Cancer is a genetic disease, which means that mutations in DNA are responsible for causing the condition. Mutations in lung cancer are mainly found in oncogenes, or genes that are normally involved in cell growth. These mutations result in faulty proteins that are always active and tell a cell to grow and divide continually. This growth becomes uncontrolled, and cancer develops.
Mutations can also be found in tumor suppressor genes (TSGs, also known as antioncogenes), which are responsible for controlling cell growth. When mutations occur in TSGs, the cell loses its ability to keep cell growth under control, which can result in cancer.
Oncogenes and TSGs work in balance to keep cells from dividing too quickly or too slowly. For example, oncogenes can be compared to the gas pedal in a car, and TSGs are the brakes. In cancer, the cells are accelerating on the gas with no brakes, leading to uncontrolled growth, division, and as a result, tumors.
There are two main forms of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Each form is classified by the types of lung cells affected. SCLC accounts for around 15 percent of lung cancer cases, and NSCLC makes up the other 85 percent.
NSCLC can be broken up into three subtypes: lung adenocarcinoma, large cell carcinoma, and squamous cell carcinoma. SCLC can be broken up into two subtypes: small cell carcinoma (oat cell cancer) and combined small cell carcinoma.
Lung cancer most often develops as a result of somatic mutations, or mutations that cannot be passed down through family. In rare cases, lung cancer can be caused by germline mutations, which can be passed down through family.
NSCLC commonly has mutations in a group of proteins known as receptor tyrosine kinases (RTKs). RTKs are proteins found on the cell surface that bind to signaling molecules known as growth factors. When this binding occurs, the RTK sends signals inside the cell telling them to grow and divide.
In healthy cells, there are processes in place to shut down RTKs once they have signaled. However, in cancer cells, this signaling does not stop and the cells grow uncontrollably. Examples of RTKs that play a role in NSCLC include epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK).
SCLC commonly has mutations in the TP53 gene but rarely has other mutations. Having few mutations can make SCLC difficult to treat because it cannot be treated with targeted therapies.
Epidermal growth factor receptor (EGFR) is a protein found on the outside of cells. When the signaling molecule epidermal growth factor (EGF) binds to the receptor, it tells the cell to grow and divide. Cells need a certain number of EGFR receptors in order to survive. In cancer, the EGFR gene can be mutated (as an oncogene) resulting in continuous and excessive signaling. When this happens, the cell will grow and divide uncontrollably.
EGFR mutations are the second most common genetic mutation found in NSCLC, accounting for about 10 percent to 20 percent of cases in white people, and at least 50 percent of cases in the Asian population. EGFR mutations are more likely to occur in people who do not smoke.
The anaplastic lymphoma kinase (ALK) gene is another protein involved in cell growth. Similar to EGFR, ALK is a receptor on the surface of cells that is responsible for telling cells to grow and divide. In lung cancer, specifically NSCLC, a mutated form of the ALK gene is fused with another gene, EML4. When this fusion occurs, the ALK receptor constantly signals to the cell to grow and divide, and it cannot be shut off. EML4-ALK mutations are classified as oncogenes.
EML4-ALK mutations occur in roughly 5 percent of NSCLC cases, especially in younger people, light smokers or non-smokers, and in those with advanced cases of NSCLC.
KRAS is a specialized enzyme, known as a GTPase, that helps send signals inside cells after an RTK binds to its signaling molecule. When it is mutated, KRAS is continuously active and cannot be shut off. As a result, it acts as an oncogene and keeps sending signals inside the cell to grow and divide, leading to cancer.
KRAS mutations are found in roughly 30 percent of lung adenocarcinomas (a subtype of NSCLC) and are most common in white people and those who smoke.
BRAF is an enzyme known as a kinase that is responsible for sending signals inside cells for growth and division. The most common mutation of BRAF in lung cancer is V600E, which continuously turns on the enzyme, leading to uncontrolled cell growth. BRAF is classified as an oncogene.
BRAF mutations are found in roughly 4 percent of NSCLC cases, specifically in lung adenocarcinoma. One percent to 2 percent of NSCLC cases have a BRAF V600E mutation, and many of these cases are linked to smoking.
Tumor protein p53, or TP53, is a gene that encodes for the protein p53. This protein is found in the nucleus of the cell and helps repair damaged DNA. DNA damage can occur for several reasons, including exposure to radiation, UV light, and chemicals. Cancer cells can also have damaged DNA because they divide too quickly and cannot repair the DNA.
When healthy cells sense this damage, p53 turns on other genes to help repair the DNA. P53 is considered a TSG and has even been given the nickname “guardian of the genome.” In lung cancer cells, however, p53 is often mutated so it cannot help repair damaged DNA. P53 mutations are almost always found in cases of SCLC but can also occur in NSCLC.
To diagnose and test for genetic mutations in lung cancer, a biopsy is often done to obtain tissue samples. Needle biopsies remove small pieces of tumor from the lungs, which are then prepared for molecular testing.
DNA sequencing is performed to look for mutations in genes commonly associated with lung cancer. Two types of sequencing can be done:
Once the mutations in your lung cancer have been identified, your doctor can prescribe targeted therapies to treat the cancer. These targeted therapies include tyrosine kinase inhibitors (TKIs), which work by blocking the function of RTKs (EGFR, ALK). Targeted therapies can be used as first-line therapies.
Besides TP53 mutations, some mutations found in lung cancer have their own set of targeted therapies used to treat them.
There are currently no drugs approved by the U.S. Food and Drug Administration (FDA) for treating KRAS-mutated lung cancer. However, there are a handful of clinical trials studying a new drug, sotorasib, for treating people with NSCLC.
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