Cancer is fundamentally a disease characterized by the uncontrolled division of abnormal cells that invade and destroy healthy tissue. At its core, every cancer is a genetic disease because it arises from damage or alterations to a cell’s DNA. However, while all cancers are genetic, only a small minority—about 5 to 10 percent—are truly hereditary, caused by a genetic mutation passed down from a parent. This distinction between a genetic change and an inherited predisposition is the central point in understanding cancer risk.
Genetic Changes: Inherited vs. Acquired
The genetic alterations that initiate cancer can be categorized into two distinct types based on when and where they occur in the body. Germline mutations are alterations present in the DNA of the sperm or egg cell, which are then passed from parent to child. Because the mutation is present in the fertilized egg, this genetic change is copied into every single cell of the body as the person develops. These germline mutations define hereditary cancer syndromes, conferring an increased risk of cancer from birth.
In contrast, somatic mutations are acquired at some point during a person’s lifetime and are confined only to specific cells or tissues. These acquired changes are not present in the reproductive cells and therefore cannot be passed on to offspring. The vast majority of cancer cases, roughly 90 to 95 percent, result from these somatic mutations accumulating over time. This difference explains why cancer often appears suddenly in a person with no relevant family history, as the cancer-causing mutations developed in a single cell during that person’s life.
The Direct Role of Heredity
Hereditary cancer syndromes involve the inheritance of a faulty gene, which gives a person a “head start” on the path to cancer development. These inherited mutations typically occur in high-penetrance genes that play a role in DNA repair or cell growth regulation. For instance, the BRCA1 and BRCA2 genes are tumor suppressor genes responsible for repairing damaged DNA.
A person who inherits a non-working copy of one of these genes already starts life with one genetic “hit” toward cancer. This significantly elevates their lifetime risk for specific cancers, such as breast, ovarian, and prostate cancer, compared to the general population. Similarly, mutations in genes like MLH1 and MSH2, associated with Lynch syndrome, impair the body’s ability to correct errors made during DNA replication.
Other inherited syndromes, such as Li-Fraumeni syndrome, involve mutations in the TP53 tumor suppressor gene. Inheriting a faulty copy of TP53 significantly increases the risk for multiple, rare, early-onset cancers. These inherited cancer syndromes are characterized by cancer occurring at younger ages and often involving multiple primary tumors. However, even with a high-penetrance germline mutation, cancer is not guaranteed.
How Acquired Mutations Drive Cancer
The majority of cancer cases are driven by acquired, or somatic, mutations that arise from damage to a cell’s DNA after birth. These mutations are not present in the germline and are often a result of exposure to environmental factors, lifestyle choices, or random errors during normal cell processes. For example, tobacco smoke contains numerous chemical carcinogens that directly damage DNA in lung cells, leading to the mutations necessary for lung cancer development.
Ultraviolet (UV) radiation from the sun is a well-known external factor that causes specific types of DNA damage in skin cells, which can result in melanoma or other skin cancers. Internal factors also contribute to the accumulation of somatic mutations. Every time a cell divides, there is a chance for the DNA replication machinery to make a mistake, leading to an error that is not corrected by the cell’s repair systems.
Over a lifetime, these random, uncorrected replication errors accumulate throughout the body. The risk of acquiring these somatic mutations is directly related to a person’s age, which is why the vast majority of non-hereditary cancers occur in older adults. Chronic inflammation, often caused by infections like the human papillomavirus (HPV) or hepatitis B, can also continuously damage DNA and accelerate the accumulation of acquired mutations.
Cancer Development: A Multi-Hit Process
The development of cancer is best explained by the multi-hit hypothesis, which posits that a single genetic mutation is rarely enough to transform a normal cell into a malignant one. Instead, a series of accumulated genetic alterations—or “hits”—are required to disable the cell’s natural growth controls and repair mechanisms. This process typically involves multiple mutations in both tumor suppressor genes and proto-oncogenes.
In cases of sporadic cancer, all of the necessary mutations must be acquired during a person’s lifetime through environmental exposure or replication errors. This sequential accumulation of hits takes a long time, which accounts for the typical late age of onset for most cancers. Inherited cancers, however, follow a different timeline because the first hit is already present in every cell from birth.
A person with a germline mutation only needs to acquire one or two more somatic hits to a specific cell for the cancer process to be initiated. This reduced number of required subsequent events explains why hereditary cancers often manifest decades earlier than their sporadic counterparts. Understanding this multi-hit process is important for risk assessment, as a strong family history suggests an inherited first hit, which often prompts earlier and more intensive cancer screening protocols.