Loss of the Y Chromosome in MDS - Age-Related Phenomenon or Clonal Abnormality?

Loss of the Y chromosome has been reported to be associated with hematopoietic diseases (Wiktor et al., 2000), but it was also described as an age-related phenomenon in males (UKCCG, 1992). Determination of clonality and prediction of prognosis and treatment outcome might benefit from a differentiation between age- and MDS-associated Y loss. The aim of this study was to evaluate if Y loss was an age- and/or MDS-associated phenomenon by retrospectively analyzing our multicenter, international DACH-, ICWG- and IMRAW-database and by testing the established hypotheses in an experimental study.

In our multicenter MDS-database of 2901 patients, 101 primary, untreated MDS patients (3.5%) with loss of the Y were identified. We analyzed them according to age, clone size, and the presence or absence of additional chromosomal aberrations and assessed the prognostic relevance of the aberrations using univariate and multivariate models. Additionally, by immunomagnetic cell sorting, we enriched clonal CD34+ cells and CD3+ T-cells not belonging to the MDS clone from peripheral blood of three patients and compared the percentage of cells with -Y using FISH.

Isolated loss of Y was observed in 65.3% (n=66) of the 101 patients identified in the multicenter MDS-database, 14.9% (n=15) of the patients displayed one additional aberration and in 19.8% (n=20) -Y occurred as part of complex abnormalities. Overall survival of patients with -Y as a sole change was significantly better compared to patients with a normal karyotype (60.8 vs. 47.4 months; hazard ratio = 0.50, p<0.01). Loss of the Y chromosome as isolated aberration was significantly less frequent in younger (<60 years) than in older patients (1.9% vs. 4.0%. p<0.01). Patients showing -Y as single aberration were older at time of first diagnosis as patients with any other abnormalities or a normal karyotype (71.5 vs. 66.7 years, p<0.01). There were no differences in clone size between patients with -Y and patients with 5q-, -7/7q-, 20q- or complex karyotypes. Studying sequential karyotypes of some patients, we observed -Y occurring during karyotype evolution. We also identified a patient with -Y at first diagnosis in a mosaic karyotype with normal cells that later developed additional aberrations in the cells with -Y during the course of the disease. These data strongly suggest that -Y is MDS-associated in these patients. To demonstrate that -Y is occurring in the clonal CD34+ cellular compartment as a somatically acquired event we studied the loss of the Y chromosome in CD34+ and CD3+ cells separately in 3 patients. The percentage of cells with -Y was significantly increased in CD34+ cells (69%, 74%, 47%) compared to CD3+ cells (8%, 7%, 2%; p=0.01). Until now, it is not clear whether the low proportion of loss of the Y chromosome in CD3+ cells that exceed in two cases only slightly our laboratory threshold of 3.8% is due to an age related loss of the Y chromosome in T-cells or to contamination of the CD3+ cells with clonal cells.

The frequency of loss of Y chromosome in MDS karyotypes is associated with age. However, the evidently better prognosis of MDS patients with loss of the Y chromosome as the sole aberration compared to MDS patients with normal karyotype, the occurrence of Y loss during karyotype evolution, the acquisition of additional abnormalities in cells with -Y as primary aberration, and the observation of -Y in clonal CD34+ cells but not in CD3+ cells suggest a clonal nature of this karyotype anomaly at least in a subset of patients with MDS. In other patients this finding is clearly age-related. The preliminary data of our experimental study will be tested by analyzing a larger cohort of patients.

No relevant conflicts of interest to declare.