GENETIC LANDSCAPE OF MYELOID NEOPLASMS IN PATIENTS WITH FANCONI ANEMIA

Introduction

Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized with chromosomal instability and a high propensity to myeloid malignancy. Although causative genes have been identified in most patients, the genetic background of the leukemic transformation in FA has not been fully understood.

Methods

We studied 2 acute myeloid leukemia (AML) and 7 myelodysplastic syndromes (MDS) developed in patients with FA using whole-genome sequencing and analyzed somatic mutations, structural variants and copy number alterations.

Results

The number of somatic mutations and copy number alterations (CNAs) in AML were 1,071 mutations and 4 CNAs per patient on average, which tended to be higher than those in MDS (265 mutations and 2.3 CNAs per patient). For mutational signatures, three known signatures were identified, which included SBS1 and SBS5 caused by endogenous mutational processes, and SBS3 related to defective homologous recombination. Mutations and structural variants affected known driver genes in myeloid malignancies, such as RUNX1 (n = 3), ASXL1 (n = 1), CBL (n = 1), NRAS (n = 1) and KDM6A (n = 1). Recurrent copy number alterations were more frequently detected, including +3q (n = 6), +1q (n = 4) and -7q (n = 2). The majority of these CNAs were clonal and all but one patient harbored either of +3q or +1q, indicating the early acquisition of copy number changes and their driver role in leukemic transformation.

Conclusions

Myeloid neoplasms related with FA were characterized by a unique pattern of CNAs and common driver mutations in myeloid malignancies.