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Germline Variant Burden Warrants Universal Genetic Testing in Pediatric Myeloid Leukemia
Lauren M Harmon1, Zachary S Hattig2, Yizhou Peter Huang1,3
1Van Andel Institute, Grand Rapids, MI, USA.
Insights
Germline genetic variants are common in pediatric acute myeloid leukemia (AML) and other myeloid malignancies, affecting over 5% of patients. These findings support routine germline genetic testing for diagnosing myeloid cancers and guiding stem cell transplantation.
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.
Abstract:
Causal germline genetic variants are frequently detected in young (under age 40) patients presenting with myelodysplastic syndromes (MDS) or bone marrow failure (BMF), where progression to acute myeloid leukemia (AML) contributes substantially to mortality in these patients. We reasoned that de novo pediatric AML, which shares clinical and biological characteristics, might also share germline genetic risk variants. We investigated germline variants in a large cohort (n=365) of pediatric AML patients with whole-genome sequencing (WGS), 29 with matched marrow-derived stromal cells, and 336 with matched remission marrow samples. Variants were deemed "likely germline" based on variant allele frequency (VAF) across available samples. Following American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) guidelines, we annotated pathogenic/likely pathogenic (P/LP) variants in 555 genes linked to leukemia risk. P/LP variants were identified in 5.5% (95% CI: (3.3%,7.9%)) of patients in genes linked to familial myeloid malignancy and an additional 3.3% (95% CI: (1.6%,5.2%)) of patients in genes conferring risk to lymphoid malignancy or solid tumors. The large cohort enabled burden testing, which we employed by comparing loss-of-function variants between patients and 2504 control subjects from the 1000 Genomes Project. There was a 6.9-fold (95% CI: (3.1,14.9)) increase in loss-of-function variants in genes implicated in myeloid malignancy risk, a 2.4-fold (95% CI: (1.7,3.2)) increase in candidate risk genes, and a 1.6-fold (95% CI: (1.1,2.3)) increase in randomly-selected genes. We then assembled cohorts totaling 4,622 pediatric and adult patients with acute leukemia or MDS from 10 published studies, and compared P/LP variant burdens across age and diagnosis. The prevalence of germline variants in myeloid malignancies across age groups exceeds 5% consistently and with high confidence. Because the National Comprehensive Cancer Network recommends that all patients receive screening if their pre-test germline variant probability exceeds 5%, our results support germline genetic variant testing as an integral component of diagnostic work-up for myeloid malignancies, including donor selection for stem cell transplantation.
