Recurrent localized hypermutation (Kataegis) in pediatric cancer.

Abstract

Kataegis is a pattern of localized hypermutation commonly defined as six or more mutations with an average inter-mutational distance of less than 1000 base pairs. The current consensus is that the APOBEC family of cytidine deaminases, which includes AID (Activation-induced cytidine deaminase), is usually responsible for the formation of kataegis. Kataegis is known to occur in roughly 60.5% of adult cancers, but in pediatric cancers, the prevalence of kataegis is currently not known. Here, we used whole-genome sequencing data from 1321 pediatric cancer patients to detect and quantify kataegis in pediatric cancer in the Netherlands. We found that kataegis is recurrent within specific genomic regions by subdividing the genome into bins of equal size and quantifying the number of patients with at least one kataegis event. This pattern of localized recurrent kataegis was named “metakataegis”. In the pediatric cancer cohort, two types of metakataegis peaks were observed. Six peaks were identified with only kataegis in lymphomas. Kataegis within these peaks can be attributed to the physiological process of somatic hypermutation in B-cells and its off-target effects in tumors. Furthermore, four metakataegis peaks not specific to lymphomas were observed. Kataegis detected here is likely the cause of technical variations and not indicative of any biological mechanism. To identify the underlying biological mechanism, the mutations within the kataegis foci of each metakataegis peak were extracted. These mutations were then compared against known mutational signatures previously observed within cancer. The metakataegis peaks present exclusively in lymphoma’s matched against signatures attributed to somatic hypermutation. In contrast, the remaining non-lymphoma peaks mostly matched against the “catch-all” signatures.