What genetic factors might increase Myelodysplastic Syndromes risk?
Myelodysplastic syndromes (MDS) are a group of blood cancers where the bone marrow does not make enough healthy blood cells. Both inherited (germline) genetic variants and acquired (somatic) mutations in blood cells can increase the risk of developing MDS. A large 2024 study found that people with certain inherited DNA changes have a higher chance of MDS, and other research shows that mutations in specific genes are common in MDS patients.
What the research says
A 2024 meta-analysis of genome-wide association studies (GWAS) across 20 rare cancers identified a new inherited risk factor for MDS: a variant near the API5 gene. People carrying this variant had about 2.2 times higher odds of developing MDS compared to those without it 3. This is considered a moderate-to-large effect size for a rare cancer. The study also found other new risk locations for cancers like gastrointestinal stromal tumor (GIST) and anal cancer, but the API5 locus was one of the strongest signals for MDS 3.
In addition to inherited factors, acquired mutations in blood stem cells are very common in MDS. Standard medical guidelines note that mutations in genes such as TET2, ASXL1, DNMT3A, and SF3B1 are frequently found in MDS patients 6. These mutations are not passed down in families but develop over a person's lifetime. They can affect how cells grow and divide, contributing to the disease.
Some MDS cases are linked to specific chromosome changes. For example, a deletion on chromosome 5 (called del(5q)) is a well-known abnormality in MDS. The drug lenalidomide is approved to treat MDS patients with this specific deletion who need blood transfusions 1. This shows that genetic testing can guide treatment choices.
Other research has explored how genetic changes affect treatment. A clinical trial of a CAR T-cell therapy for MDS and acute myeloid leukemia (AML) after stem cell transplant found that the treatment could cause side effects like cytokine release syndrome, but it did not focus on genetic risk factors for developing MDS 2. Similarly, a study of itacitinib to prevent graft-versus-host disease after transplant included MDS patients but did not address genetic risk 5.
What to ask your doctor
- Should I consider genetic testing for inherited MDS risk factors, such as the API5 gene variant?
- What acquired mutations (like TET2, ASXL1, DNMT3A, SF3B1) are most relevant for my MDS diagnosis or risk?
- Does my MDS have a specific chromosome abnormality, such as del(5q), that might affect treatment options?
- How do my genetic results influence my prognosis or the choice of therapy?
- Are there any family members who should also be evaluated for inherited MDS risk?
This question is drawn from common patient questions about this topic and answered using cited medical research. We do not provide individualized advice.