Changes in Genes

Gene mutations

Mutations are abnormal changes in the DNA of a gene. The building blocks of DNA are called bases. The sequence of the bases determines the gene and its function. Mutations involve changes in the arrangement of the bases that make up a gene. Even a change in just one base among the thousands of bases that make up a gene can have a major effect.

A gene mutation can affect the cell in many ways. Some mutations stop a protein from being made at all. Others may change the protein that is made so that it no longer works the way it should or it may not even work at all. Some mutations may cause a gene to be turned on, and make more of the protein than usual. Some mutations don't have a noticeable effect, but others may lead to a disease. For example, a certain mutation in the gene for hemoglobin causes the disease sickle cell anemia.

Cells become cancer cells largely because of mutations in their genes. Often many mutations are needed before a cell becomes a cancer cell. The mutations may affect different genes that control cell growth and division. Some of these genes are called tumor suppressor genes. Mutations may also cause some normal genes to become cancer-causing genes known as oncogenes (oncogenes and tumor suppressor genes are discussed in more detail later).

We have 2 copies of most genes, one from each chromosome in a pair. In order for a gene to stop working completely and potentially lead to cancer, both copies have to be “knocked out” with mutations. That means for most genes, it takes 2 mutations to make that gene stop working completely.

Types of mutations

There are 2 major types of gene mutations, inherited and acquired:

An inherited gene mutation is present in the egg or sperm that formed the child. After the egg is fertilized by the sperm, it created one cell called a zygote that then divided to create a fetus (which became a baby). Since all the cells in the body came from this first cell, this kind of mutation is in every cell in the body (including some eggs or sperm) and so can be passed on to the next generation. This type of mutation is also called germline (because the cells that develop into eggs and sperm are called germ cells) or hereditary. Inherited mutations are thought to be a direct cause of only a small fraction of cancers.

An acquired mutation is not present in the zygote, but is acquired some time later in life. It occurs in one cell, and then is passed on to any new cells that are the offspring of that cell. This kind of mutation is not present in the egg or sperm that formed the fetus, so it cannot be passed on to the next generation. Acquired mutations are much more common than inherited mutations. Most cancers are caused by acquired mutations. This type of mutation is also called sporadic, or somatic.

Mutations and cancer

Experts agree that it takes more than one mutation in a cell for cancer to occur. When someone has inherited an abnormal copy of a gene, though, their cells already start out with one mutation. This makes it all the easier (and quicker) for enough mutations to build up for a cell to become cancer. That is why cancers that are inherited tend to occur earlier in life than cancers of the same type that are not inherited.

Even if you were born with healthy genes, some of them can become changed (mutated) over the course of your life. These acquired mutations cause most cases of cancer. Some acquired mutations can be caused by things that we are exposed to in our environment, including cigarette smoke, radiation, hormones, and diet. Other mutations have no clear cause, and seem to occur randomly as the cells divide. In order for a cell to divide to make 2 new cells, it has to copy all of its DNA. With so much DNA, sometimes mistakes are made in the new copy (like typos). This leads to DNA changes (mutations). Every time a cell divides, it is another opportunity for mutations to occur. The numbers of gene mutations build up over time, which is why we have a higher risk of cancer as we get older.

It is important to realize that gene mutations happen in our cells all the time. Usually, the cell detects the change and repairs it. If it can’t be repaired, the cell will get a signal telling it to die in a process called apoptosis. But if the cell doesn't die and the mutation is not repaired, it may lead to a person developing cancer. This is more likely if the mutation affects a gene involved with cell division or a gene that normally causes a defective cell to die.

Some people have a high risk of developing cancer because they have inherited mutations in certain genes. To learn more about this, see Family Cancer Syndromes.


For dominant genes and mutations, the term penetrance is used to indicate the proportion of those carrying a mutation who will have the trait, syndrome, or disease. If all of the people who inherit the mutation have the disease, it is called complete penetrance. If not all of the people who have the mutation get the disease, it is called incomplete penetrance. In general, inherited mutations leading to cancer have incomplete penetrance, meaning not everyone with the mutation will get cancer. That is in part because although the person has a mutation in one copy of the gene, they need to acquire at least one more mutation for the gene to stop working completely and cancer to occur. Since not everyone gets the second mutation, not everyone gets cancer. Incomplete penetrance can also be because even if the mutation makes it so that a gene doesn’t function, other factors may be needed for the cancer to start.

