Mosaic Mutants

Genetics are very complicated. There are so many factors that influence how we become who we are on the cellular level and beyond.

A good friend of mine always points out- there are many ways to make a family. Those of us in the support group learned that as we have become a family of misfit mutants. Yet even within our small numbers, there are the rare of the rare. I remember at the conference in Boston, talks turned to questions over the topic of mosaicism. There is no easy way to explain it, understand it or definitively peg it’s role in how Li-Fraumeni Syndrome is inherited or develops. We, as mutants are pretty used to chartering uncharted territories- so let’s give it a shot!

Art by Inge Vandormael. Coloring by Bella. Not all cells may have the TP53 mutation. Mosaicism is one of these cases.

MOSAICISM- WHAT IS IT? 

Pretty tile murals? How I would like to tile the swimming pool I have in my dream home? Where a person has cells of different genetic make up? Yep, that is the one.

Genetic Mosaicism starts in the GERM cells (eggs and sperm).  It often is silent, meaning the mutation is there, but doesn’t produce the effect (cancer, in the case of LFS) in the person.  As the cells divide during pregnancy, a zygote (little pre-baby alien conglomerate of cells) forms and sometimes a mutation occurs. Depending on where and when this mutation occurs, this affects what percentage of all cells are mutated, and how many are mutated. If the mutation is early in development, many cells will be affected, if the mutation occurs later, fewer cells are affected.

So if a person has a TP53 mosaic mutation, some tissues (for example, it could be just skin, ovaries and breasts) may have the mutated gene, while others do not. The tissues that have the mutation will have a greater risk of developing cancer because p53’s job is to help suppress tumors, and mutant p53 doesn’t always do this properly.

Here is Wendy Kohlmann, MS, CGC, a licensed genetic counselor at the University of Utah Huntsman Cancer Institute, explaining mosaicism to LLFS board member Andi Last for the Learning Li-Fraumeni Syndrome podcast:

HOW DO WE TEST FOR TP53 MOSAICISM?

Generally, LFS is already on the doc’s radar if you’ve been referred for genetic testing. These times are where Geneticists and Genetic Counselors are worth their weight in gold! To test for LFS, we test for the TP53 mutation while considering family history.

Testing for TP53 mutations can be done several ways, but usually by blood test. If there is a known mutation in a family, they test for that mutation. If there is not, they do a multi-gene sequencing panel to try and find a mutation.  The blood can have cells with different chromosome make up, but this isn’t always the case. If the mutation is in the blood, there will be a certain percentage of changes.

To truly understand where the mutation is, we would have to test all the different cells in the body. That it a daunting and seemingly painful task. This is where the knowledgeable genetic professional becomes a HUGE asset. A geneticist will be able to help determine what testing is necessary and how to go about it for diagnosis.

And HAVING A MOSAIC MUTATION MEANS WHAT?

Right, so here you are in the LFS club. Rarest of the Rare. You have an increased risk of cancer, you just don’t know where or when. No one with LFS knows. That’s why we screen. The benefit to identifying mosaicism is knowing that there is an increased risk, and you can potentially pass along the mutation to your children. Since people with mosaicism have fewer cells affected by the mutation, they tend to have less severe cases of LFS.

That’s not particularly helpful as far as screening goes, unless you know which tissues are affected. We can not yet predict how a mosaic TP53 mutation will affect mutants. But guess what? We can’t predict yet how a non-mosaic TP53 mutation will affect mutants either. Having an increased risk of cancer sucks, no matter what way you slice it.  This is why paying attention you your body, your gut and having a dedicated team will help you navigate these shark-infested waters.

Living LFS is a balance of advocacy and knowledge. Being rare does not mean you cannot get the best care – it means you are human. We are each unique. By knowing we have a rare mutation, we can do our best to fight cancer in a way our bodies can handle. Knowing what you are up against is your best chance at preparing.


MOSAICISM in Li-Fraumeni Syndrome

We have this question pop up frequently in our support group. What is mosaicism? On a very basic level, genetic mosaicism means a person has mixture of cells with different genetic make up. LFS Mosaics have some cells that have Tp53 mutations and some cells that do not, where as someone who inherits LFS from a parent will have mutations in all of their cells. Theoretically since mosaics do not have mutations in all of their cells, the cells that do not have mutant p53 are less likely to go rogue and turn into cancer or have the same risk of everyone else.

