UV-induced mutations accumulate during early clonal expansion in aneuploid subtypes of pediatric B-cell precursor acute lymphoblastic leukemia

Abstract

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.