Loss of the Y Chromosome in MDS - Age-Related Phenomenon or Clonal Abnormality?
Bibliographic record
Abstract
Abstract Abstract 4008 Introduction: 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. Patients and Methods: 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. Results: 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. Conclusion: 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. Disclosures: No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".