TY - JOUR T1 - Recapitulation of human germline coding variation in an ultra-mutated infant leukemia JF - bioRxiv DO - 10.1101/248690 SP - 248690 AU - Alexander M Gout AU - Rishi S Kotecha AU - Parwinder Kaur AU - Ana Abad AU - Bree Foley AU - Kim W Carter AU - Catherine H Cole AU - Charles S Bond AU - Ursula R Kees AU - Jason Waithman AU - Mark N Cruickshank Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/02/11/248690.abstract N2 - 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. Infant leukemias typically carry few somatic lesions, however we identified a case with over 100 somatic point mutations per megabase. The patient presented at 82 days of age, among 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. The patient’s 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. These data suggest similar molecular processes shaping population-scale human genome variation also underlies the rapid evolution of an infant ultra-mutated leukemia. ER -