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. Highlights: The study identified 82 different clinically significant CNVs including chromosomal aberrations in MDS. The transcriptome data revealed that CNVs majorly affect genes associated with biological functions such as transcriptions, cell cycle, and immunity. A high frequency of CNVs/loss of heterozygosity was identified at 2p22.3 chromosomal region and found to be associated with disease prognosis. Combination of SNP array with gene mutations successfully established a new genetic-based MDS entity, i.e., MDS-biTP53, in 33.3% of TP53-mutated patients. [ABSTRACT FROM AUTHOR]