Genetic Mutations and Non-Small Cell Lung Cancer

Every cell is made up of genes, which determine how the cell functions, grows, and changes. When the genetic makeup of a cell mutates, it affects the cell's ability to divide properly and stop dividing when necessary. Genetic mutations lead to abnormal cell behavior, which can lead to cancer development. 

There are different types of genetic mutations, which can happen for different reasons. Two types of gene mutations are somatic and germline mutations. Somatic mutations are related to outside factors, such as exposure to toxins or harmful chemicals. Germline mutations are hereditary, meaning they are passed down from a family member. The genetic mutations related to the development of lung cancer tend to be primarily somatic. 

Non-small cell lung cancer (NSCLC) can be caused by several different gene mutations. Being aware of any gene mutations that are responsible for a lung cancer diagnosis can help with targeting the treatment plan that will work best. 

Types of Gene Mutations in NSCLC

Non-small cell lung cancer genetic mutations may be related to the following genes:

EGFR

EGFR gene mutations are related to up to 23% of non-small cell lung cancer cases. EGFR stands for epidermal growth factor receptor and it helps cells grow and divide. If it is found that a person has lung cancer related to the EGFR mutation, they will likely be diagnosed as having EGFR-positive cancer. 

TP53

The TP53 gene helps to suppress damaged cells, a process that typically helps reduce the risk of developing cancer. This gene produces a protein called P53, which naturally targets abnormal cells to prevent issues. TP53 gene mutations are commonly involved in NSCLC, related to about 50% of cases. Although this gene mutation is commonly at play with non-small cell lung cancer, many doctors do not recommend testing for it since there is not yet a targeted therapy designed for it. 

KRAS

Mutations of the gene KRAS are found in about 30% of non-small cell lung cancer cases. The KRAS mutation is usually found in people who have smoked and can occur with other gene mutations as well, such as TP53, STK11, and KEAP1. 

MET

There are two different ways that the MET gene can mutate in lung cancer. One is called MET gene amplification, which means that there are extra copies of the gene. MET is a growth receptor, so when there are high copies of this gene, extra growth signals can cause cancer cells to grow. 

The other gene mutation related to MET is called exon 14 skipping. This mutation occurs when an essential step in the cell breakdown process gets skipped. When the MET protein isn’t needed anymore, there is another protein called CBL that helps to break it down. 

CBL joins with MET, and another gene called exon 14 helps with the breakdown process. When the MET gene is mutated in this way, the exon 14 gene gets skipped, causing MET proteins to stick around for longer than they are supposed to, which can prompt cancer growth. 

Anaplastic lymphoma kinase (ALK)

ALK stands for anaplastic lymphoma kinase. ALK gene mutations are sometimes seen in lymphoma, but they are also seen in NSCLC as well. The ALK gene exists in the body while you are still developing in the womb, aiding in the development of the gut and nervous system. 

Usually, the gene turns off before birth but for some people, it turns back on and joins or fuses with other genes, which can lead to lung cancer. This type of genetic mutation is called an ALK fusion or ALK rearrangement. ALK gene mutations are more commonly seen in lung cancer patients who do not smoke and who are younger.

ROS1

ROS1 gene mutations are only seen in about 1% to 2% of lung cancer patients. If your lung cancer doctor finds that you have cancer related to a mutation in the ROS1 gene, you’ll be told you have ROS1-positive cancer. The ROS1 gene can fuse with another gene, leading to excessive cell growth and cancer. ROS1 gene mutations are commonly seen in lung cancer patients who are younger and do not have a smoking history. 

BRAF

The BRAF protein is responsible for controlling cell growth. Mutation in the BRAF gene can cause an abnormal protein to be created, sending abnormal cell growth signals. This leads to uncontrolled cell growth and cancer. The BRAF protein usually works with another protein called MEK to help regulate cell growth. For this reason, you may hear lung cancer specialists talk about the MEK protein when determining the best treatment to target a BRAF mutation. This gene mutation is commonly seen in people who have a history of smoking, and it affects about 3% to 4% of patients with NSCLC. 

