Genetic Mutations and Non-Small Cell Lung Cancer (NSCLC)
Genes exist in every cell of our bodies, directing specific processes, physical traits, and how we produce new cells. When a gene mutates, some of the body’s functions are affected. Some genetic mutations affect the body’s ability to divide cells correctly. In other cases, the mutation causes cells to divide faster than they should. This process leads to abnormal cell growth, which is how cancer develops.
There are two types of genetic mutations — somatic and germline mutations. Somatic mutations are related to factors outside the body, such as exposure to harmful chemicals or toxins. Germline mutations are hereditary or passed down from a family member. The genetic mutations related to the development of lung cancer are primarily somatic, usually the result of exposure to the chemicals in cigarette smoke.
More than one gene mutation can cause non-small cell lung cancer (NSCLC). Your oncologist will conduct biomarker testing to determine if you have any gene mutations related to lung cancer. The results of the tests will determine which drugs are likely to work best.
Which Gene Mutations Cause Non-small Cell Lung Cancer?
A mutation in one or more of the following genes is related to non-small cell lung cancer:
EGFR
EGFR, or epidermal growth factor receptor, determines how cells grow and divide. Mutations to this gene can cause cells to replicate uncontrollably. The EGFR genetic mutation is related to approximately 23% of NSCLC diagnoses. Individuals who have lung cancer related to an EGFR mutation will usually be diagnosed with an EGFR-positive cancer.
KRAS
The KRAS gene is responsible for the production of K-RAS protein. This protein relays the signals responsible for telling the cell when to replicate and divide and is also responsible for the differentiation of the cells. Found in about 30% of non-small cell lung cancer diagnoses, it’s most common in patients who have a history of smoking, and the mutation can occur in combination with other genetic mutations.
FGFR1
Found in up to 20% of non-small cell lung cancer patients, the FGFR1 mutation affects how your cells grow and spread. It's more likely to happen if you have the squamous carcinoma type of NSCLC and if you have a history of smoking.
ALK
ALK, or anaplastic lymphoma kinase, is commonly associated with lymphoma but is also found in non-small cell lung cancer. The ALK gene creates the gut and nervous system while a baby is still in the womb. This gene is typically turned off before birth but can sometimes reactivate or fuse with other genes. Either of these issues can lead to cancer.
This mutation, called ALK rearrangement or ALK fusion, occurs in up to 7% of NSCLC patients. These mutations are more common in young lung cancer patients and those who do not smoke.
MET
The MET gene mutation is often found in non-small cell lung cancer genetic test results, but there are two different ways this mutation can result in cancer. The first is through MET gene amplification. This means there are additional copies of the gene. Because MET is a growth receptor, the extra copies of the gene cause the cancer cells to grow more rapidly.
The other way the MET gene mutation can result in cancer is through what is called Exon 14 skipping. This happens when a crucial step is skipped in the cell breakdown process. Usually, when the MET protein is no longer needed, another protein called CBL and the gene Exon 14 break it down. However, when CBL joins with the other gene mutation related to MET, it is called exon 14 skipping. When the MET gene is mutated, the Exon 14 gene is skipped, and this causes the MET protein to stay longer than it should. This delay promotes cancer growth.
BRAF
The BRAF protein helps to control the rate of cell growth. Mutations in this gene create an abnormal protein. Unfortunately, this protein signals that the cells are supposed to grow and causes increased cell growth and cancer. The BRAF protein usually works with the MEK protein to regulate cell growth. You may hear lung cancer specialists discussing the MEK protein when working with patients with the BRAF mutation. This mutation is responsible for about 3-4% of patients who are diagnosed with non-small cell lung cancer and is found more often in patients who have a history of smoking.
ROS1
The ROS1 genetic mutation is rarely seen in non-small cell lung cancer patients and is found only in about 1-2% of individuals with NSCLC. This mutation is caused by the ROS1 gene fusing with another gene, leading to cell overgrowth and, ultimately, cancer. ROS1 is a genetic mutation that is found more often in younger patients and those without a history of smoking.
