Pathogenic germline variants identified in adults with acute myeloid leukemia
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Approximately 14% of adults with acute myeloid leukemia harbored germline pathogenic or likely pathogenic variants in a hematologic malignancy predisposition gene, according to study results published in Blood.
Researchers additionally identified variants in novel candidate genes for further investigation for their role in leukemia susceptibility.
Rationale and methods
“Inherited predisposition to myeloid malignancies is more common than previously appreciated,” Fei Yang, MD, assistant professor of pathology and laboratory medicine at Oregon Health & Science University School of Medicine, and colleagues wrote.
Researchers examined whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adults included in the Beat AML 1.0 consortium. They used the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation and curated 1,547 unique variants from 228 genes.
Key findings
Overall, researchers identified pathogenic or likely pathogenic variants in 53 patients (13.6%) in 34 genes. Among them, 6.39% of patients harbored pathogenic or likely pathogenic variants considered clinically actionable and 41.5% of patients had pathogenic or likely pathogenic variants linked to DNA damage response.
The most common mutated genes included CHEK2 in eight patients and DDX41 in seven patients. Researchers additionally found pathogenic germline variants in new candidate genes, including DNAH5, DNAH9, DNMT3A and SUZ12.
They did not identify a strong association between the germline mutational rate and age at disease onset.
Of the 49 patients who reported having at least one family member with a hematologic malignancy, six harbored pathogenic or likely pathogenic variants and 43 had at least one variant of uncertain significance.
“Using CHEK2 as an example, we also show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies,” Yang and colleagues wrote. “Further, we evaluated an in silico approach that applies ACMG curation in an automated manner using the tool for assessment and prioritization in exome studies, which can minimize manual curation time for variants.”
Implications
The findings suggest a need to comprehensively understand the predisposition potential of many germline variants, thus enabling closer monitoring for disease management and treatment interventions for affected patients and families, according to Yang and colleagues.
“This study made clear that routine germline genetic profiling of patients with leukemia could overcome some of the deficits of incomplete family history,” Anna L. Brown, MD, researcher at University of South Australia and University of Adelaide, wrote in an accompanying editorial. “As the field continues to move toward precision medicine in the diverse fields of diagnosis, prognosis, treatment and monitoring for AML, this study adds to the accumulating evidence that including prospective assessment of the germline genetics in patients is an important consideration.”
References:
Brown AL, et al. Blood. 2022;doi:10.1182/blood.2021013771.
Yang F, et al. Blood. 2022;doi:10.1182/blood.2021011354.
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Yang F, et al. Blood. 2022;doi:10.1182/blood.2021011354.
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