Genome-Wide Abnormality Patterns of B-Lineage Acute Lymphoblastic Leukemia in Adults in Comparison with Pediatric Cases

BACKGROUND

B-lineage acute lymphoblastic leukemia (B-ALL) represents the most common subtype in ALL. Genomic sequence information has been lacking in adult B-ALL, whose outcome remains dismal, while a comparison between genomic abnormalities in adult and pediatric groups is useful to further decipher disease mechanisms.

METHODS

We used whole exome sequencing (WES), copy number variation and molecular cytogenetics to catalog somatic mutations in 95 B-ALL patients (43 adults and 52 children).WES was conducted with appropriate depths for paired genomic DNA from bone marrow mononuclear cells at diagnosis and their matched peripheral blood samples during complete remission (CR) or saliva samples. Targeted deep sequencing (TDS) was performed in a validation cohort of 179 adult and 199 pediatric B-ALLs.

RESULTS

Eighty-four recurrent gene mutations were revealed by WES. Integrative analysis identified the involvement of 9 functional categories of genes: key fusions (KFs), epigenetic modifiers (EMs), signaling molecules (SMs), transcription factors (TFs), tumor suppressors (TSs), actin binding/cytoskeletons (ABCs), ion binding proteins (IBPs), trans-membrane proteins (TPs) and the others. Mutually cooperative or exclusive relationships were revealed among some of these categories. Genomic landscapes suggested two distinct mechanisms involved in the leukemogenesis: one is mainly driven by KFs together with mutations of TFs and TSs; the other results from the abnormalities of TFs and TSs, in cooperation with mutations of EMs, SMs, ABCs and IBPs recapitulating the role of KFs. A panel of histone/DNA methylation modifiers (HMMs) were revealed to bear potential value of relatively favorable prognosis in both adult and childhood patients.

CONCLUSIONS

We described the genome-wide abnormality patterns in adult B-ALL patients in comparison with those of pediatric cases, contributing to the understanding of leukemogenesis and the identification of potential new prognostic markers.