Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia

ABSTRACT: Despite high survival rates in pediatric acute lymphoblastic leukemia (ALL), relapse remains a leading cause of cancer-related death in children. Many patients suffer from adverse drug effects during treatment and other complications later in life, and would benefit from improved relapse prediction at diagnosis. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients with pediatric ALL. Somatic mutations were called using individually matched remission samples as controls, and allelic expression of the mutations in the ALL cells was assessed using RNA-sequencing. These analyses identified 29 previously known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, and 20 mutated driver genes occurred in individual samples. We detected putative non-coding mutations in regulatory regions of seven additional genes that have not been described previously in ALL. We observed an increased burden of somatic mutations at relapse. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression. In an “ancestral clone trajectory”, the major cell clone at relapse originated from a founder clone that was not detectable at diagnosis. In a “rising diagnostic clone trajectory”, a minor cell clone at diagnosis expanded to form the major cell clone at relapse. In a “persistent diagnostic clone trajectory”, the major cell clone at diagnosis persisted during treatment until relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163634 | GEO | 2021/08/11

REPOSITORIES: GEO