Germline Variant Burden Warrants Universal Genetic Testing in Pediatric Myeloid Leukemia

Area of Science:

• Genetics
• Oncology
• Hematology

Background:

• Causal germline genetic variants are prevalent in young patients with myelodysplastic syndromes (MDS) or bone marrow failure (BMF).
• Progression to acute myeloid leukemia (AML) is a significant cause of mortality in these patients.
• Pediatric AML shares clinical and biological characteristics with MDS/BMF, suggesting potential shared germline genetic risk variants.

Purpose of the Study:

• To investigate the presence and impact of germline genetic variants in pediatric AML.
• To determine the prevalence of pathogenic/likely pathogenic (P/LP) variants in genes associated with leukemia and other malignancies.
• To compare germline variant burdens across different age groups and diagnoses of acute leukemia and MDS.

Main Methods:

• Whole-genome sequencing (WGS) was performed on a cohort of 365 pediatric AML patients.
• Variants were classified as "likely germline" based on variant allele frequency (VAF).
• Pathogenic/likely pathogenic (P/LP) variants were annotated using American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) guidelines.
• Loss-of-function variant burden testing was conducted by comparing pediatric AML patients with control subjects from the 1000 Genomes Project.
• Meta-analysis of 10 published studies including 4,622 pediatric and adult patients with acute leukemia or MDS was performed.

Main Results:

• Pathogenic/likely pathogenic (P/LP) germline variants were identified in 5.5% of pediatric AML patients in genes linked to familial myeloid malignancy and an additional 3.3% in genes conferring risk to lymphoid malignancy or solid tumors.
• Loss-of-function variant burden testing revealed a 6.9-fold increase in genes implicated in myeloid malignancy risk, a 2.4-fold increase in candidate risk genes, and a 1.6-fold increase in randomly-selected genes compared to controls.
• The prevalence of germline variants in myeloid malignancies consistently exceeds 5% across all age groups.

Conclusions:

• Germline genetic variants are a significant factor in pediatric acute myeloid leukemia (AML) and other myeloid malignancies.
• The consistent prevalence of germline variants across age groups supports their integral role in the diagnostic work-up of myeloid malignancies.
• Germline genetic variant testing is recommended for all patients with myeloid malignancies, aiding in diagnosis and donor selection for stem cell transplantation.