In February 2024, a study led by Professor Hongyan Tong from the First Affiliated Hospital, Zhejiang University School of Medicine was published in the international academic journal ——American Journal of Hematology (IF=12.8). The title of the study is “Mutation landscape of normal karyotype myelodysplastic syndromes and their prognostic impact“.  This study sheds light on the prognostic implications of gene mutations in myelodysplastic syndromes with a normal karyotype.

Myelodysplastic syndromes (MDS) encompass a heterogeneous group of hematological disorders characterized by dysplastic changes in the bone marrow, ineffective hematopoiesis, and a risk of progression to acute myeloid leukemia (AML). Despite advances in prognostication, predicting outcomes in MDS patients, particularly those with a normal karyotype (NK), remains challenging. The integration of molecular data into prognostic models has emerged as a promising approach to enhance predictive accuracy and refine risk stratification.

This comprehensive study involved 237 de novo NK MDS patients from the First Affiliated Hospital of Zhejiang University. Rigorous diagnostics, including next-generation sequencing (NGS) on a predetermined gene panel and hematological assessments, were performed to delineate the mutation spectrum and ascertain its prognostic value. Additionally, an external validation cohort from the International Working Group for the Prognosis of MDS (IWG-PM) was accessed to contrast findings and validate prognostic implications. Statistical analyses, including Kaplan-Meier curves and Cox regression analyses, were utilized to generate meaningful insights into survival outcomes.

The patients included in the study were diagnosed with de novo NK MDS based on established criteria. Comprehensive hematological assessments, including complete blood counts, peripheral blood smears, and bone marrow examination with cytogenetic analysis, were conducted to confirm the diagnosis and assess disease severity. Next-generation sequencing (NGS) was performed on a predetermined gene panel, which included genes known to be frequently mutated in MDS, such as ASXL1, TET2, RUNX1, and TP53. Rigorous quality control measures were implemented to ensure the accuracy and reliability of the sequencing data.

The mutation analysis revealed distinct patterns in gene mutation prevalence, with ASXL1, TET2, and RUNX1 being the most frequently mutated genes. TP53 mutations, which are detrimental in complex karyotypes, were not as prevalent in NK MDS patients. Survival outcomes differed significantly between the study cohort and the IWG-PM validation cohort, with a median overall survival (OS) of 7.38 years in our group and 4.99 years in the IWG-PM cohort, underpinning the variability and necessity for karyotype-specific prognostic models.

The methodological rigor of this study ensured accurate classification of NK MDS patients and robust analysis of gene mutations. NGS, coupled with comprehensive pre-treatment diagnostics, facilitated precise identification of mutations and their prognostic implications. Notably, a 100% follow-up data completion rate strengthened the reliability of the findings, while statistical analyses provided valuable insights into survival outcomes. The incorporation of an external validation cohort enhanced the generalizability of the findings and validated prognostic implications across diverse patient populations.

Analysis of a wide spectrum of gene mutations identified eight mutations with significant negative prognostic implications, consistent across both cohorts studied. Additionally, factors such as In(PLT) and HB levels emerged as protective, while age and higher bone marrow blast percentages were identified as risk factors.

The study concluded that the mutation profile in NK MDS patients carries a unique prognostic signature, distinct from patients with complex karyotypes. The prognostic importance of TP53 mutations in NK MDS patients differed from prior research, emphasizing the need for karyotype-specific considerations in prognostication.

In conclusion, this comprehensive study sheds light on the prognostic implications of gene mutations in myelodysplastic syndromes with a normal karyotype. The unique mutation profile identified in NK MDS patients underscores the need for karyotype-specific prognostic models to accurately predict outcomes and guide treatment decisions. By integrating molecular data into prognostic models, we can improve risk stratification and potentially enhance patient outcomes in MDS. Further research is needed to validate these findings and explore potential therapeutic targets based on the identified mutations.