the lung tissue begin almost immediately. At first your body may be able to repair this damage. But with each repeated exposure, normal cells that line your lungs are increasingly damaged. Over time, the damage causes cells to act abnormally and eventually cancer may develop. Your lungs are full of blood vessels and lymph vessels, giving lung cancer cells easy access to travel to other parts of your body. For this reason, lung cancer may spread to other parts of your body before you experience any signs or symptoms. In many cases, lung cancer may spread before it can even be detected in the lungs. Types of lung cancer Doctors divide lung cancer into two major types based on the appearance of lung cancer cells under the microscope. Your doctor makes treatment decisions based on which major type of lung cancer you have. The two general types of lung cancer include: Small cell lung cancer. Small cell lung cancer, sometimes called oat cell carcinoma, occurs almost exclusively in heavy smokers and is less common than non-small cell lung cancer. Non-small cell lung cancer. Non-small cell lung cancer is an umbrella term for several types of lung cancers that behave in a similar way. Non-small cell lung cancers include squamous cell carcinoma, adenocarcinoma and large cell carcinoma.
Diagnosis	Performing a chest x-ray is the first step if a patient reports symptoms that may be suggestive of lung cancer. This may reveal an obvious mass, widening of the mediastinum (suggestive of spread to lymph nodes there), atelectasis (collapse), consolidation (pneumonia), or pleural effusion. If there are no x-ray findings but the suspicion is high (such as a heavy smoker with blood-stained sputum), bronchoscopy and/or a CT scan may provide the necessary information. Bronchoscopy or CT-guided biopsy is often used to identify the tumor type. The differential diagnosis for patients who present with abnormalities on chest x-ray includes lung cancer, as well as nonmalignant diseases. These include infectious causes such as tuberculosis or pneumonia, or inflammatory conditions such as sarcoidosis. These diseases can result in mediastinal lymphadenopathy or lung nodules, and sometimes mimic lung cancers.
Treatment	Treatment for lung cancer depends on the cancer's specific cell type, how far it has spread, and the patient's performance status. Common treatments include surgery, chemotherapy, and radiation therapy. Surgery If investigations confirm lung cancer, CT scan and often positron emission tomography (PET) are used to determine whether the disease is localised and amenable to surgery or whether it has spread to the point where it cannot be cured surgically. Blood tests and spirometry (lung function testing) are also necessary to assess whether the patient is well enough to be operated on. If spirometry reveals poor respiratory reserve (often due to chronic obstructive pulmonary disease), surgery may be contraindicated. Surgery itself has an operative death rate of about 4.4%, depending on the patient's lung function and other risk factors. Surgery is usually only an option in non-small cell lung carcinoma limited to one lung, up to stage IIIA. This is assessed with medical imaging (computed tomography, positron emission tomography). A sufficient pre-operative respiratory reserve must be present to allow adequate lung function after the tissue is removed. Procedures include wedge resection (removal of part of a lobe), segmentectomy (removal of an anatomic division of a particular lobe of the lung), lobectomy (one lobe), bilobectomy (two lobes) or pneumonectomy (whole lung). In patients with adequate respiratory reserve, lobectomy is the preferred option, as this minimizes the chance of local recurrence. If the patient does not have enough functional lung for this, wedge resection may be performed.Radioactive iodine brachytherapy at the margins of wedge excision may reduce recurrence to that of lobectomy. Chemotherapy Small cell lung carcinoma is treated primarily with chemotherapy and radiation, as surgery has no demonstrable influence on survival. Primary chemotherapy is also given in metastatic non-small cell lung carcinoma. The combination regimen depends on the tumor type. Non-small cell lung carcinoma is often treated with cisplatin or carboplatin, in combination with gemcitabine, paclitaxel, docetaxel, etoposide or vinorelbine.In small cell lung carcinoma, cisplatin and etoposide are most commonly used. Combinations with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan and irinotecan are