Uncovering Putative Causal Non-coding RNAs in Acute and Chronic Myeloid Leukemia: A Genome-Wide Mendelian...

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Non-coding RNAs (ncRNAs) are increasingly recognized for their roles in cancer development.
• The specific causal involvement of ncRNAs in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) requires further elucidation.

Purpose of the Study:

• To investigate the potential causal effects of a wide range of ncRNAs on the risk of developing AML and CML.
• To identify specific ncRNAs that may play a direct role in the pathogenesis of these myeloid leukemias.

Main Methods:

• A genome-wide, two-sample Mendelian randomization (MR) study design was employed.
• Utilized summary statistics from large-scale expression quantitative trait loci (eQTL) and genome-wide association studies (GWAS) including FinnGen and UK Biobank.
• Employed the generalized inverse-variance weighted (GIVW) method as the primary analysis, supported by MR-Egger, weighted median, and comprehensive sensitivity analyses to ensure robustness.

Main Results:

• Identified a causal link between upregulated HCG22 and RP11-42I10.1 and an increased risk of AML.
• Found a positive association between the GMDS-AS1 locus and an increased risk of CML.
• Results were consistent across multiple MR methods and validated in independent datasets, with no significant evidence of bias or confounding.

Conclusions:

• This research provides robust evidence for causal relationships between specific ncRNAs and distinct subtypes of myeloid leukemia.
• Highlights HCG22 and RP11-42I10.1 as potential causal factors in AML development.
• Identifies the GMDS-AS1 locus as a potential causal factor in CML pathogenesis.