RET

Alterations in RET can occur when the gene is moved around and fused to other genes, creating a “fusion” protein that is hyperactive and drives tumor growth. There are 2 FDA approved medications that target these fusion proteins that can halt and reverse tumor growth. RET is commonly tested by many genomic panels used in cancer care. RET alterations occur in 1-2% of lung cancers.

NTRK

Fusions can also occur in the NTRK proteins. This is another alteration that has FDA approved oral medications. This is very rare and less than 1% of lung cancers have this change.

How Are Genetic Mutations of Lung Cancer Determined?

If you receive a diagnosis of non-small cell lung cancer, your doctor will likely recommend testing to look for genetic mutations. You may hear of this testing referred to as biomarker testing. There are several different ways that pathologists test for genetic mutations. 

A biomarker test is usually done as part of a tissue biopsy. This means that a small piece of tissue is removed and sent to a lab for testing. Biopsies for lung cancer can be performed in several different ways, including a long needle inserted through the skin or a scope placed down the throat. 

Your tissue sample will be analyzed in a lab where a pathologist can look for certain genetic mutations in the cells. 

Another common approach is called next-generation sequencing (NGS). This approach uses a machine that looks for several different biomarkers all at once. Your doctor may recommend a liquid biopsy to test for biomarkers, which involves using a blood sample for testing. 

There are two ways to test for genetic changes for lung cancer. The first is to use the pathology tissue from a biopsy sample. The second is to draw circulating blood and send it for analysis to look for circulating cancer cells and DNA in the bloodstream, particularly if patients have evidence of high amounts of cancer at baseline. Your doctor may do one, or both of these tests, possibly at the same visit to increase the effectiveness of testing and detection.

NSCLC Treatment That Targets Gene Mutations

The treatment your lung cancer doctor recommends for NSCLC will depend on your specific diagnosis. Knowing your biomarkers and if there are any gene mutations at play will help your doctor recommend treatment.

Non-small cell lung cancer caused by genetic mutations are often treated with targeted therapies, which specifically target certain proteins on the cells to kill cancer cells with minimal damage to the healthy surrounding cells. Your treatment will also depend on the NSCLC stage or whether it has spread throughout the body.

Common treatment approaches for NSCLC based on genetic mutations include:

  • BRAF-positive lung cancer is commonly treated with targeted therapies such as dabrafenib and trametinib (drugs that specifically target this mutation) or immunotherapy. 
  • NSCLC caused by KRAS mutation is commonly treated with surgery, radiation, chemotherapy, or immunotherapy. A combination of these treatment types may be used based on the cancer’s stage.
  • EGFR-positive lung cancer may be treated with a type of targeted therapy drug called tyrosine kinase inhibitors (TKIs). There are multiple different TKIs, including Afatinib, Dacomitinib, Erlotinib, Gefitinib, and Osimertinib. 
Advances in Targeted Therapy for Lung Cancer Treatment

Related Reading

New Technologies in Targeted Therapy for Advanced NSCLC Treatment

The best lung cancer treatment plan will vary depending on several factors. Your lung cancer specialist will work closely with you to determine a cancer treatment based on genetic mutations, the stage of the cancer, and any other health conditions you have. 

Clinical trials are currently underway to develop new targeted therapies for lung cancer based on specific genetic mutations. The WVCI team is excited to be able to participate in some of these trials, making it possible to provide the most advanced lung cancer treatments to our patients.

Lung Cancer Care Based on Genetic Mutations of NSCLC at WVCI

Willamette Valley Cancer Institute and Research Center offers state-of-the-art approaches for diagnosing and treating lung cancer. Our cancer experts can help to pinpoint the type of lung cancer you have to recommend a personalized treatment plan. Our cancer clinics are located in Albany, Corvallis, Eugene, Florence, Lincoln City, and Newport, Oregon​​; schedule your visit today. 

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