also used. Adjuvant chemotherapy for non-small cell lung carcinoma Adjuvant chemotherapy refers to the use of chemotherapy after surgery to improve the outcome. During surgery, samples are taken from the lymph nodes. If these samples contain cancer, then the patient has stage II or III disease. In this situation, adjuvant chemotherapy may improve survival by up to 15%. Standard practice is to offer platinum-based chemotherapy (including either cisplatin or carboplatin). Adjuvant chemotherapy for patients with stage IB cancer is controversial as clinical trials have not clearly demonstrated a survival benefit. Trials of preoperative chemotherapy (neoadjuvant chemotherapy) in resectable non-small cell lung carcinoma have been inconclusive. Radiotherapy Radiotherapy is often given together with chemotherapy, and may be used with curative intent in patients with non-small cell lung carcinoma who are not eligible for surgery. This form of high intensity radiotherapy is called radical radiotherapy. A refinement of this technique is continuous hyperfractionated accelerated radiotherapy (CHART), where a high dose of radiotherapy is given in a short time period. For small cell lung carcinoma cases that are potentially curable, in addition to chemotherapy, chest radiation is often recommended. The use of adjuvant thoracic radiotherapy following curative intent surgery for non-small cell lung carcinoma is not well established and controversial. Benefits, if any, may only be limited to those in whom the tumor has spread to the mediastinal lymph nodes. For both non-small cell lung carcinoma and small cell lung carcinoma patients, smaller doses of radiation to the chest may be used for symptom control (palliative radiotherapy). Unlike other treatments, it is possible to deliver palliative radiotherapy without confirming the histological diagnosis of lung cancer. Patients with limited stage small cell lung carcinoma are usually given prophylactic cranial irradiation (PCI). This is a type of radiotherapy to the brain, used to reduce the risk of metastasis. More recently, PCI has also been shown to be beneficial in those with extensive small cell lung cancer. In patients whose cancer has improved following a course of chemotherapy, PCI has been shown to reduce the cumulative risk of brain metastases within one year from 40.4% to 14.6%. Recent improvements in targeting and imaging have led to the development of extracranial stereotactic radiation in the treatment of early-stage lung cancer. In this form of radiation therapy, very high doses are delivered in a small number of sessions using stereotactic targeting techniques. Its use is primarily in patients who are not surgical candidates due to medical comorbidities. Interventional radiology Radiofrequency ablation should currently be considered an investigational technique in the treatment of bronchogenic carcinoma. It is done by inserting a small heat probe into the tumor to kill the tumor cells. Targeted therapy In recent years, various molecular targeted therapies have been developed for the treatment of advanced lung cancer. Gefitinib (Iressa) is one such drug, which targets the tyrosine kinase domain of the epidermal growth factor receptor (EGF-R) which is expressed in many cases of non-small cell lung carcinoma. It was not shown to increase survival, although females, Asians, non-smokers and those with bronchioloalveolar carcinoma appear to derive the most benefit from gefitinib. Erlotinib (Tarceva), another tyrosine kinase inhibitor, has been shown to increase survival in lung cancer patients and has recently been approved by the FDA for second-line treatment of advanced non-small cell lung carcinoma. Similar to gefitinib, it appeared to work best in females, Asians, non-smokers and those with bronchioloalveolar carcinoma. The angiogenesis inhibitor bevacizumab (in combination with paclitaxel and carboplatin) improves the survival of patients with advanced non-small cell lung carcinoma. However this increases the risk of lung bleeding, particularly in patients with squamous cell carcinoma. Advances in cytotoxic drugs, pharmacogenetics and targeted drug design show promise. A number of targeted agents are at the early stages of clinical research, such as cyclo-oxygenase-2 inhibitors, the apoptosis promoter exisulind, proteasome inhibitors, bexarotene and vaccines. Future areas of research include ras proto-oncogene inhibition, phosphoinositide 3-kinase inhibition, histone deacetylase inhibition, and tumor suppressor gene replacement.