Somatic Mutation Screening in Adult Patients with Myeloid Malignancies Provides Insights into Likely Germline Variants

Introduction Emerging evidence has shed light on the prevalence of germline variants (GV) that increase the risk of myeloid neoplasms in adults. Despite the use of next-generation sequencing (NGS) in the diagnostic workup of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), establishing a standard-of-care approach to screening patients for GV has been difficult due to a rapidly evolving list of candidate variants and inconsistent referral patterns for confirmatory testing. Here we describe our efforts to characterize molecular features at diagnosis and in remission based on tumor-only sequencing for patients with possible germline predisposition syndromes to myeloid neoplasms. Methods We retrospectively analyzed molecular pathology records of adult patients treated at the University of Pennsylvania who were diagnosed with AML and/or MDS between 2013 to 2022, had somatic NGS performed with diagnostic bone marrow biopsy, and had identified variants in genes affiliated with known or emerging MDS/AML germline predisposition syndromes. These variants (Fig. 1A) were based on those defined in ELN 2022 as well curated from the hereditary hematologic malignancy panel at the Children's Hospital of Philadelphia . Analysis focused on pathogenic and likely pathogenic variants. Results We reviewed records from 364 patients with a diagnosis of AML (n=311), MDS or MDS/MPN overlap (n=48), or other myeloid neoplasm (n=5). Median age of diagnosis was 66 years (range 21-92 years) with 11%