The Epidermal Growth Factor Receptor (EGFR) is a protein found on the surface of many cells. Its primary role is to act as a receiver for external signals, such as growth factors, which instruct the cell to grow and divide. When the gene that produces the EGFR protein undergoes a change, the resulting protein can become permanently active, like a switch stuck in the “on” position. This uncontrolled signaling drives the abnormal proliferation of cells, a hallmark of cancer, particularly Non-Small Cell Lung Cancer (NSCLC). Determining if this gene change is present from birth or develops later determines the risk for an individual and their family.
Understanding Somatic and Germline Mutations
Genetic changes are categorized by the type of cell in which they originate, determining if they can be passed down through generations. A germline mutation occurs in the reproductive cells, specifically the sperm or the egg, and is therefore incorporated into the DNA of the developing embryo at conception. Because the mutation is present in the first cell, it is copied into virtually every cell in the resulting person’s body. Thus, a germline mutation is inherited from a parent and can be passed on to the person’s own children.
In contrast, a somatic mutation is an acquired change that happens after conception in any non-reproductive cell, such as a lung or skin cell. These changes can be passed on to all daughter cells that result from the mutated cell’s division, which is how a tumor grows. However, because the change is confined to non-reproductive tissues, it cannot be inherited by offspring.
The Dominant Form: Acquired Somatic EGFR Changes
The vast majority of clinically significant EGFR mutations found in cancers are acquired somatic changes that occur during a person’s lifetime. These mutations are confined to the tumor cells and are not found in the patient’s healthy tissues or passed to their children. The two most common types of activating EGFR mutations are deletions in Exon 19 and the L858R point mutation in Exon 21, which together account for over 80% of all EGFR mutations in NSCLC. These changes are detected in about 10–15% of NSCLC cases in Western populations, with prevalence reaching 40–50% in East Asian populations.
The acquisition of a somatic EGFR mutation generally results from random errors during DNA replication and cell division. These errors accumulate as a person ages, increasing cancer risk. Environmental factors, such as exposure to carcinogens or general genetic instability, can also contribute to these changes in the lung tissue. The presence of these mutations is a predictive factor for response to targeted therapies called tyrosine kinase inhibitors (TKIs), which block the overactive EGFR signaling pathway. This confirms that these changes are the primary driver of the tumor’s growth, highlighting their sporadic nature.
When EGFR Mutations Are Inherited
While the majority of EGFR mutations are acquired, rare exceptions exist where a germline EGFR change is inherited, predisposing an individual to cancer. This scenario involves specific, less common variants, such as the EGFR T790M mutation, R776H, or G724S, which are present in the germline. These inherited mutations are associated with a familial syndrome that significantly increases the lifetime risk of developing lung cancer, often at a younger age. Studies show that over half of individuals carrying the germline EGFR T790M variant may develop lung cancer by age 60.
The inherited EGFR mutation does not immediately cause cancer but acts as a strong vulnerability requiring a second somatic change to activate the disease. For instance, tumors developing in individuals with germline EGFR T790M almost always acquire a second, typical EGFR driver mutation, such as Exon 19 deletion, in the same cell. This two-step process confirms inherited vulnerability coupled with a later-life acquired event. Individuals with a strong family history of lung cancer, especially those with multiple affected first-degree relatives and EGFR-positive tumors, may be candidates for germline testing and genetic counseling. Genetic counseling is important to accurately assess the familial risk and discuss potential surveillance strategies, such as regular computed tomography (CT) scans, for early detection in high-risk family members.