Identification of potential germline variants associated with hereditary predisposition to myeloid hematologic malignancies in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) at Barretos Cancer Hospital

Keywords

germline variants - somatic sequencing - acute myeloid leukemia - hereditary predisposition - myelodysplastic syndromes

Background: Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) associated with hereditary predisposition syndromes account for 5-20% of global adult cases. Germline testing is recommended for individuals diagnosed at age 50 or younger, as well as those with a family history or dysmorphic abnormalities. Germline variants in the TP53, CEBPA, GATA2, RUNX1, ETV6, and DDX41 genes are most frequently implicated. The first four genes together explain up to 30% of germline variants in AML and MDS, while DDX41 variants are found in 2.6% of adult AML cases. Ideally, DNA testing would utilize non-blood contaminated tissue samples, such as fibroblasts from skin biopsies, though these methods can be logistically challenging. Somatic testing, being more accessible, can potentially flag germline variants.

Aim: Identify potential germline variants in adult AML or MDS patients treated at a cancer center in Brazil.

Methods: From July 2022 to July 2024, patients with AML, MDS, mixed phenotype leukemia with a myeloid component, or myeloid sarcoma underwent routine somatic next-generation sequencing using a myeloid gene panel. Somatic variants were retrospectively reviewed. Variants with a variant allele frequency of 30% or higher in the genes CEBPA, DDX41, RUNX1, ANKRD26, ETV6, and GATA2 were considered potentially germline, as well as the c.1010G>A variant in TP53. For patients with additional available tumors, the c.1010G>A variant in TP53 was also assessed in non-hematological tumors. Clinical and pathological data were collected.

Results: A total of 45 adult patients were included, with ages ranging from 22 to 83 years (median age: 52 years). Diagnoses included MDS in 26%, myeloid sarcoma in 2%, mixed phenotype leukemia in 4%, and AML in 68%. Eight patients (18%) had potentially germline variants. Two patients had the TP53 variant c.1010G>A: a 22-year-old female with MDS and an 83-year-old male with MDS whose variant was previously identified in a lung cancer sample. Suspected germline CEBPA variants were found in four patients (ages 32 to 70), including one with MDS and three with AML. Additionally, a suspected germline DDX41 variant was identified in a 64-year-old male with AML, and a suspected RUNX1 germline variant was found in a 75-year-old male with AML secondary to MDS. This study underscores the potential of somatic NGS in identifying germline variants in AML and MDS patients. Further research is required to validate this approach.

Corresponding author: Roberta Martins Queiroz Barbosa (e-mail: [e-mail]).