A GUIDE TO MUTATIONS
CHROMOSOMEs
Chromosomes are structures within cells that contain a person’s genes. Every person has 46 chromosomes. Each chromosome contains thousands of genes.
Genes
Genes, contained in chromosomes, are segments of deoxyribonucleic acid (DNA) that contain the code for making a specific protein that functions in one or more t ypes of cells in the body.
MUTATIONS
Mutations occur when a gene is damaged and alters the genetic message.
Mutation testing is gaining importance in MDS. It is estimated that 90% of patients with MDS harbor one or more genetic mutations. Chromosomes contain several thousand genes. Genes are shorter sections of DNA. Each gene acts as a code or set of instructions for making a specific protein. These proteins control the cell’s activity, telling the cell what to do. Genes can become mutated (altered, faulty).
When a gene becomes mutated over time, it is called a somatic or an acquired mutation. Some mutations are present from birth. These are called inherited mutations. Inherited mutations may increase the risk for MDS or other cancers throughout the lifetime. Inherited mutations indicate a hereditary risk for an MDS diagnosis. When a hereditary risk is identified, there may be testing and management options for family members who may have also inherited the same mutation. Family members cannot inherit somatic (acquired) mutations. Most mutations seen on testing will be somatic. It is rare to have an inherited mutation related to MDS. A genetic counselor can help you determine whether additional testing would be necessary to determine if any of the mutations seen on your MDS testing were inherited.
There are other factors that may raise concern for a hereditary risk for MDS. You may benefit from seeing a genetic counselor if you were diagnosed with MDS at any age, AML under 50 years old or have additional family members that have also been diagnosed with MDS or AML. The National Comprehensive Cancer Network recommends genetic counseling for anyone with an MDS diagnosis. Undergoing inherited mutation testing can be helpful for those who are considering related donors for transplant or to provide MDS risk information to their family members.
In most cases, the cause of these mutations is not fully understood but we know that somatic mutations accumulate as we age. Knowing which genes are mutated can help your doctor understand how you are likely to be affected by your MDS. In some cases, a mutated gene can be targeted to interrupt the abnormal production of blood cells common in MDS.
Mutations are currently identified by sequencing the DNA, commonly using a technique called “next generation sequencing” (NGS) using the material from a bone marrow or blood sample. Today, the mutation profile is used primarily for estimating prognosis. Several clinical trials are exploring the potential therapeutic benefit of targeting genes known to promote MDS. Importantly, the mutation profile may change over time. This is why it is important to re-characterize MDS at points of progression.
The International Working Group for Prognosis in MDS (IWG-PM) is working to better define individual molecular (genetic) abnormalities and their significance in MDS. There are many clinical trials focused on exploring the potential benefits of targeting genes known to cause and promote MDS. In some cases, the production of abnormal cells can be interrupted and lead to improved blood counts.
Your doctor may have ordered a DNA sequencing study to identify mutated genes in your MDS cells. This test can help confirm your diagnosis and provide information about which subtype of MDS you have. Some mutated genes are associated with lower risk disease while others may indicate greater risk. Mutations can potentially identify effective therapies to treat your disease. Knowing which genetic mutations are present in your MDS cells will open discussions with your healthcare provider about individualized risk assessment and treatment. Your genetic profile may change over time therefore it is important to re-characterize MDS at points of progression.
COMMONLY MUTATED GENES IN MDS
| Gene Abbreviation | Gene Name | Chromosome location | Frequency in MDS | Significance |
|---|---|---|---|---|
| ASXL1 | Additional Sex Combs Like 1 | 20Q11 | >10% | Lower response for hypomethylating agents |
| BCL2 | B-Cell Lymphoma 2 | mitochondria | – | Agents in clinical trials |
| CEBPA | Ccaa/Enhancer Binding Protein A | 19Q13.1 | <1% | Lower response for hypomethylating agents |
| DNMT3A | Dna-Methyltransferase 3 Alpha | 2P23 | >10% | Related to mechanism or action for hypomethylating agents. |
| EZH2 | Enhancer Of Zeste Homolog 2 | 7Q35-36 | 1-10% | Unfavorable; histone deacetylation agents in clinical trials |
| FLT3 | Fms-Related Tyrosine Kinase 3 | 13Q12 | <1% | More common in AML |
| GATA2 | Gata Binding Protein 2 | 3Q21.3 | <1% | Agents in clinical trials |
| IDH1 | Isocitrate Dehydrogenase 1 | 2Q33.3 | 1-10% | More common in AML FDA approved targeted treatment: Ivosidenib |
| IDH2 | Isocitrate Dehydrogenase 2 | 15Q26.1 | <1% | More common in AML FDA approved targeted treatment: Enasidenib |
| JAK2 | Janus Kinase 2 | 9P24 | 1-10% | More common in overlap syndromes |
COMMONLY MUTATED GENES IN MDS
| Gene Abbreviation | Gene Name | Chromosome location | Frequency in MDS | Significance |
|---|---|---|---|---|
| KIT | V-Kit Oncogene Homolog | 4Q11-12 | 1-10% | More common in AML |
| KRAS | Kirsten Sarcoma Viral Oncognene | 12P12-11 | Agents in clinical trials | |
| NPM1 | Nucleophosim | 5Q35.1 | <1% | More common in AML |
| NRAS | Neuroblastoma Ras Oncogene | 1P13.2 | 1-10% | More common in AML; Targeted agents in clinical trials |
| RUNX1 | Runt-Related Transcription Factor 1 | 21Q22.12 | 1-10% | Unfavorable |
| SF3B1 | Splicing Factor 3b, Subunit 1 | 2Q33.1 | >10% (UP TO 40%) | Favorable Agents in clinical trials |
| SRSF2 | Serine/arginine-rich splicing factor 2 | 17Q25.1 | >10% | Agents in clinical trials |
| TET2 | Tet methylcytosine deoxygenase 2 | 4Q24 | >10% | More likely to respond to hypomethylating agents when a sole abnormality |
| TP53 | Tumor protein p53 | 17P13.1 | 1-10% | Unfavorable; Targeted agents in clinical trials |
| U2AF1 | U2 small nuclear RNA auxiliary factor 1 | 21Q22.3 | 5-12% | Unfavorable, could benefit more from HMA therapy |