Non-Small Cell Lung Cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of all diagnoses. It is fundamentally driven by genetic changes within the lung cells. Most NSCLC cases arise from genetic alterations that develop during a person’s lifetime, often due to environmental exposures. A minority of cases are linked to inherited changes that increase an individual’s susceptibility to the disease.
Defining the Genetic Landscape: Acquired vs. Inherited Changes
NSCLC develops from two distinct types of genetic errors: acquired and inherited changes. Understanding the difference between these two categories is fundamental to grasping the disease’s biology.
Acquired mutations, also known as somatic mutations, are the primary cause of most NSCLC cases. These changes occur in a single cell during a person’s life and are present only within the tumor cells, not in every cell of the body. They usually result from DNA damage caused by factors like tobacco smoke, air pollution, or random errors during cell division. These somatic mutations cannot be passed down to children.
In contrast, inherited mutations, or germline mutations, are passed down from a parent and are present in every cell of the body from conception. These changes do not typically cause the tumor directly but instead increase a person’s overall risk of developing NSCLC. They may affect how the body repairs damaged DNA or metabolizes cancer-causing toxins. Only about 8% of lung cancers are linked to these inherited changes.
Key Acquired Genetic Alterations Driving NSCLC
Acquired genetic alterations in NSCLC tumors act as “driver mutations,” providing cancer cells with a growth advantage. These changes flip an “on switch” for uncontrolled cell proliferation. Identifying these specific somatic changes is now a routine part of diagnosis because they determine which targeted therapies will be effective.
The Epidermal Growth Factor Receptor (\(EGFR\)) gene is mutated in 10% to 20% of European patients and 30% to 50% of East Asian patients with adenocarcinoma, a common NSCLC subtype. \(EGFR\) mutations cause the protein to become constantly active, continually signaling the cell to grow and divide. Kirsten Rat Sarcoma (\(KRAS\)) mutations are the most frequently detected oncogene in NSCLC, occurring in 20% to 40% of patients with lung adenocarcinoma, and are more common in current or former smokers.
Other alterations involve gene fusions, where a piece of one gene breaks off and joins with another, creating an abnormal, cancer-driving protein. The Anaplastic Lymphoma Kinase (\(ALK\)) rearrangement is found in 3% to 5% of NSCLC cases, often in younger patients who have never smoked. The \(ROS1\) fusion is present in 1% to 2% of non-small cell lung cancers and is typically seen in non-smokers. Other targetable alterations include changes in \(BRAF\), \(MET\), and \(RET\) genes.
The Role of Heredity and Family Risk
While most NSCLC cases are not hereditary, a family history of lung cancer represents an increased risk. Having a first-degree relative (a parent, sibling, or child) diagnosed with lung cancer increases an individual’s risk by approximately 50% compared to the general population. This increased risk is observed in both smokers and non-smokers, suggesting underlying genetic susceptibility.
The hereditary component is rarely linked to a single, highly penetrant gene. Instead, it is linked to small variations in multiple genes that collectively increase susceptibility. These inherited changes can affect the efficiency of DNA repair mechanisms or the body’s ability to detoxify carcinogens. For instance, certain inherited changes on chromosome 6 have been linked to a higher likelihood of developing the disease.
In rare instances, NSCLC can be part of a broader hereditary cancer syndrome, although this is uncommon. Certain germline mutations in tumor suppressor genes like \(TP53\) or \(RB1\) are associated with syndromes that include an elevated risk for lung cancer. For the majority of patients with a family history, the increased risk stems from a combination of inherited susceptibility genes and shared environmental exposures, like radon or secondhand smoke.
Genetic Testing and Targeted Treatment
The identification of acquired genetic alterations in NSCLC has transformed treatment through molecular profiling or genetic testing. This testing analyzes a tumor sample, usually obtained through a biopsy, to pinpoint the specific gene mutations or fusions driving the cancer’s growth. This process is also referred to as genomic or biomarker testing and is a fundamental step in personalizing care.
The primary purpose of this profiling is to identify “actionable” mutations—alterations for which a corresponding targeted therapy exists. Targeted therapies are drugs designed to specifically block the activity of the mutated protein causing the cancer cell to grow. For example, a patient with an \(EGFR\) mutation may receive an \(EGFR\) inhibitor that effectively shuts down the constant growth signal.
Targeted therapy offers a distinct advantage over traditional chemotherapy because it focuses on cancer cells while minimizing damage to healthy cells. This precision allows for a more personalized treatment plan, often involving oral medications. Identifying these specific genetic drivers is central to making informed decisions about the most effective treatment approach for patients with NSCLC.