Recapitulation of human germline coding variation in an ultra-mutated infant leukemia

Background: Mixed lineage leukemia/Histone-lysine N-methyltransferase 2A gene rearrangements occur in 80% of infant acute lymphoblastic leukemia, but the role of cooperating events is unknown. While infant leukemias typically carry few somatic lesions, we identified a case with over 100 somatic point mutations per megabase and here report unique genomic-features of this case. Results: The patient presented at 82 days of age, one of the earliest manifestations of cancer hypermutation recorded. The transcriptional profile showed global similarities to canonical cases. Coding lesions were predominantly clonal and almost entirely targeting alleles reported in human genetic variation databases with a notable exception in the mismatch repair gene, MSH2 . There were no rare germline alleles or somatic mutations affecting proof-reading polymerase genes POLE or POLD1 , however there was a predicted damaging mutation in the error prone replicative polymerase, POLK . The patient9s diagnostic leukemia transcriptome was depleted of rare and low-frequency germline alleles due to loss-of-heterozygosity, while somatic point mutations targeted low-frequency and common human alleles in proportions that offset this discrepancy. Somatic signatures of ultra-mutations were highly correlated with germline single nucleotide polymorphic sites indicating a common role for 5-methylcytosine deamination, DNA mismatch repair and DNA adducts. Conclusions: These data suggest similar molecular processes shaping population-scale human genome variation also underlies the rapid evolution of an infant ultra-mutated leukemia.