High vs. low penetrance

Gene mutations can cause large changes in the function of a gene. They may even cause that copy of the gene to stop working altogether. When an inherited mutation has a large enough effect on the function of a gene to cause a disease or noticeable problem in most of the people who have it, that mutation is called “high penetrance.”

High-penetrance mutations in cancer susceptibility genes can lead to many people in a family getting certain kinds of cancers – a family cancer syndrome. These are thought to cause only a small fraction of cancers that run in a family. For example, only about 1/5 of the breast cancer that runs in families is thought to be caused by high-penetrance mutations in genes like BRCA1 and BRCA2.

Some inherited mutations, though, don’t seem to affect gene function very much and don’t often cause obvious problems. These mutations are called “low-penetrance.” Low-penetrance mutations can affect cancer risk through subtle effects on things like hormone levels, metabolism, or other things that interact with risk factors for cancer. Low-penetrance mutations, together with gene variants (discussed below) are thought to be responsible for most of the cancer risk that runs in families.

Gene variants

People can also have different versions of genes that are not mutations. Common differences in genes are called variants. These versions are inherited and are present in every cell of the body. The most common type of gene variant involves a change in only one base (nucleotide) of a gene. These are called single nucleotide polymorphisms (SNPs, pronounced “snips”). There are estimated to be millions of SNPs in each person’s DNA.

Other types of variants are less common. Many genes contain sequences of bases that are repeated over and over. A common type of variant involves a change in the number of these repeats.

Some variants have no apparent effect on the function of the gene. Others tend to influence the function of genes in a subtle way, such as making them slightly more or less active. These changes don’t cause cancer directly, but can make someone more likely to get cancer by affecting things like hormone levels and metabolism. For example, some gene variants affect levels of estrogen and progesterone, which can affect the risk of breast and endometrial cancers. Others can affect the breakdown of toxins in cigarette smoke, making a person more likely to get lung and other cancers.

Gene variants can also play a role in diseases that impact cancer risk – like diabetes and obesity.

Variants and low-penetrance mutations can be similar. The main difference between the two is how common they are. Mutations are rare, while gene variants are more common.

Still, since these variants are common and someone can have many of them, their effect can add up. Studies have shown that these variants can influence cancer risk and, together with low penetrance mutations, they may account for a large part of the cancer risk that runs in families.

Other ways cells change genes and gene activity

Although all of the cells of your body contain the same genes (and DNA), different genes are active in some cells than in others. Even within a certain cell, some genes are active at some times and inactive at others. Turning on and off of genes in this case isn’t based on changes in the DNA sequence (like mutations), but by other means called epigenetic changes.

DNA methylation: In this type of epigenetic change, a molecule called a methyl group is attached to certain nucleotides. This changes the structure of the DNA so that the gene can’t start the process of making the protein for which it codes (this process is called transcription). This basically turns off the gene. In some people with a mutation in one copy of a cancer susceptibility gene, the other copy of the gene becomes inactive not by mutation, but by methylation.

Histone modification: Chromosomes are made up of DNA wrapped around proteins called histones. Histone proteins can be changed by adding (or subtracting) something called an acetyl group. Adding acetyl groups (acetylation) can activate (turn on) that part of the chromosome, while taking them away (deacetylation) can deactivate it (turn it off). Methylation is also used to activate and deactivate parts of chromosomes. Histone proteins can also be changed by adding or subtracting methyl groups (methylation and demethylation). Although abnormal histone modification isn’t known to cause cancer, drugs that alter histone modifications can help in the treatment of cancer by turning on genes that help control cell growth and division.

RNA interference: RNA (ribonucleic acid) is important inside cells as the middle step that allows genes to code for proteins. But some small forms of RNA can interfere with gene expression by attaching to other pieces of RNA, or even affecting histones or DNA itself. Drugs are being developed that affect abnormal genes in cancer cells through RNA interference.

The American Cancer Society medical and editorial content team

Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as journalists, editors, and translators with extensive experience in medical writing.

Last Revised: June 25, 2014

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