MDS typically affects older adults, and hereditary factors have been considered less contributory to disease pathogenesis. Moreover, their impact is obscured by the complexity of the clinical presentation and history. Similarly, familial MDS and pediatric MDS is rare and likely distinct from adult MDS occurring in younger adults. Younger MDS patients (pts), excluding those who present with treatment-related disease, may represent a distinct subtype of MDS characterized by a specific molecular pattern of lesions. We compared two groups of MDS pts focusing on pathological diagnosis at presentation, family history of solid malignancies and blood disorders (Leukemia and MDS) in first and second degree relatives, cytogenetic abnormalities and somatic mutations.

Our analysis of 1030 MDS pts included MDS, MDS/myeloproliferative neoplasm (MPN) and secondary acute myeloid leukemia (sAML) pts. Overall the median age at presentation of this population was 71years (range 14-100); we classified the younger subset as those falling into the lower 8thpercentile of age to identify. Accordingly, the younger population was characterized by age less than 50 years (range 14-49; median age 41), and the older population age ≥ 50years (range 50-100; median age 75). Treatment-related MDS was excluded.

Younger MDS pts more frequently presented with higher-risk disease compared to the older population (46% vs. 31%; P=.004). There was no significant difference between the two groups with regard to family history of cancers (40 vs. 47%; P=.21) and blood disorders (10 vs. 6%; P= .1). When we compared cytogenetic abnormalities between these patient subsets, there was no difference in detection of rate of abnormal cytogenetics (53% vs. 52%; P=.5) or complex karyotype (23 vs. 25%; P=.86). However, del 20q was more common in the older subset (19 vs. 6%; P=.03). We then investigated somatic mutational patterns using new generation deep sequencing for the 60 most commonly encountered MDS mutations (defined in the 200 MDS exome cohort presented in other abstract from our group). Data were available for 26 younger pts and 179 older pts. By analyzing comprehensive mutational spectrum, the average number of somatic mutational events (mean; 2.4/case) was significantly higher in the older subgroup compared to the younger (1.8/case; P<.001). RUNX1, PHF6, TP53 (12% each) are the most frequently affected genes in MDS associated with the younger population. Interestingly, germline mutations of these 3 genes are all associated with congenital syndromes, which lead to susceptibility for hematological neoplasms. Conversely, somatic mutations of TET2 (24%) and ASXL1 (15%) were most prevalent in the older MDS cohort. Notably, these 2 genes associated with older populations were less prevalent in younger MDS cases (<4%; P=.02 and < 4% P=.11 for TET2 and ASLX1 respectively). In contrast, there was no significant difference between these subgroups (old vs. young MDS) in the frequency of RUNX1 (9 vs. 12%; P=.67), U2AF1 (11 vs. 12%; P=.88), BCOR family (9 vs. 15%; P=.35), PRC2 family (10 vs. 4%; P= .34), RAS family (11 vs. 12%; P=.88), or many other gene mutations.

In sum, 8% of MDS pts present at a younger age in our cohort. MDS in younger pts presents with more advanced disease and is less commonly affected by del20q- and TET2 mutations, consistent with less common myeloproliferative features in this population.


Makishima:AA & MDS international foundation: Research Funding; Scott Hamilton CARES grant: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.