Rare variants in Fanconi anemia genes are enriched in acute myeloid leukemia

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy caused by somatically acquired changes affecting a well-defined set of genes1. While rare high-risk variants affecting specific transcription factors account for a proportion of myelodysplastic syndrome (MDS) and AML associated with a family history, the contribution of other germline variants conferring low-intermediate risk has not yet been determined, partly because these are more difficult to identify from pedigree analysis. Here we use an Australian AML patient cohort to analyze rare, deleterious variants affecting genes involved in the rare recessive bone marrow failure syndrome Fanconi Anemia (FA). FA is caused by bi-allelic germline mutations in any of the 22 FANC genes (except for FANCB and FANCR which are X-linked and autosomal dominant), and is associated with profoundly increased risk of AML. The proteins encoded by the FANC genes participate in the removal of interstrand crosslinks (ICL) and the protection and resolution of stalled replication forks, an essential step for faithful DNA replication. Deficiency for these genes, combined with other mutations, results in pre-leukemia or leukemia in mouse models.