How does Mosaicism Happen?

LFS is a dominant trait, which means that it is the trait we see, it kind of overpowers the other gene. If a parent carries the gene there is a 50:50 chance of passing along LFS to their children. But remember, it’s like flipping a coin- a person with LFS could have all of their children with LFS, none of their children with LFS or a mix. Each person has 23 pairs of chromosomes- just like the Ark- chromosomes travel 2 by 2- one comes from a mother and one comes from a father. This article, DNA Double Take in the New York Times explains some of the complexity of DNA, of which mosaicism is a big issue.

Sometimes cells in a parent’s reproductive organs are mutated. So when that parent has children, the mutation could be passed along. The parent may not have any history of cancer and no way of knowing they have mutated cells. Depending on the situation and location of mosaic cells, multiple children in a family could be affected.  It is not unusual for siblings of a child with mosaicism to be tested, even if the parents test negative for LFS. Sometimes in the journey to finding out about mutations and heredity, there are uncomfortable questions of possible parentage of a child. It’s not fun to answer questions like that, but it’s not personal- it’s kind of like an investigation- leave no stone unturned.

Other times during pregnancy,  the embryo is mutated at very early stages of development and only certain cells then develop with the mutation. Just like there are many events that lead to mutations that turn into cancer, there are several different events that could lead to mosaicism. The diagram below is a good example of some of the ways mutations can be inherited.

Mosaicism image from www.mdpi.com

Could I be Mosaic?

Mosaicism is thought to be very rare. Considering LFS is rare- that makes it rare of rare.  If you were tested for a TP53 mutation and it came back positive, you have LFS and the mutation is present in all of your cells. According to an article in The Scientist Magazine last summer, we are all a little bit mosaic and have a mixture of DNA in various tissues, for example male DNA in a woman’s brain tissue, an example of how mothers carry some of their sons’ DNA with them always. This article questioned whether or not mosaicism was really as rare as we think it is, or if it rather was the beginning of an evolutionary adaptation. You can read the article here.  Further research is needed to understand what the frequency of mosaicism is, when mutations are inherited this way and why some are not.

If you have certain cancer types that are considered LFS core cancers and other criteria for having LFS but no mutations that are known, you might be mosaic, you might have Li-Fraumeni Like Syndrome, or you could have a mutation that isn’t known. Many cases of mosaicism are found when children are diagnosed with one or multiple LFS cancers that have TP53 mutations in the tumor, yet test negative for germline mutations. The best thing to do is talk with a Genetic Counselor about your history and risk. They are trained to help you understand and interpret test results and they are a wonderful resource for those with LFS or with a family history of LFS. A doctor can refer you to genetic counseling or counselors in your area can be found HERE.

If you have suspected Mosaicism, it’s a good idea to discuss a screening regimen with your team of medical professionals.  Many have had to answer the awkward question of- are you sure you are both the parents of the child. One of the tricky parts of LFS is not knowing where cancer might pop up or when. With mosaicism, you may be able to get a better idea of which tissues have mutations and those areas should be monitored because we don’t know how much higher the risk of cancer developing there is or if it is higher than for the average person. Again, a Genetic Counselor is an excellent resource in helping to tailor a screening routine that is appropriate.

What Does This All Mean?

Mosaicism is just one part of the bigger picture of our individual genetics that researchers know will give them a better understanding of how LFS is inherited and how cancer develops, but we just don’t know right now. There isn’t a simple answer and no simple way of determining which tissues are at risk.

Li-Fraumeni Syndrome can be frustrating. There are so many parts of the disease and the mutations that are just not understood yet. Some day we will hopefully be able to predict which cancers are linked to certain mutations and then even prevent cancer from forming . One day living with LFS might mean focusing on prevention more than treatment of cancer, no matter if some or all of your cells have the mutation.

 

 

References

Somatic TP53 mutation mosaicism in a patient with Li-Fraumeni syndrome.

A Pathogenic Mosaic TP53 Mutation in Two Germ Layers Detected by Next Generation Sequencing

Many Mosaic Mutations 

Freed, D.; Stevens, E.L.; Pevsner, J. Somatic Mosaicism in the Human Genome. Genes 2014, 5, 1064-1094. Link to article 

DNA Double Take- The New York Times

Mosaic Mutations May Not be Rare- The Scientist