Cancer is fundamentally a genetic disease, characterized by the uncontrolled division and spread of abnormal cells. This behavior results exclusively from changes, or mutations, in the cell’s DNA. These genetic faults disrupt the instructions that govern a cell’s life cycle, including when to grow, divide, and die. The critical distinction lies in when these genetic changes occur, as the vast majority of cancer cases are not caused by genes passed down from a parent.
Acquired Mutations: The Primary Driver of Cancer
The overwhelming majority of cancers (90 to 95 percent of all diagnoses) arise from mutations acquired during a person’s lifetime. These are known as somatic mutations, meaning they occur in non-reproductive cells and cannot be transmitted to the next generation. Somatic mutations accumulate over decades through random errors and external damage. Every time a cell divides, the molecular machinery occasionally makes mistakes that are missed by internal repair mechanisms.
These acquired genetic flaws are localized to the specific cell where they first appear and its descendants, forming a clone of abnormal cells. For a healthy cell to become cancerous, it requires the accumulation of multiple mutations in specific genes that govern growth and division. This steady accumulation explains why age is the single greatest risk factor for developing most types of cancer.
Inherited Predisposition: When Genes Increase Risk
Only a small fraction of all cancers, estimated at 5 to 10 percent, are linked to an inherited genetic change. These are called germline mutations because they are present in the parent’s germ cells and are found in every cell of the child’s body from conception. Inheriting this mutation does not mean a person inherits cancer, but rather a significantly increased risk or predisposition for developing it.
People who inherit a germline mutation essentially start life with one required genetic “hit” toward cancer already in place. This often involves a damaged tumor suppressor gene, such as \(BRCA1\) or \(BRCA2\), which normally functions to repair DNA damage. Because this initial genetic protection is compromised from birth, fewer subsequent acquired mutations are necessary to cause malignancy. Consequently, cancers linked to inherited predispositions often develop earlier in life.
External Factors That Trigger Genetic Change
Environmental and lifestyle exposures are the primary non-inherited causes leading to the acquired mutations that drive most cancers. These external factors, known as carcinogens, physically or chemically damage the DNA structure, forcing the cell to make mistakes during repair. The damage caused by these factors follows specific molecular pathways.
Chemical Carcinogens
Tobacco smoke contains chemical carcinogens like Benzo[a]pyrene (B(a)P) that are converted into highly reactive molecules. These molecules form bulky attachments, called DNA adducts, that covalently bond to DNA bases. This leads to characteristic G to T transversions in tumor suppressor genes like \(p53\). Smoke also contains aldehydes that inhibit DNA repair enzymes, compounding the damage.
Infectious Agents
Infectious agents also trigger genetic change, such as the human papillomavirus (HPV) in cervical and head and neck cancers. High-risk HPV types integrate their viral DNA into the host cell’s genome. Their cancer-promoting proteins, E6 and E7, target human proteins for destruction. E6 forces the degradation of the tumor suppressor protein p53, while E7 inactivates the retinoblastoma protein (pRb), disabling key mechanisms for halting uncontrolled division.
Radiation
Other external factors, such as ultraviolet (UV) radiation from the sun, cause direct structural damage to DNA. UV radiation creates pyrimidine dimers, which are kinks in the DNA helix that impede accurate replication.
How Mutations Drive Uncontrolled Cell Growth
Regardless of whether a mutation is inherited or acquired, cancer results from the deregulation of two key classes of genes that control cell growth.
Proto-Oncogenes and Oncogenes
The first class is the proto-oncogenes, which normally promote cell division and survival. A mutation in a proto-oncogene is often a gain-of-function change that turns it into an oncogene, acting like a car’s accelerator stuck in the “on” position. For example, a single point mutation in the RAS gene family locks the resulting protein into a permanently active state. This leads to continuous signaling for the cell to divide, contributing to over 30 percent of human cancers.
Tumor Suppressor Genes
The second class is the tumor suppressor genes, which normally act as the cell’s brakes and repair crew. Mutations in these genes, such as \(p53\) or \(pRb\), are typically loss-of-function events. These events disable the protein’s capacity to halt the cell cycle or initiate cell death in the presence of damage. The concurrent loss of a tumor suppressor and the activation of an oncogene provides the necessary molecular environment for uncontrolled growth.