Myelodysplastic Syndromes (MDS) are a group of bone marrow disorders where the body’s blood-forming cells do not mature properly, leading to a shortage of healthy blood cells. This can result in various symptoms such as fatigue, increased infections, and easy bruising. MDS is considered a type of cancer, and in some cases, it can progress to acute myeloid leukemia (AML), a more aggressive blood cancer. The development of MDS is linked to genetic changes, predominantly those acquired during a person’s lifetime, though a small proportion of cases are due to inherited genetic predispositions.
Acquired Genetic Changes
The vast majority of MDS cases arise from acquired, or somatic, genetic mutations. These mutations occur in the DNA of blood-forming stem cells within the bone marrow during an individual’s life and are not passed down from parents. They can happen spontaneously or be influenced by external factors like chemical exposure, radiation, or previous cancer treatments. These acquired changes are specific to the affected bone marrow cells and do not exist in other cells of the body.
These somatic mutations disrupt the normal processes of blood cell production and maturation in the bone marrow.
For instance, the TP53 gene, a tumor suppressor, is mutated in 5-10% of new MDS cases and up to 30-40% of therapy-related MDS. This leads to a dysfunctional protein that cannot properly regulate cell growth and DNA repair.
Mutations in SF3B1 are common, found in about 20% of MDS patients, particularly those with ring sideroblasts. They alter RNA splicing, affecting protein production and leading to ineffective red blood cell production and iron metabolism dysregulation.
Other frequently mutated genes include TET2, ASXL1, RUNX1, and SRSF2. TET2 mutations, present in approximately 20-30% of MDS cases, influence DNA methylation and gene expression, contributing to abnormal blood cell development. ASXL1 mutations are found in about 15-20% of MDS patients and are associated with a less favorable prognosis and a higher risk of progression to AML, impacting chromatin remodeling. RUNX1 mutations, whether present at diagnosis or acquired during disease progression, can disrupt blood cell development and are linked to poorer outcomes. Similarly, SRSF2 mutations, found in a notable proportion of MDS patients, particularly in chronic myelomonocytic leukemia (CMML), affect RNA splicing and can impact disease progression.
Inherited Genetic Predisposition
A smaller proportion of MDS cases are linked to inherited genetic predispositions. These involve germline mutations, which are present in all cells of the body from birth and can be passed down through families. While individually rare, these inherited conditions collectively account for a meaningful subset of MDS diagnoses, especially in children and younger adults.
Genes associated with inherited MDS include GATA2, RUNX1, DDX41, ANKRD26, and ETV6. For instance, germline GATA2 mutations can lead to a complex multi-system disorder that includes an increased risk of MDS, often presenting with variable blood cell deficiencies and bone marrow failure. These mutations impact transcription factors essential for blood cell formation.
Inherited RUNX1 mutations also predispose individuals to familial platelet disorder with associated myeloid malignancies, increasing the risk of MDS. DDX41 germline mutations are a common inherited cause of MDS in adults. While ANKRD26 and ETV6 are implicated in inherited predispositions to myeloid malignancies, they contribute to a broader spectrum of blood disorders beyond solely MDS. These inherited mutations create a susceptibility, meaning individuals with them have a higher chance of developing MDS, but the disease may still require additional acquired genetic changes or environmental factors to fully manifest.
Role of Genetic Testing
Genetic testing plays a role in the diagnosis, prognosis, and treatment planning for individuals with MDS. Bone marrow biopsies identify somatic mutations in blood-forming cells, while blood tests detect germline mutations indicating an inherited predisposition. Identifying specific genetic mutations provides insights into the disease’s likely course.
For instance, TP53 mutations are associated with a poorer prognosis and a higher risk of transforming into acute myeloid leukemia, influencing treatment decisions due to their resistance to some conventional therapies. Conversely, SF3B1 mutations are often linked to a less aggressive form of MDS. Identifying them can guide the use of targeted therapies like luspatercept, which has shown promise in reducing anemia and transfusion dependence. The presence of TET2 mutations may indicate a favorable response to hypomethylating agents, a class of drugs used in MDS treatment.
Genetic profiling helps predict disease progression and guides therapeutic choices, including the potential for stem cell transplantation. For example, genetic analysis of blood cells after a stem cell transplant can predict the likelihood of disease recurrence, allowing for early intervention. Genetic counseling is also important, particularly for individuals with suspected inherited forms of MDS, to help them understand their risks and implications for family members. This comprehensive genetic evaluation allows for a more personalized approach to managing MDS.