Myelodysplastic Syndromes (MDS) represent a group of disorders where the bone marrow fails to produce sufficient numbers of healthy, mature blood cells, leading to cytopenias like anemia and an increased risk of progression to acute myeloid leukemia (AML). The disease is overwhelmingly caused by genetic mutations acquired during a person’s lifetime, known as somatic changes. A small percentage of cases, however, involve an inherited genetic predisposition that is present from birth. Understanding the nature of these genetic alterations is fundamental to diagnosing the condition and determining the most appropriate management approach.
The Acquired Genetic Basis of MDS
The primary mechanism driving the development of MDS involves somatic mutations, which are genetic changes that occur in a single blood stem cell within the bone marrow over time and are not passed down from a parent. These mutations grant the affected cell a survival advantage, allowing it to multiply and establish a population of abnormal cells, a process termed clonal hematopoiesis. This abnormal clone gradually outcompetes the healthy blood-producing cells, leading to the characteristic ineffective blood cell production seen in MDS.
Mutations in RNA splicing factor genes, such as SF3B1, SRSF2, and U2AF1, are common, found in up to 50% of all MDS cases. These changes disrupt the cell’s ability to properly assemble proteins. This disruption is believed to be an early, driving event in the disease’s development.
Frequent mutations also affect epigenetic regulators, including TET2, DNMT3A, and ASXL1. These regulators control how genes are turned on or off without altering the underlying DNA sequence. The accumulation of these somatic alterations is strongly correlated with age, as the median age of diagnosis for MDS is around 70 to 75 years old. Patients typically have an average of five to ten such genetic changes present in the abnormal clone.
Inherited Risk Factors
While the vast majority of MDS cases are acquired, a small percentage, estimated to be between 4% and 15% of all cases, involves an underlying inherited predisposition. These cases are traced back to germline mutations. The presence of this germline error significantly increases an individual’s lifetime risk of developing MDS, often at a much younger age than the general population.
Specific genetic syndromes are now recognized as causes of familial MDS, involving genes that govern fundamental cellular processes like DNA repair and blood cell development. Examples include mutations in the RUNX1 gene, which is associated with a familial platelet disorder, and mutations in GATA2, which can cause a broader immunodeficiency syndrome in addition to MDS predisposition. Germline mutations in DDX41 are another example, typically associated with an adult-onset form of familial MDS/AML.
Inherited disorders of telomere biology, such as those caused by mutations in TERT or TERC, also predispose individuals to MDS by accelerating the natural shortening of telomeres. Identifying these germline mutations is important for the patient’s clinical management and for genetic counseling of family members.
Non-Genetic Risk Factors and Environmental Triggers
Certain external factors can increase the risk of developing MDS by causing DNA damage in bone marrow stem cells. Prior exposure to chemotherapy or radiation therapy used to treat an earlier cancer is one factor, leading to a subtype referred to as therapy-related MDS. Alkylating agents and topoisomerase II inhibitors, common types of chemotherapy drugs, are implicated in this process.
Long-term occupational exposure to the solvent benzene, used in the petroleum, rubber, and chemical industries, is an identified risk factor. Other chemical exposures, including tobacco smoke and some pesticides, contain agents that damage the DNA of bone marrow cells, initiating the mutational events that drive the disease. While the majority of MDS cases occur without any identifiable external cause, the presence of these non-genetic risk factors underscores how DNA damage sets the stage for the acquired genetic changes that define the disease.
How Genetic Information Guides Treatment
Genetic information obtained from a patient’s bone marrow is routinely used to guide clinical decisions. Analyzing the specific somatic mutations present helps physicians predict the disease’s likely course, including the risk of progression to AML and overall prognosis. The Revised International Prognostic Scoring System (IPSS-R) for MDS now incorporates specific genetic markers alongside traditional factors like blast count and cytopenias.
The presence of a TP53 mutation is associated with a less favorable prognosis and a high risk of leukemic transformation, whereas an SF3B1 mutation correlates with a more stable, lower-risk disease course. This prognostic data helps determine the intensity of treatment, such as whether a patient is a candidate for an allogeneic hematopoietic stem cell transplant.
Genetic analysis also points toward targeted therapies. Patients with the chromosomal abnormality deletion on the long arm of chromosome 5 (del(5q)) show a favorable response to the drug lenalidomide, which selectively targets the abnormal clone. Furthermore, the presence or absence of certain mutations, such as TET2, can predict a patient’s response to hypomethylating agents, demonstrating the direct influence of a patient’s genetic profile on therapeutic outcomes.