Lung cancer involves the uncontrolled growth of abnormal cells within the lungs, forming tumors that impede normal lung function. This disease is fundamentally rooted in changes to the genetic material within these cells. These alterations disrupt the precise instructions that govern cell growth, division, and death, driving the transformation of healthy lung cells into cancerous ones.
Understanding Genetic Changes in Lung Cancer
Genes are segments of DNA that provide instructions for cell function. In cancer, changes to these instructions, known as mutations, cause cells to behave abnormally, leading to unchecked growth.
Most lung cancer mutations are acquired during a person’s lifetime, called somatic mutations, occurring in specific lung cells. Factors like tobacco smoke or environmental carcinogens can induce these. Less commonly, inherited germline mutations are present in all body cells. However, the vast majority of lung cancer cases arise from acquired mutations.
Certain acquired mutations, called “driver mutations,” actively promote cancer growth. These frequently affect genes controlling cell proliferation, survival, or DNA repair. Identifying driver mutations is important, as they often represent direct targets for precise cancer treatments.
Common Mutated Genes in Lung Cancer
Genetic analysis has revealed several common mutations that drive non-small cell lung cancer (NSCLC), the most prevalent type. These genetic changes disrupt normal cellular processes, leading to uncontrolled growth. Understanding these mutations is a significant step toward personalized treatment strategies.
Epidermal Growth Factor Receptor (EGFR)
The Epidermal Growth Factor Receptor (EGFR) gene plays a role in cell growth and division. Mutations in EGFR, such as exon 19 deletions and L858R substitutions in exon 21, cause the receptor to be constantly activated, leading to continuous cell proliferation. These mutations are found in 10-15% of lung cancers, often in adenocarcinomas and more frequently in non-smokers and Asian populations.
Anaplastic Lymphoma Kinase (ALK)
The Anaplastic Lymphoma Kinase (ALK) gene, when fused with other genes like EML4, forms an abnormal protein that continuously signals for cell growth. ALK rearrangements are observed in 4-5% of NSCLC cases, particularly in younger, non-smoking patients.
KRAS
The KRAS gene is an oncogene involved in cell growth and division. Mutations in KRAS, particularly the G12C variant, cause this gene to be constantly active, leading to uncontrolled cell division. KRAS mutations are the most common genetic alteration in lung cancer, occurring in 25-30% of NSCLC adenocarcinomas and more prevalent in patients with a smoking history.
ROS1
The ROS1 gene encodes a receptor tyrosine kinase that contributes to cell growth. ROS1 can fuse with other genes, creating a fusion protein that continuously drives abnormal cell growth. ROS1 fusions are found in 1-2% of NSCLC patients, often in younger individuals with adenocarcinoma and little to no smoking history. These fusions are typically mutually exclusive with EGFR and ALK mutations.
BRAF
The BRAF gene regulates cell growth. Its mutations, particularly BRAF V600E, lead to abnormal protein production that sends constant growth signals. BRAF mutations are present in 1-2% of NSCLC patients, more frequently found in women, adenocarcinomas, and often in patients with a smoking history.
MET
The MET gene is involved in cell growth and survival. Its alterations, such as exon 14 skipping mutations, lead to increased signaling that promotes cancer. MET exon 14 skipping mutations occur in 2-4% of NSCLC cases, frequently observed in older patients, often women, and non-smokers.
RET
The RET gene is a proto-oncogene. RET gene fusions, where RET joins with another gene, lead to uncontrolled cell growth signals. These fusions are identified in 1-2% of NSCLC patients, typically in adenocarcinomas, and are often seen in younger, non-smoking patients. RET fusions are generally mutually exclusive with other common driver mutations like EGFR or ALK.
TP53
The TP53 gene is a tumor suppressor that regulates the cell cycle, repairs DNA damage, and triggers cell self-destruction. Mutations in TP53 are highly frequent in lung cancer, found in many NSCLC cases. When mutated, TP53 loses its ability to control cell proliferation, allowing damaged cells to divide uncontrollably.
NTRK
The NTRK genes (NTRK1, NTRK2, NTRK3) encode TRK proteins. Fusions involving NTRK genes can create oncogenic proteins that drive uncontrolled cell growth. Although rare, occurring in less than 1% of NSCLC cases, NTRK fusions are important because effective targeted therapies exist for them.
How Gene Mutations Guide Treatment
Identifying specific gene mutations in lung cancer has transformed treatment approaches, ushering in an era of precision medicine. This strategy tailors medical care to individual patients based on their tumor’s unique genetic profile, contrasting with traditional chemotherapy that broadly targets rapidly dividing cells.
Detecting these mutations typically begins with gene testing on a tumor tissue sample obtained through a biopsy. For cases where tissue collection is challenging, a less invasive liquid biopsy can be utilized. This blood test analyzes cell-free DNA shed by tumor cells into the bloodstream, providing a snapshot of the tumor’s genetic irregularities.
The presence of specific mutations allows doctors to select “targeted therapies.” These drugs are designed to block the activity of the mutated gene or the abnormal proteins it produces, disrupting cancer growth pathways. For example, if an EGFR mutation is identified, therapies like tyrosine kinase inhibitors can be used to inhibit the overactive EGFR pathway.
Targeted therapies offer several advantages over conventional chemotherapy. They are more precise, primarily attacking cancer cells while sparing most healthy cells, which often leads to fewer side effects. This personalized approach can result in improved treatment responses and better overall outcomes for patients whose tumors harbor these specific genetic alterations. This advancement in understanding the genetic basis of lung cancer allows for more effective and less toxic treatment options, significantly improving the quality of life for many individuals.