Cancer develops through the accumulation of genetic changes, known as somatic mutations, within a cell’s DNA. These alterations occur throughout a person’s lifetime due to errors in DNA replication or exposure to environmental factors. A normal cell becomes cancerous only after acquiring mutations that disrupt the balance of cell growth and division. Genomic sequencing shows that cancer cells harbor thousands of these changes, but only a small fraction are directly responsible for driving the disease. Scientists classify these alterations based on their functional role in promoting or failing to promote the uncontrolled growth that characterizes malignancy.
Defining the Two Key Types of Somatic Mutations
The genetic alterations found in a tumor are divided into two major categories: driver mutations and passenger mutations. Driver mutations confer a selective growth advantage to the cell, actively promoting the development and progression of cancer. These changes transform a normal cell into one with malignant properties, such as sustained proliferation or resistance to cell death.
These driver events are often found in a small number of genes, like TP53 or KRAS, and are positively selected for because they enhance the fitness of the cancer cell population. In contrast, passenger mutations are somatic alterations that do not provide any selective advantage to the cell and do not directly contribute to the cancer phenotype. They are essentially neutral or only mildly harmful to the cell that carries them.
Passenger mutations are present because they occurred in a cell that subsequently acquired a driver mutation, essentially “hitchhiking” along with the successful cell line. When the driver mutation causes rapid proliferation, all the non-functional passenger mutations present in the original cell are copied and passed down. This explains why a typical solid tumor contains tens of thousands of mutations, with an estimated 97% being passengers.
The distinction between the two types is one of function, not location, though driver mutations tend to recur in the same genes across many different patients. A driver mutation is like the accelerator in a car, actively causing movement, while a passenger mutation is like a scratch on the car’s paint that has no influence on its speed or direction. The sheer volume of passenger mutations makes them a pervasive feature of the cancer genome.
How Passenger Mutations Accumulate
The high number of passenger mutations is rooted in genomic instability, a fundamental characteristic of cancer. Cancer cells often have defective DNA repair machinery, meaning errors during replication are not corrected effectively. This failure results in a dramatically increased mutation rate compared to healthy cells.
The rapid rate of cell division further exacerbates this issue, as each division is an opportunity for new errors to be introduced. Passenger mutations are largely random errors resulting from this accelerated replication process. They are acquired continuously over the entire period of tumor growth, accumulating proportionally to the age of the tumor and the cell’s mutation rate.
Exposure to environmental mutagens also contributes significantly to this accumulation. For instance, the mutational patterns seen in lung cancers are often linked to chemicals in tobacco smoke, while skin cancers bear the signature of ultraviolet radiation damage. These external factors introduce random changes across the genome, most of which fall in non-functional regions or functional genes without affecting cell fitness, classifying them as passengers.
The Impact on Tumor Evolution
While passenger mutations were traditionally viewed as harmless genetic baggage, modern cancer biology acknowledges their indirect impact on tumor evolution. The accumulation of thousands of passengers is the primary source of genetic diversity within a single tumor, known as tumor heterogeneity. This diversity means that not all cancer cells are genetically identical, even if they share the same core driver mutations.
This genetic reservoir provides the raw material for natural selection within the tumor microenvironment. Although an individual passenger mutation might be neutral, the collective diversity increases the tumor’s ability to adapt to new selective pressures, such as changes in nutrient supply or the introduction of a drug. A highly heterogeneous tumor is more likely to contain a subclone of cells that possess a genetic trait enabling survival under stress.
Recent research has challenged the notion of passengers as purely neutral, suggesting that many are mildly deleterious, meaning they slightly reduce the fitness of the cancer cell. The constant accumulation of these slightly harmful mutations, a process sometimes called “mutational meltdown,” can slow tumor growth or even lead to periods of dormancy. This suggests that tumor progression is a constant evolutionary tug-of-war between the growth-promoting drivers and the collectively damaging effects of the passengers.
A subset of passenger mutations can also impact the tumor’s visibility to the immune system. The process of generating new proteins from these mutations creates “neoantigens” on the cell surface, which the immune system can recognize as foreign. A high total number of passenger mutations, or a high mutational load, can therefore make a tumor more immunogenic, potentially affecting how it responds to certain immunotherapies.
Clinical Significance for Cancer Treatment
Distinguishing between driver and passenger mutations is a central challenge in modern genomic medicine. When a tumor’s DNA is sequenced, scientists must use computational tools to filter out the numerous passengers and identify the few actionable drivers. Identifying these drivers is paramount because they are the targets for precision medicine, where specific drugs inhibit the function of the mutated protein fueling the cancer.
Passenger mutations are not just “noise” to be ignored; their patterns hold diagnostic information. The characteristic types and contexts of passenger mutations, known as mutational signatures, can be analyzed to trace the underlying cause of the cancer. A signature of specific DNA damage might indicate past exposure to smoking, UV light, or a defect in a particular DNA repair pathway, offering clues about the tumor’s biology and origin.
The total number of passenger mutations, or the tumor mutational burden, has become a valuable biomarker in treatment selection. Tumors with a high mutational burden often respond favorably to checkpoint inhibitor immunotherapies. This is because the high number of passenger-derived neoantigens makes the cancer cells more visible to the patient’s immune system. Passenger mutations are now an indirect but important consideration for guiding clinical decisions.