Comprehensive Study of Chromosomal Copy Number Variations and Genomic Variations Predicting Overall Survival in Myelodysplastic Syndromes.

Introduction: Myelodysplastic syndrome (MDS) is a heterogeneous disease characterized by cytopenia, marrow dysplasia and has a propensity to develop into acute myeloid leukemia. The disease progression is majorly affected by genetic defects. However, about 40-50% of patients with MDS present with a normal karyotype and develop different courses of disease. Hence, there remains a room to advance the biological understanding and find molecular prognostic markers for cytogenetically normal MDS.

Methods: We performed a high-resolution CGH + SNP array along with next-generation sequencing (NGS) of 77 primary diagnosed MDS patients, and also they were clinically followed up.

Results: Our study revealed 82 clinically significant genomic lesions (losses/gains) in 49% of MDS patients. CGH + SNP array reduced the proportion of normal karyotype by 30%. SNP array in combination with NGS confirmed the biallelic loss of function of the TP53 gene (2/6), which is a clinically relevant biomarker and new genetic-based MDS entity, i.e., MDS-biTP53, as per the new WHO classification 2022. Genomic region 2p22.3 presented with frequent lesions and also with a more hazard ratio (2.7, 95% CI: 0.37-21) when analyzed by Kaplan-Meier survival analysis.

Conclusion: CGH + SNP array changed the cytogenetic and IPSS-R risk group in 18% and 13% of patients, respectively, with an improved prediction of prognosis. This study emphasizes the cytogenetic heterogeneity of MDS and highlights that abnormality with chromosome 2 may have a diagnostic and prognostic impact.