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High-proportion LOY is likely an MDS associated aberration
A
B
Mutations with a high VAF as well as presence of two or more mutations, especially including mutations in TET2, DNMT3A and/or ASXL1, are known to correlate strongly with the presence of MDS or to have a clinical course indistinguishable from that of MDS with the same muta- tion profile.32
Incidence of somatic mutations in patients with ≥75% loss of chromosome Y is higher than that in the age-matched general population
We compared the proportion of patients with any muta- tion in myeloid neoplasia-related genes to the incidence of clonal hematopoiesis of indeterminate potential compiled from the published literature (Table 4).33 The overall inci- dence of mutations in myeloid neoplasia-related genes in our cohort of patients with any LOY was higher (58%) than that seen in healthy individuals >70 years of age (10- 15%). Moreover, the incidence was much higher when only patients with ≥75% LOY were considered (81%), close to the incidence of somatic mutations seen in
Figure 2. Loss of chromosome Y in ≥75% metaphases is associated with somatic mutations in myeloid neoplasia-related genes. (A) Box plot demonstrating per- centage of metaphases with loss of chro- mosome Y (LOY) compared to number of myeloid neoplasia related genes mutated. (B) Scatter plots demonstrating relation between total number of mutations and pathologic diagnosis in patients with ≥75% LOY and <75%. MDS/MPN-RS-T: myelodysplastic/myeloproliferative neo- plasm with ring sideroblasts and thrombo- cytosis; MDS/t-MDS: myelodysplastic syn- drome/therapy-related myelodysplastic syndrome.
patients with MDS (85-90% in most series with broad testing panels).
Progression of loss of chromosome Y over time
We identified 30 sequential samples with matching NGS data from 12 patients for evaluation of changes over time. These samples were obtained at varying time intervals after the first (median 22 months; range, 7-72 months). Of these 12 patients, seven did not demonstrate morphological fea- tures diagnostic of myeloid neoplasia at initial presentation with LOY (Figure 4). On follow-up, four of these seven patients progressed to having overt MDS, all of whom showed either an increased percentage of metaphases with LOY or persistent 100% LOY. The remaining three patients did not demonstrate evidence of progression to a myeloid neoplasm, despite an increase in the percentage of LOY metaphases in two. Of the five patients who had morpho- logical diagnostic features of MDS at presentation, three maintained 100% LOY, while the remaining two showed an increase in percentage of LOY over the follow-up period.
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