What Is Loss of Heterozygosity?

What to Make of This Genetic Mutation

Loss of heterozygosity (LOH) refers to a specific type of genetic mutation during which there is a loss of one normal copy of a gene or a group of genes. In some cases, loss of heterozygosity can contribute to the development of cancer.

LOH of particular genes is associated with specific cancer types, such as such as colorectal cancer and small-cell lung cancer. LOH is also particularly significant in individuals who have inherited a predisposition for cancer.

What Is Heterozygosity?

You inherit your genetic material (DNA) from your parents which contains the information needed for your body to make the many proteins that it needs. Your genes, which are specific segments of DNA, encode this necessary information. Researchers estimate that there are approximately between 19,000 and 22,000 different genes encoded in this DNA, and almost all of your cells contain a copy.

Genes can have slight variations that contribute to differences between human beings. These genetic variations are called “alleles.” For most genes (with the exception of sex chromosomes) you should inherit two copies: one from your mother and one from your father.

If a person has two of the same variations of the same gene, they are called homozygous for that allele. If a person has two different variations of that gene, they are called heterozygous for that allele.

There are many different genetic conditions caused by abnormal gene variations. Some of these occur only in people who are homozygous for the abnormal gene (with two copies), whereas others occur in people who have only one copy of the abnormal gene (heterozygous).

What Is Loss of Heterozygosity?

In LOH, a gene or a whole group of neighboring genes are lost and no longer present inside the affected cell. This could happen when that part of the DNA is accidentally deleted, perhaps when the cell is undergoing normal division and replication.

The gene might be completely gone, or part of it might have been moved to another location on the DNA. In either case, the protein encoded by the gene cannot be correctly made. Instead of having two different versions of the same gene present (heterozygosity), one copy of the gene is now gone. This is why it is called loss of heterozygosity.

It is easy to confuse LOH with homozygosity. However, people who are homozygous for a gene have two very similar copies of the same gene, while people with LOH have only one copy.

Role of Carcinogens

Carcinogens can make LOH and other types of genetic errors more likely to occur. Carcinogens are substances that can damage your DNA through direct or indirect means. Some common sources of carcinogens are smoking, asbestos, and ultraviolet light from the sun. Exposure to these carcinogens increases the chance that LOH will happen.

LOH and Cancer

LOH is a very common event in the process of oncogenesis, the process by which a normal cell turns into a cancerous one and begins to abnormally replicate. It is one of the types of genetic mutations that can play a role in cancer development.

Cancerous cells usually show multiple types of genetic changes—LOH in one or more genes may be one of these changes to occur. LOH can be present in both hereditary cancer syndromes and in other types of cancer.

There are at least a couple of different ways that LOH can be problematic. Sometimes after LOH occurs, the cell can’t make enough of the normal protein from the remaining gene. Other times, there is a bad mutation in the remaining gene—it could either be present from birth or occur later on. In either case, not enough normal protein can be made from the necessary gene.

Some genes might be lost to LOH without causing a problem. However, LOH in specific types of genes is more of a concern. These genes, called tumor suppressor genes, are very important genes for cancer prevention and they normally work to regulate the cell cycle. They make sure that the cell doesn’t replicate and divide unnecessarily.

When tumor suppressor genes are absent or nonfunctional due to LOH, the cell may begin to divide abnormally and become cancerous.

LOH is thought to occur in many different types of cancer. However, researchers have discovered LOH in particular genes to be very common in specific cancer types. Some examples are:

Mutations such as LOH in other tumor suppressor genes such as p53 are thought to be present in many different individuals with many different cancer types. In general, LOH of one gene or another is thought to be relatively common in cancer of all types.

LOH and Hereditary Cancers

Though LOH is seen in a number of different types of cancer, it may be particularly important for certain hereditary types of cancer.

If a person has a hereditary cancer disorder, they may several family members with the same type of cancer, and have a higher risk of getting cancer at a younger age. This often occurs because a person has inherited one or more defective genes from their parents. Many people are most familiar with hereditary cancers that occur in some people with breast cancer.

It is thought, for instance, that many cases of retinoblastoma arise from a hereditary cancer disorder. The person may inherit a bad copy of an RB1 gene (an important tumor suppressor gene) but she also inherits a good copy from her other parent. If LOH occurs and eliminates the copy of the good gene, she is likely to develop retinoblastoma.

Individuals in these cases often develop multiple tumors at a young age.

LOH and Cancer Treatment

Many people don’t realize that the term “cancer” refers to a large and diverse group of diseases. Even cancers of the same organ may have different physical and genetic characteristics. Perhaps more importantly, different types of cancers may respond differently to cancer treatments.

Researchers are starting to develop specific treatments that help treat cancers caused by particular types of mutations, such as for people with specific kinds of chronic myeloid leukemia.

As researchers understand more about the different subtypes of cancer caused by different mutations, this will lead to more personalized and specifically tailored cancer treatment. This developing field of medicine is called precision medicine.

For the most part, research is still in its early phases. Currently, it is usually only people with certain types of cancer, such as some lung cancers, who benefit from having their tumor genetically sequenced. However, this may become more common as sequencing techniques become more streamlined and as more treatments become available for people with specific mutations.

As another example, it may make sense for people with certain kinds of glioma to get information about the mutations present in their cancer cells. Some evidence suggests that people who have a glioma and a specific type of LOH (termed 1p/19q) may respond better if they have radiation in addition to standard chemotherapy treatments.

As more is learned about the specific types of LOH and other genetic problems present in cancer, researchers will likely develop more and more targeted treatments. Because LOH is such a common occurrence in cancer, it is likely that treatments aimed at addressing specific instances of LOH may become more common in the future. New innovations occur in this field every year.

A Word From Verywell

LOH and cancer genetics are complex topics, so it is normal to not understand everything fully at first. Don’t hesitate to ask your doctor if sequencing your cancer’s genetics makes sense in your particular situation. In some cases, it may not be helpful because it wouldn’t change your treatment. However, in some situations, it may be beneficial to perform such testing.

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