TP53
The TP53 gene helps to suppress damaged cells. Stopping cell replication is a process that is typically associated with reducing the risk of developing cancer. This gene makes a protein called P53. This protein targets abnormal cells and prevents additional cell replication. TP53 diagnoses are related to approximately 50% of cases. While this genetic mutation is one of the most common factors involved in cancer, it is rarely a recommended test because there are no targeted therapies designated to counteract this mutation. However, clinical research is underway to see if it’s possible to counteract this mutation and slow the growth of lung cancer cells.
NTRK
When a NTRK1, NTRK2, or NTRK3 gene fuses or joins with another gene, this causes an error in the NTRK gene resulting in abnormal, uncontrollable cell growth. These fusions are relatively rare but can occur in non-small cell lung cancer (less than 1% of cases). When NTRK gene fusions are present, they drive tumor growth and signal other cells to multiply further.
ERBB2
This gene is also known as HER2. When it mutates it results in an overexpression or amplification of the HER2 protein. When HER2 is amplified, it can boost cell growth contributing to cancer progression. This mutation is relatively rare in NSCLC compared to other cancers like breast cancer.
How to Determine the Genetic Mutations in NSCLC
Biomarker testing is required to determine if genetic mutations exist. This is usually completed after a diagnosis of non-small cell lung cancer, especially if the diagnosis is late-stage. It can be performed earlier for some patients.
Most biomarker tests are done using tissue collected during a biopsy or from tissue removed during lung cancer surgery. It is then evaluated in a lab where a pathologist looks for specific genetic mutations.
Another testing approach is called next-generation sequencing, or NGS. This study uses a machine to look for a variety of biomarkers simultaneously. These tests typically require a blood sample; doctors call this a liquid biopsy.
New NSCLC Treatments Can Target Genetic Mutations
The results of lung cancer biomarker testing will inform your cancer care team about genetic mutations that are present. Currently, targeted therapies focusing on specific gene mutations are available to Stage IV lung cancer patients or patients whose NSCLC has returned. Extensive research is underway to see how these treatments may be incorporated sooner in the treatment plans for NSCLC patients.
If the patient qualifies, targeted therapy cancer treatments are available for some of the genetic mutations. These drugs focus on the proteins causing the cancer to grow without harming the healthy cells around a tumor.
Some of the most common non-small cell lung cancer genetic mutations that have targeted therapies available are:
- EGFR-positive lung cancer and ALK-positive lung cancer - These types of cancer are frequently treated with a targeted therapy pill called a tyrosine kinase inhibitor or TKI. These drugs can control the cancer for months or even years, but they cannot cure advanced lung cancer.
- BRAF-positive lung cancer - This type of lung cancer can be treated with a combination of targeted therapies or an immunotherapy and chemotherapy combination.
- KRAS mutation - Most patients with the KRAS mutation will receive other first-line treatments, including surgery, radiation, chemotherapy, or immunotherapy. If the first-line treatments no longer work effectively, a KRAS inhibitor targeted therapy can be used in about half of patients.
There are other mutations your oncologist may treat with targeted therapy. There is extensive research ongoing, which will produce new drugs and ways to treat various genetic mutations associated with lung cancer.
Most patients receive other therapies along with targeted therapy to slow the growth of lung cancer. Several factors will help your oncology team determine your best lung cancer treatment plan. Your lung cancer specialist will help you identify treatment options based on your unique case and develop a personalized medication based on genetic mutations of lung cancer.
Related reading: Additional Therapies Bring New Hope to Lung Cancer Patients
Lung Cancer Care Based on Genetic Mutations in NSCLC Are Available in Virginia
At Virginia Oncology Associates, we offer the latest approaches for diagnosing and treating lung cancer. Our lung cancer specialists are experts in identifying the type of lung cancer you have and help you create a personalized treatment plan that meets your needs. Our cancer clinics are conveniently located in Chesapeake, Newport News, Norfolk, Suffolk (Harbour View and Obici), Virginia Beach, Williamsburg, Virginia, and Elizabeth City, North Carolina.
