Cancer develops when cells acquire changes in their DNA, known as somatic mutations, which are not inherited but occur during a person’s lifetime. These genetic alterations disrupt the tightly controlled processes of cell growth and division, leading to the uncontrolled proliferation that defines the disease. The transformation of a normal cell into a cancerous one is driven by the accumulation of these genetic mistakes. Not all mutations detected within a tumor contribute to its growth and spread, which necessitates classifying them to understand the disease accurately.
Fundamental Distinction: Driver vs. Passenger
The vast number of mutations discovered in a typical tumor genome are sorted into two primary categories: driver mutations and passenger mutations. Driver mutations confer a selective growth advantage to the cell, actively pushing the transformation process forward. These alterations initiate or promote the uncontrolled growth and survival of the cell lineage.
In contrast, passenger mutations are random genetic changes that do not contribute to the development or progression of the tumor. They are “hitchhikers” that arise coincidentally in a cell that has also acquired a driver mutation. The presence of a passenger mutation does not provide any functional benefit or disadvantage to the tumor’s ability to grow.
This distinction is based on the mutation’s impact on cellular fitness, which is the net replication rate of the cell compared to its neighbors. A driver mutation is positively selected because it increases this fitness, allowing the cell to outcompete normal cells. Passenger mutations are carried along through cell division without being actively selected for or against.
The Mechanisms of Driver Mutations
Driver mutations disrupt the normal regulatory pathways that control cell proliferation and survival. These alterations typically affect one of two major classes of genes: oncogenes and tumor suppressor genes. The resulting change provides a growth advantage, allowing the mutated cell to divide more rapidly or resist programmed cell death.
Proto-oncogenes normally regulate cell growth and division, but become cancer-promoting oncogenes when they acquire a gain-of-function driver mutation. This mutation is often compared to stepping on the cell’s accelerator, as it results in the protein product being overactive or constantly “on,” promoting uncontrolled cell division. Examples include mutations in genes like BRAF or KRAS.
The second category is tumor suppressor genes, which act as the cell’s brakes, restricting proliferation and triggering repair or cell death. Driver mutations here are typically loss-of-function changes that inactivate the gene, such as an early stop codon or a large deletion. For these genes, both copies must usually be inactivated for the cancer-promoting effect to take hold, effectively cutting the brakes on cell growth. This selective advantage allows the cell population to expand and dominate over time.
Accumulation and Neutrality of Passenger Mutations
Passenger mutations accumulate as an unavoidable byproduct of the high rate of cell division and the associated genomic instability characteristic of cancer. Cancer cells frequently have defects in their DNA repair mechanisms, causing them to acquire genetic changes much more rapidly than normal cells. Every time a cancer cell divides, new random mutations are introduced across the genome.
Since passenger mutations do not affect the cell’s fitness, they are simply carried along as the cell lineage expands, a process known as clonal expansion. A typical solid tumor can contain tens of thousands of mutations, with the vast majority—as high as 97%—being passengers. These mutations are often unique to an individual tumor.
While traditionally viewed as neutral, recent studies suggest that a large load of passenger mutations can be mildly deleterious to the cancer cell. This accumulation can collectively slow the tumor’s growth rate or make it more vulnerable to certain therapies. However, their primary characteristic remains their lack of a direct, positive role in driving the disease.
Why the Distinction Matters for Treatment
Distinguishing between driver and passenger mutations is fundamental to modern cancer treatment and research, forming the basis of precision oncology. Targeted therapies are designed to inhibit the protein product of a driver mutation. By targeting the specific mechanism actively driving the cancer’s growth, these drugs can stop the proliferation of tumor cells.
A drug designed to inhibit a passenger mutation would be ineffective because that mutation is merely a bystander and not causally involved in the cancer’s survival. Identifying the few active drivers among the thousands of silent passengers is a major challenge in genomic sequencing. Pinpointing these functional mutations allows clinicians to select treatments tailored to the specific genetic makeup of a patient’s tumor, maximizing efficacy while minimizing side effects.