UV-induced mutations accumulate during early clonal expansion in aneuploid subtypes of pediatric B-cell precursor acute lymphoblastic leukemia.
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Prolonged exposure to ultraviolet (UV) light leads to DNA damage, causing mutation accumulation and cancer, particularly in the skin. Recent studies revealed that patients with aneuploid subtypes of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) commonly present with single base substitution signature 7a (SBS7a), a hallmark of UVbased DNA damage, but its origin is unclear. We screened a cohort of 191 whole genome sequenced BCP-ALL cases and confirmed the presence of SBS7a in high hyperdiploid, iAMP21 and low hypodiploid subtypes. Screening of an in-house pediatric pan-cancer cohort (n=1033) detected SBS7a, apart from BCP-ALL, only in tumors with proven cutaneous localization. Subsequent characterization of 43 BCP-ALL samples from 27 SBS7a-positive patients revealed no causative DNA repair defects. Furthermore, the mutational characteristics in SBS7a-positive BCP-ALL were very similar to those encountered in SBS7apositive adult skin cancers (n=273) and pediatric cutaneous anaplastic large cell lymphomas (n=7), suggesting a shared UV-induced etiology. Subtle differences in aneuploid patterns were observed between SBS7a-positive and SBS7a-negative high hyperdiploid and iAMP21 cases. In several cases, we detected SBS7a-positive subclones at primary diagnosis, or relapses with apparently newly acquired SBS7a-associated mutations, together suggesting prolonged UV damage during expansion. Single-cell whole genome sequencing in two other cases confirmed some level of SBS7a-induced clonal diversity, but no indications for ongoing SBS7a-associated mutagenesis during bone marrow progression. Our data suggest that SBS7a-associated mutations occur in a subset of aneuploid BCP-ALL subtypes due to UVinduced damage during early expansion in extramedullary sites before bone marrow expansion.