The Ataxia-telangiectasia mutated (ATM) is the most important gene for repairing the DNA in Myelodysplastic Neoplasm.

Myelodysplastic Neoplasm (MDS) is a cancer associated with aging, often leading to acute myeloid leukemia (AML). One of its hallmarks is hypermethylation, particularly in genes responsible for DNA repair. This study aimed to evaluate the methylation and mutation status of DNA repair genes (single-strand - XPA, XPC, XPG, CSA, CSB and double-strand - ATM, BRCA1, BRCA2, LIG4, RAD51) in MDS across three patient cohorts (Cohort A-56, Cohort B-100, Cohort C-76), using methods like pyrosequencing, real-time PCR, immunohistochemistry, and mutation screening. Results showed that XPA had higher methylation in low-risk MDS compared to high-risk MDS. For double-strand repair genes, ATM displayed higher methylation in patients who transformed to AML (p = 0.016). ATM gene expression was downregulated in MDS compared to controls (p = 0.042). When patients were classified according to the WHO 2022 guidelines, ATM expression progressively decreased from low-risk subtypes (e.g., Hypoplastic MDS) to high-risk MDS and AML. Patients who transformed to AML had a higher 5mC/5hmC ratio compared to those who didn't (p = 0.045). Additionally, poor cytogenetic risk patients had higher tissue methylation scores than those with good risk (p = 0.035). Analysis using the cBioPortal platform identified ATM as the most frequently mutated DNA repair gene, with various mutations, such as frameshift and missense, most of which were classified as oncogenic. The findings suggest that ATM is frequently silenced or downregulated in MDS due to methylation or mutations, contributing to the progression to AML. This highlights ATM's potential role in the disease's advancement and as a target for future therapeutic strategies.