What is Cancer-Predisposition Gene Mutation Testing?
Cancer-predisposition gene mutation testing can be a very useful addition to your preventive healthcare. This type of testing involves an outside laboratory extracting genetic material from saliva, blood, other fluid or tissues. (At Avenue Medical Associates, we send a tube of blood obtained during a well examination.) Then, the laboratory looks for specific mutations in specific genes. These mutations are known to increase your likelihood of developing cancer. If you are “positive” for a mutation, other family members may also be positive.
Let’s start with some definitions, then review how inherited mutations can actually result in cancer.
DNA, deoxyribonucleic acid: The molecule that carries instructions for the development and function of living organisms (except prions and RNA viruses, but we won’t go there!).
GENES: Segments of DNA that provide instructions for building our proteins. We have tw o similar copies of most genes, one from each parent.
PROTEINS: Large molecules that make up our organs and tissues and are involved in nearly every process that goes on in our bodies.
MUTATIONS: Alterations in the DNA that make up genes. These alterations then affect proteins, which can adversely affect any organ or process in the body. Some of these mutations cause cancer.
GERMLINE MUTATION: A change in the DNA sequence that occurs in your reproductive cells (sperm or egg).
SOMATIC MUTATION: A change in the DNA sequence that occurs in a cell AFTER fertilization. These could be very early cells, before organ or specific tissues develop (pre-embryo stage), up to and including fully developed cells (for example, kidney, intestine, liver, etc.).
How Inherited Gene Mutations Increase Cancer Risk:
1. Two “Hits” (The Alfred Knudson, Jr., MD, PhD “Two-Hit” hypothesis):
First “Hit”: You inherit a gene mutation from one parent (GERMLINE MUTATION). This “hit” affects one copy of one gene. Luckily, you still have one working gene copy and the mutated gene does not result in cancer. The mutation is referred to as “recessive.”
Second “Hit”: Cancer develops if the second, functional copy of the same gene acquires a SOMATIC MUTATION during your lifetime.
The Result: With both copies now mutated, genes that normally suppress tumor growth, often by repairing errors in DNA that normally occur when our cells divide (they are literally called “Tumor Suppressor Genes”), no longer function properly. This is also called a loss-of-function mutation.
In summary: You are born with one “hit” due to inheritance from one parent, then you get a second “hit” afterwards. This second “hit” can occur due to exposure to things that cause cancer, such as smoking, radiation, etc., or merely during the process of aging. A specific gene then stops working, and this results in cancer.
2. When One “Hit” Is Enough
Gain-of-function mutations: Some germline mutations affect genes that regulate cell growth. Unlike tumor suppressor genes which usually require two hits, these genes can cause cancer through a single gain-of-function germline mutation.
This results in a “permanently on" signal for cell division, promoting continuous and uncontrolled duplication of one abnormal (cancer) cell.
In summary: You are born with one “hit” and this mutation is, by itself, enough to result in eventual cancer. Your normal gene copy cannot counteract the effect of the defective copy. We therefore say the mutation is “dominant.”
Haploinsufficiency: In some cases, having only one functional copy of a gene may not produce enough gene product/protein for normal cellular function, creating the potential for cancer development.
Altered Cell “Environment:” Germline mutations can occur in cells that do not, themselves, become cancer. When these cells stop functioning properly, they then permit the growth of cancer involving other cells of the body. For instance, mutations that affect our immunity make it easier for cancer to grow.
Changes in Metabolism: Mutations in certain genes involved in metabolism (chemical reactions that occur in the body) can lead to conditions that promote cancer.
Why test for germline mutations?
Detecting germline mutations early can affect:
- How frequently you are screened for cancer. For example, a colonoscopy may be necessary every five years instead of ten.
- The method by which you are screened for cancer. For example, a breast MRI alternating with your routine mammogram/breast sonogram.
- Whether or not you need to be screened for a cancer for which we normally do not screen. For example, having a yearly pancreas MRI to detect pancreatic cancer.
- The cancer risk of relatives with the same mutation.
The NCCN (National Comprehensive Cancer Network), the ASCO (American Society of Clinical Oncology), The USPTF (United States Preventive Services Task Force) and other organizations provide guidance for cancer-predisposition gene mutation testing.
If you are an established patient at our office, please feel free to call our office with further questions!
Thank you!
Julian Klapowitz, MD