What are genetic mutations?

Our genes are the instructions that spell out how to make proteins, which are the building blocks of our body. They are an instruction manual that defines how our bodies work.

A mutation in our genes is like a spelling error in that manual, and that alters the function of the gene. 

Why do genetic mutations matter?

Genetic mutations can increase your risk of developing certain cancers.

Let’s take BRCA1 and BRCA2 as examples: Every one of us has BRCA genes, and we inherit two copies, one from each of our parents. They are called tumour suppressor genes, and their job is to repair damage in cells and prevent them from growing and dividing too rapidly. Mutations in these genes can cause cells to become abnormal and grow in an uncontrolled way. 

This is why having a mutation in one of these genes can increase a woman’s risk of both breast cancer and ovarian cancer- the “misspelling” in the gene stops the protein from working and the body cannot control cell growth in the normal way. 

Lynch syndrome (LS) used to be known as “hereditary nonpolyposis colorectal cancer” (HNPCC) and is less well-known than BRCA1/ BRCA2. It is a genetic condition that gives a person a higher risk of a number of cancers including colorectal cancer, ovarian cancer and cancer of the womb (uterine cancer). There are a number of genes that have been linked to Lynch Syndrome, including MLH1, MSH2, MSH6, PMS2, and EPCAM. These genes are called mismatch repair genes, and usually stop cancer from developing, but a mutation means this process doesn’t work properly. For more information, click here.

What are the risks?

The tables below show the estimated lifetime risk (up to age 70) for these genetic mutations:

BRCA

(There is research suggesting an increased risk of pancreatic cancer for people who have these mutations, but research is ongoing into how much they increase risk.)

Lynch syndrome

Other genetic mutations linked to ovarian cancer risk 

Whilst BRCA and Lynch syndrome are the more common and most well-known, there are other, less common faulty genes that are linked to ovarian cancer.


Figure 1: Susceptibility genes and their prevalence in hereditary ovarian syndromes (Adapted from Angela Toss, Chiara Tomasello, Elisabetta Razzaboni, Giannina Contu, Giovanni Grandi, Angelo Cagnacci, Russell J. Schilder, Laura Cortesi, "Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes", BioMed Research International, vol. 2015, Article ID 341723, 11 pages, 2015)  

Some of the faulty genes we know about that may cause an increased risk of ovarian cancer include: 

• RAD51C 
• RAD51D 
• BRIP1 
• PALB2 
• STK11 (Peutz-Jeghers syndrome) 

There are also other faulty genes that we just don’t know enough about yet, and can’t test for. Over the coming years there will be more and more information discovered about our genes and how they impact our risk. 

How common are genetic mutations?

BRCA1/2
Most cases of breast/ovarian cancer are not due to a genetic mutation. It is thought that, in the general population, around 1 in every 400 to 1 in every 800 people carry a BRCA1/2 gene mutation. This figure is, however, significantly higher in certain backgrounds. For example, it rises to 1 in 40 for people from an Ashkenazi Jewish background and it is believed that those from Dutch, Icelandic, Norwegian, Pakistani, Polish and Swedish populations are more likely to have a BRCA1/2 gene mutation than some other populations.

There are three specific mutations that are common in individuals with Ashkenazi Jewish ancestry. These are known as “founder mutations”:

• 185delAG in BRCA1 (also known as 187delAG)
  
• 5382insC in BRCA1
  
• 6174delT in BRCA2
  

Lynch Syndrome

Most colorectal cancer occurs with no genetic component and only around 3-5% of all cases of colorectal cancer are linked to LS. The estimated prevalence of LS in the population is 1/440.

What are the chances of inheriting or passing on one of these mutations?

Whether you’re a mother or a father, if you have a mutation in either the BRCA1/2 genes or a gene involved in Lynch syndrome, then there is a 50% chance of passing the mutation on to your children. This means if your parent has a known mutation, it is 50/50 whether you will inherit it. 

Although you have two copies of these genes, you only need to inherit one faulty copy for your risk of cancer to be increased. 

The only way to know for certain is to have a genetic test. 

Important things to remember

*A genetic mutation such as BRCA1 or BRCA2 means you have an increased risk, it is not a guarantee that you will get cancer.

*MEN! You have just as much chance of inheriting and passing on these genetic mutations as women!

*You can inherit these genetic mutations from your mother or father, and can pass them on whether you are a man or a woman. 

Why get tested?

Knowing your BRCA status can affect your treatment pathway if you are diagnosed with ovarian cancer and provide a significant opportunity for preventing future cases of cancer, for both you and your family members. Here are some points to consider:

• Preventative options such as risk-reducing surgery and increased surveillance could reduce the number of cases of ovarian cancer by around 17% – a potential 1,000 cases per year.
• BRCA1/2 gene mutations are genetic, so if you are a carrier then there is a chance that other members of your family are too.
• If you test positive for a BRCA1/2 gene mutation you can tell other members of your family that they may be at risk, giving them the option to get tested themselves if they wish.
• Those with a BRCA1/2 gene mutation or Lynch Syndrome have a 50% chance of passing the mutation on to their children.

Everyone has the right to choose whether or not to be tested and it’s not a decision to be taken lightly. If you are thought to be at risk, genetic counselling can be provided to help you make this decision.

For a more detailed introduction to BRCA1/2 mutations, please click here.

For more information about Lynch Syndrome visit www.lynch-syndrome-uk.org