What It Means to Have a Genetic Predisposition to Cancer

A genetic predisposition or genetic susceptibility to cancer means that a person has an increased risk of developing the disease due to their genetic makeup. Having a genetic predisposition to a particular cancer or cancer in general does not mean you will get the disease. There also different degrees of risk, with some people having a very high risk of developing cancer, and others being only at a slightly increased risk of the disease. Overall, roughly 10% of cancers are considered genetic, though the degree that heredity plays a role varies with different types.

We will look at the meaning of a genetic predisposition to cancer, who may have one, examples, and the role of genetic counseling and testing.

Definition and Meaning

A genetic predisposition is an inherited risk of developing a disease or condition. With cancer, a person may be more likely than average to develop one type or several types of cancer, and if a cancer occurs, it may develop at a younger age than is average for people without a genetic susceptibility. There are several concepts that are important to understand when talking about a genetic risk for cancer.

A Genetic Predisposition Does Not Mean You Will Get Cancer

If you have a genetic predisposition to cancer it does not mean that you will develop the disease. Likewise, if you do not have a genetic predisposition you may still be at risk.

Most Cancers are Multifactorial in Causation

A Genetic Predisposition Does Not Cause Cancer

Having a genetic predisposition to cancer does not mean that you will get that disease—in other words, it does not directly cause cancer—though your risk is higher. In many cases, a genetic predisposition is due to mutations in genes known as tumor suppressor genes.

Tumor suppressor genes code for proteins that repair damaged DNA. When the DNA in a cell is damaged (due to carcinogens resulting from normal metabolic processes in the body or environmental exposures), the body ordinarily repairs the damage or eliminates the abnormal cell. An accumulation of mutations in a cell that are not repaired (and if the cell is allowed to live) can thus result in a cancer cell.

Most Cancers are Multifactorial in Causation

Most cancers are not the result of a single mutation (or other genomic alteration), but rather an average of six. These mutations may occur over time and due to different exposures. It's thought that most cancers are multifactorial, meaning that a combination of factors (genetic, environmental, lifestyle, medical, etc.) either increases or decreases the risk.

Degree of Risk Can Vary Widely

A genetic predisposition can be moderate or high and this varies widely. For example, one genetic mutation may confer a lifetime risk of a cancer of 70%, while another may increase the risk only slightly over the average. This concept of "penetrance" is very important to understand if you have learned you have a genetic predisposition.

Family History is Not Always Helpful

People may have a genetic predisposition to cancer even if they do not have a family history of the disease. For example, a woman may develop hereditary ovarian cancer even if she has never had a female relative with the disease.

Similarly, genetic testing is not always helpful. A person may have negative results on testing but still have a genetic predisposition to cancer based on family history.

Even when a person has a family history of cancer, it does not necessarily mean they have a genetic predisposition to the disease. Cancers that run in families may be related to common exposures (such as smoking or radon) or lifestyle practices rather than genetics.

Having a Genetic Predisposition to Cancer is Not Always Bad

Some people have actually argued that having a known genetic predisposition to cancer can helpful at times. For example, of the roughly 10% of people who have a genetic predisposition to breast cancer, screening, as well as preventive options are available. In contrast, the 90% of people who develop the disease who do not have a genetic predisposition may be less likely to undergo screening (or the right type of screening such as MRI), may dismiss early symptoms, or may be less likely to address other factors that may raise their risk.

Who Has a Genetic Predisposition?

In some cases, determining whether a person may have a genetic predisposition to cancer is relatively straightforward, whereas other times it is more challenging.

A Family History of Cancer

A family history of cancer alone does not mean a person has a genetic predisposition. After all, one in two men and one in three women are expected to develop cancer during their lifetime. But certain patterns are of more concern.

• Three or more relatives with the same type of cancer
• Combinations of certain cancers. For example, having one family member with breast cancer and another on the same side with pancreatic cancer may suggest a BRCA2 gene mutation even more than if two or three family members had breast cancer.
• A family member who developed cancer at a young age.

The closer a family member is (such as a first degree relative), the more likely you are at risk. First-degree relatives include parents, siblings, and children. Second-degree relatives include grandparents, aunts, uncles, nieces, nephews, and half-siblings. Third-degree relatives include first cousins, great-grandparents, and great grandchildren.

In talking about family history, it's important to differentiate hereditary mutations or other anomalies and acquired mutations. Genetic testing is now done with several types of cancer to determine if targeted therapies may be effective. Mutations such as EGFR mutations in lung cancer or BRAF mutations in melanoma are almost always acquired mutations, or mutations that develop in the process of a cell becoming a cancer cell. These mutations only occur in the cancerous cells and can not be passed down to children.

