Understanding Genetics and RUNX1-FPD

Understanding genetics and gene variants (commonly referred to as mutations) is an important part of understanding why and how cancer begins in the body. Since everyone’s knowledge base of genetics may vary, let’s begin with a quick summary of basic human genetics before we unpack how genetic changes can occur and affect our health.

Where can you find DNA in our bodies? In each and every cell (which is close to 37 trillion cells). DNA is genetic material organized into structures called chromosomes. Humans have 46 chromosomes in total, organized into 23 pairs in every cell of the body. Of these 23 pairs, 22 pairs are called autosomes (non-sex chromosomes), while one pair is composed of the sex chromosomes (either XX or XY). Autosomes carry the genes that play a role in determining our various traits and characteristics unrelated to biological sex. These genes contain instructions for building proteins, which are essential for the functioning of our cells and bodies.

Since we inherit one chromosome from our mother and one from our father (and each chromosome contains the same genes), geneticists use the term “allele” to refer to one of the two copies of each gene (each of which has sequence variations). The combination of the two alleles plays a crucial role in determining exactly which traits and characteristics we end up inheriting. Some alleles may be dominant, meaning their effects are visible even when only one copy is present (ex: brown eyes). Others may be recessive, requiring two copies to be visible (ex: blue eyes).

A gene variant refers to a change in the DNA code that makes up the instructions for a particular gene. Some variants can alter the function of proteins, or simply change the amount of a protein, either increasing or decreasing protein levels. Such changes can cause a cell to die, to no longer function properly, or can even cause a cell to grow uncontrollably. It is important to note that gene variants do not all occur in the same way. Variants are categorized as either germline or somatic, based on how and when they occur.

Germline 

A germline variant (also called an inherited variant) is passed down from one or both parents. This variant is present in the DNA of the egg or sperm at the time of conception and ultimately exists in every cell of the fully developed child’s body. RUNX1-FPD is an autosomal dominant disease, which means that having just one affected allele is sufficient to cause the disorder to occur - it will always dominate over the healthy allele. 

There are other disorders like cystic fibrosis where the disease manifests only when the child receives variant alleles from both parents. This is referred to as an autosomal recessive genetic disorder. 

De Novo Germline

A de novo variant (Latin for "from the beginning") is a variant that appears for the first time in an individual for two possible reasons. First, the variant may spontaneously occur in the DNA of the egg or sperm of a parent before a child's conception. Alternately, the variant may arise in a fertilized egg early in the embryo development of that child. In both cases, the variant will appear in all cells of the child's body but will NOT be present in all cells of either parent. De novo variants can occur due to various factors, including errors during DNA replication or a parent’s advancing age.

Somatic

A somatic variant (also called an acquired variant) does not occur at conception but later, just before birth and beyond. It happens sometime during your lifetime, and there is little to no risk of passing an acquired variant on to your children. The longer we live, the more likely we are to acquire these variants that happen by chance. This is why most cancers occur later in life after decades of somatic variant accumulation.

For example, exposure to substances such as tobacco smoke, certain industrial chemicals or environmental pollutants can increase the risk of acquiring gene variants because they can directly damage DNA in a cell. While damaged cells often die, any surviving cell can pass on these exposure-induced variants to other cells during cell division. 

Somatic variants can also arise naturally during DNA replication process, where cells may make mistakes such as deleting, adding or switching DNA letters - much like accidental spelling mistakes when you're writing. Although the body has its own “proofreading” systems to prevent or correct these mistakes, they are not foolproof. While not all mistakes result in dysfunctional genes, variants can accumulate over time and impact our health.

Does your RUNX1 variant cause RUNX1-FPD? 

Only germline RUNX1 variants (including de novo) represent the root cause of RUNX1-FPD. While somatic RUNX1 variants are also associated with blood cancers, they do not cause RUNX1-FPD as the RUNX1 variant is not present in every cell of the body. 

It is important to note that not all variants are disease-causing. One can have a germline RUNX1 variant that is classified as benign, meaning that the individual does not have RUNX1-FPD. A genetic report will provide a classification for each specific variant found. There are 5 categories: Benign, Likely Benign, Variant of Uncertain Significance, Likely Pathogenic and Pathogenic. Only those germline RUNX1 variants deemed Likely Pathogenic or Pathogenic are known to cause RUNX1-FPD.

It is important to know if you have a germline or somatic RUNX1 variant, as this knowledge can help you and your healthcare team make informed decisions regarding your care, cancer surveillance (checking for signs of cancer development) and cancer treatment for you and your family. If you know you have a RUNX1 variant but are uncertain what type it is, RUNX1 Research Program can help you learn more. 

How do variants impact your cancer risk and what can you do?

The accumulation of variants (germline or somatic) in certain cancer-associated genes, including RUNX1, contributes to cancer development. Individuals with RUNX1-FPD are at much higher risk for blood cancer because they are born with a variant in a gene that, when functioning properly, suppresses cancer. Again, germline RUNX1 variants increase the risk of blood cancer, but they cannot cause it alone.

This is why not every RUNX1-FPD individual goes on to develop blood cancer. A single RUNX1 variant is not enough. Additional somatic variants in the blood are required to develop blood cancer, which is why cancer surveillance is so important. Catching cancer early can give you and your loved ones a better chance at beating it.

Though we do not fully understand all of the processes involved in the development of cancer for an individual with RUNX1-FPD, we do know that attempting to minimize your exposure to carcinogens that could cause somatic variants, as well as making healthy lifestyle choices in terms of food and exercise, will help your body function at its best. A healthy, fit body is made up of healthier cells, and healthier cells can do things like correct DNA damage and limit the number of somatic variants.