The role of genetic predisposition to hematologic malignancies has been increasingly recognized in recent years. In the case of myelodysplastic syndrome (MDS), current National Comprehensive Cancer Network guidelines recommend germline testing for patients with myeloid neoplasms who are diagnosed at younger than 50 years, have a history of at least one additional cancer, have a family history of myeloid neoplasm, or are otherwise clinically suspected to have a predisposition syndrome based on features such as a hypocellular marrow or congenital anomalies. The recommendation to test patients diagnosed with MDS at a younger age is based on data showing that pathogenic germline variants are found in 13 to 20 percent of pediatric and young adult patients.1,2 Germline predisposition variants (e.g., in DDX41) have also been identified in older patients.3,4 However, the frequency of pathogenic germline variants in older patients with MDS has not been well characterized.
To evaluate the frequency of pathogenic/likely pathogenic (P/LP) germline variants in patients with MDS of various ages, Dr. Simone Feurstein and colleagues recently conducted an analysis of samples collected from a Center for International Blood and Marrow Transplant Research cohort of patients with MDS who underwent allogeneic stem cell transplantation from a related donor; DNA collected from the donors was also analyzed. Following DNA extraction from peripheral blood samples collected prior to transplantation, they performed augmented whole-exome sequencing and analyzed for variants in 233 genes that have been associated with germline predisposition to hematologic malignancies. P/LP variants were identified as germline if they were either found in both the patient with MDS and the patient’s related donor, or if the variant was previously only reported as germline and was detected with a variant allele frequency of 40 to 60 percent.
This study included 404 patients with MDS (n=364), chronic myelomonocytic leukemia (n=39), and juvenile myelomonocytic leukemia (n=1). P/LP germline variants were detected in 28 (7%) of 404 patients. Notably, germline variants were identified in patients with MDS of all ages, ranging from 11 to 71 years. Although the frequency of germline P/LP variants was highest in the group of patients who were 11 to 20 years old (33%), germline variants were also identified in 6 to 8 percent of older patients. Variants associated with bone marrow failure were more common in the youngest patients, while variants associated with telomere biology disorders, general tumor predisposition, and DDX41 were seen in the older patients. DNA collected from the patients’ related donors identified shared autosomal-dominant P/LP germline variants in 20 donor/recipient pairs. The authors observed no significant differences in outcomes for the recipients who received transplants from related donors sharing the germline P/LP variants, though the numbers were too small to draw conclusions.
In Brief
This study demonstrates that germline predisposition to MDS is common (≥6%) even in older patients with MDS. An important limitation of this study is that because only DNA from peripheral blood was available (rather than a germline DNA specimen such as skin fibroblasts), the authors were conservative in calling P/LP variants germline, which means that the true frequency of germline predisposition to MDS is likely higher than what was reported in this article. Indeed, the authors found that when “presumed” P/LP germline variants were also included, the frequency of germline P/LP variants was 11 percent. This study serves as an important reminder that germline predisposition to myeloid neoplasms is not a rare occurrence. Additionally, diagnosis at an older age should not be used to assume that a patient does not require genetic counseling and testing, which is especially important prior to undergoing a transplantation from a related donor.
Competing Interests
Dr. McMahon indicated no relevant conflicts of interest.
