Lung cancer is a complex disease driven by uncontrolled cell growth, and its development is fundamentally linked to changes in a cell’s genetic material. These changes, known as mutations, provide the instructions that transform a normal lung cell into a cancerous one. Understanding the specific genetic landscape of a tumor is now paramount, as it has shifted the focus of treatment from generalized approaches to highly personalized strategies. This genetic understanding is the foundation for modern precision medicine, which allows doctors to match a patient’s unique cancer profile to a targeted therapy.
Inherited Risk Versus Acquired Mutations
When discussing the genetics of lung cancer, it is important to distinguish between mutations inherited from a parent and those acquired during a person’s lifetime. Inherited, or germline, mutations are present in every cell of the body from birth and can increase a person’s lifetime susceptibility to developing cancer. However, only a small percentage of lung cancer cases, estimated to be around 8%, are linked to these hereditary factors, which means lung cancer is rarely an inherited disease.
The vast majority of lung cancer cases originate from acquired, or somatic, mutations, which occur only in the lung cells and are not passed down to children. These somatic changes happen as a result of DNA damage caused by environmental factors like tobacco smoke, air pollution, or radon gas. Because these acquired mutations directly cause tumor growth, they are the primary focus for treatment, which involves identifying and targeting the specific genetic change.
Key Genetic Drivers of Lung Cancer
Lung cancer cells accumulate multiple genetic changes, but a few specific mutations act as the primary “drivers” that initiate and sustain uncontrolled growth. These driver genes fall into two main categories: oncogenes and tumor suppressor genes. Oncogenes, such as EGFR, KRAS, ALK, and ROS1, are often mutated in a way that permanently switches them to an “on” state. This permanent activation causes the cell to constantly receive signals to grow and divide, leading to tumor formation.
For instance, EGFR mutations, which are common in non-smokers and patients with adenocarcinoma, typically involve deletions or point mutations that result in the continuous activation of the protein, promoting cell proliferation. Similarly, ALK and ROS1 often involve a rearrangement where the gene fuses with another, creating an abnormal, hyperactive protein that drives the cancer. A tumor suppressor gene like TP53 normally monitors DNA damage and forces a cell to self-destruct if the damage is too severe. When TP53 is mutated or inactivated, the damaged cells are allowed to survive and divide, enabling the accumulation of further cancer-promoting changes.
Molecular Profiling and Biomarker Testing
Identifying the specific genetic drivers in a tumor is a necessary step before treatment begins, a process known as molecular profiling or biomarker testing. This testing analyzes the tumor’s DNA, RNA, and protein levels to create a comprehensive genomic profile of the cancer. Oncologists use this information to determine if a patient has an “actionable” mutation, meaning one that can be targeted by a specific drug.
The testing is typically performed on a tissue sample obtained through a biopsy or surgery, but it can also be conducted using a liquid biopsy, which analyzes tumor DNA circulating in a patient’s blood. While a tissue biopsy may take a few weeks for results, a liquid biopsy can often provide results more quickly and is sometimes used when a tissue sample is unavailable or insufficient. This genomic analysis is used to select targeted therapies and assess predictive markers that help guide the use of immunotherapy.
Precision Medicine: Targeting Genetic Alterations
Precision medicine in lung cancer involves highly customized treatment based on the tumor’s genetic makeup. The goal is to match a patient’s specific genetic alteration with a corresponding targeted drug, which is generally more effective and causes fewer side effects than traditional chemotherapy. This strategy is particularly successful for cancers driven by oncogenes like EGFR and ALK.
For patients with activating EGFR mutations, targeted drugs called tyrosine kinase inhibitors (TKIs), such as osimertinib, are the standard first-line treatment. These small-molecule inhibitors work by blocking the activity of the hyperactive EGFR protein, effectively shutting down the continuous growth signal the cancer cells rely on. Similarly, if a tumor harbors an ALK gene rearrangement, a different class of TKIs, including alectinib or brigatinib, is used to inhibit the abnormal ALK protein. These targeted drugs significantly improve outcomes compared to chemotherapy.
Genetic analysis also plays a role in determining eligibility for immunotherapy, a treatment that harnesses the patient’s own immune system to fight the cancer. Two key genetic factors are assessed: PD-L1 expression and Tumor Mutational Burden (TMB). PD-L1 is a protein on the surface of some cancer cells that can bind to a receptor on immune cells, preventing the immune system from attacking the tumor. Tumors with high levels of PD-L1 expression often respond favorably to immune checkpoint inhibitors, which block this signaling pathway.
TMB measures the total number of mutations within the tumor’s DNA. A high TMB suggests the cancer is more likely to be recognized as foreign by the immune system, often correlating with a better response to immunotherapy. By combining the results of PD-L1 and TMB testing with the identification of specific driver mutations, doctors can select the most appropriate treatment, maximizing the chance of a positive outcome.