Cancer at a Young Age

Developing cancer at a young age (or at least younger than the average age at diagnosis) increases the chance that you have a genetic predisposition. For example, breast cancer in young women (less than age 30 to 40) is more likely to be related to a genetic predisposition.

Cancer Not Typical For That Sex

Male breast cancer is much more likely to be related to a genetic predisposition than breast cancer in women.

Children With Cancer

Children who develop cancer may have a genetic predisposition, but they do not always have a family history of cancer. A 2015 study of over 1000 children with cancer found that 8.3% had predisposing gene mutations. Of the children with gene mutations, however, only 40% had a family history of cancer.

Rare Cancers

People who develop some uncommon cancers such as retinoblastoma or some endocrine tumors are more likely to have a genetic predisposition.

Multiple Primary Tumors

A 2018 study looked at the incidence of abnormalities (alterations in cancer predisposition genes) in people who had developed more than one primary cancer (two or more unrelated cancers). Looking at people who had been diagnosed with two primary cancers before age 60 or three primary tumors before age 70, cancer predisposition genes were identified in a third. Of note is that this was done with comprehensive whole-genome sequencing, and it's thought that at least half of these abnormalities would have gone undetected with conventional targeted sequencing.

Causes

A genetic predisposition refers to a genetic variation which increases the likelihood of disease. These are passed on from parents to children, but not all children will necessarily receive the gene types which predispose to disease.

Many people are familiar with single gene mutations (such as those in the BRCA gene), but a combination of changes on several genes may also confer a genetic predisposition. Genome wide association studies that are now being done that look for single changes in DNA (single gene polymorphisms) that are relatively common in the population. With diseases such as cancer, it may be combination of variations in several genes that confers risk, rather than single gene mutations. The science is young with cancer, but it shedding light in many conditions. For example, age-related macular degeneration was once thought to be primarily environmental, but gene wide association studies have found that variations in three genes may account for as many as 75% of cases.

We are now learning that polymorphisms that influence the function of miRNA may help predict the risk of female cancers.

Examples of Specific Genes and Hereditary Cancer Syndromes

A few examples of gene mutations that predispose to cancer and hereditary cancer syndromes include:

• BRCA mutations that raise breast and ovarian cancer risk (as well as others)
• Non-BRCA mutations that raise breast cancer risk
• Non-BRCA mutations that raise ovarian cancer risk
• RB1: Roughly 40% of children who develop retinoblastoma have an abnormal RB1 gene
• Familial adenomatous polyposis (FAP)
• Lynch syndrome (hereditary non-polyposis colorectal cancer)
• Li-Fraumeni syndrome

In addition to these and several others, it's likely that more genetic predisposition genes will be found in the future.

Genetic Testing

Genetic testing is now available for several cancers, including:

• Breast cancer
• Ovarian cancer
• Colon cancer
• Thyroid cancer
• Prostate cancer
• Pancreatic cancer
• Melanoma 
• Sarcoma
• Kidney cancer
• Stomach cancer

Caution Regarding Home Genetic Testing

A strong word of caution is in order for people who are considering home genetic testing for cancer. If these tests are positive, you may have a predisposition, but a negative home test could be very misleading. For example, the 23andme test detects only three of over one thousand BRCA mutations.

Importance of Genetic Counseling

Genetic counseling is important for people who may have a genetic predisposition to cancer for a few reasons. One is to understand accurately the limitations of testing and to be prepared

A very important reason to pursue genetic counseling is that the genetic tests we have available at the current time are incomplete. You may have genetic testing which is negative but still be at risk for hereditary cancer. A good genetic counselor may be able to determine if you are at risk by looking closely at your family history.

The Silver Lining of Having a Genetic Predisposition

Having a genetic predisposition to a disease such as cancer can be frightening, but it may be helpful to think of this in another way if you are anxious. If you have an increased likelihood of developing a condition you may be on alert for symptoms, and your doctor may check you more carefully than someone without that predisposition. What this could mean is that if you do develop the disease, it may be caught earlier than if you were not watching for the disease; and in this sense, you may actually have a greater chance of surviving a condition than if you were not on the lookout.

An example of this could be someone with a genetic predisposition to breast cancer. Based on a possible increased risk you might be more likely to do breast exams, see your doctor more frequently, perhaps begin having mammograms earlier or even yearly breast MRIs. If you did develop breast cancer it may be detected at an earlier—and more survivable stage—than it would be in someone who is not alerted to the possibility. Those who are at a very high risk may consider preventive tamoxifen or a preventive mastectomy.