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 genes. Having a genetic predisposition to a particular kind of cancer does not mean you will get the disease. There are 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. 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 cancer occurs, it may develop at a younger age than average for people without a genetic susceptibility.

A Genetic Predisposition Does Not Cause Cancer

Having a genetic predisposition to cancer does not mean that you will get that disease because the gene does not directly cause cancer—though the 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, the body ordinarily repairs the damage or eliminates the abnormal cell. If the mutations (genetic changes) are not repaired, it can result in a cancer cell.

Most Cancers are Multifactorial in Causation

It's thought that most cancers are multifactorial, meaning that a combination of factors (genetic, environmental, lifestyle, medical, etc.) increase or decrease the risk.

Furthermore, most cancers are not the result of a single mutation, but rather an average of six. These mutations may occur over time and due to different exposures.

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. 70% lifetime risk of cancer, while another may increase the risk only slightly over the average.

Limitations of Determining Genetic Predisposition

Family history and genetic testing both have their limitations in how well they can tel if you have a genetic risk of cancer.

Examples of limitations:

• Family members who have the gene might not have the disease: 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.
• The gene is not identified: Genetic testing is not always helpful. Not all genes that predispose to cancer have been identified. A person may have negative results on testing but still have a genetic predisposition to cancer, based on family history.
• Lifestyle factors: 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 be helpful at times. For example, of the roughly 10% of people who have a genetic predisposition to breast cancer, screening and preventive options are available.

If you are at risk, you may be more likely to do breast exams, see your healthcare provider more frequently, and begin having diagnostic screening tests earlier. 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 very high risk may consider preventive treatment.

In contrast, the 90% of people who develop the disease who do not have a genetic predisposition may be less likely to undergo screening, may dismiss early symptoms, or may be less likely to avoid other factors that may raise their risk (like smoking).

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. Family members might get cancer even if they don't have a genetic predisposition.

Certain patterns are concerning:

• 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
• 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 from 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. These mutations only occur in the cancerous cells and cannot be passed down to children.

Cancer at a Young Age

Developing cancer at a younger than average age is associated with 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 uncommon cancers such as retinoblastoma or certain endocrine tumors are more likely to have a genetic predisposition.

Multiple Primary Tumors

A 2018 study looked at the incidence of abnormalities in cancer predisposition genes among people who had developed more than one primary cancer (two or more unrelated cancers). Of those 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. 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 that increases the likelihood of disease. These are passed on from parents to children, but not all children will necessarily receive the genes that predispose to the disease.

For some types of cancer, a combination of changes in several genes may confer a genetic predisposition, rather than single gene mutations. 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 genetic factors 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

If you are considering home genetic testing for cancer, it's important to be cautious. If these tests are positive, you may have a predisposition, but a negative home test could be misleading. For example, the 23andme test detects only a few of over one thousand BRCA mutations.

Importance of Genetic Counseling

Genetic counseling is important for people who may have a genetic predisposition to cancer.

A genetic counselor may be able to determine if you are at risk by examining your family history, and may be able to advise you about the potential outcomes for your offspring.

The Silver Lining of Having a Genetic Predisposition

Having a genetic predisposition to a disease such as cancer can be frightening, but there are some advantages to knowing your risk. If you have an increased likelihood of developing a condition, you can learn about the symptoms, and your healthcare provider may screen you for signs of the disease. If you develop cancer, it may be caught earlier and you may have a better chance of surviving a condition than if you were not on the lookout.