Publication Date:
2020-11-05
Description:
Targeted interventions and new risk stratification approaches for the improvement of outcomes in B cell precursor acute lymphoblastic leukemia (BCP-ALL) require an understanding of high-risk driver subtypes, their clinical phenotypes and actionable targets. Currently, over 20 BCP-ALL subtypes have been identified based on genomic driver alterations and corresponding gene expression signatures, in particular in pediatric ALL. This complex molecular landscape is so far only partially defined in adult BCP-ALL patients. To characterize driver subtypes and their clinical phenotypes we performed transcriptome sequencing (Illumina) on Ph-negative adult BCP-ALL patients (n=376) treated on subsequent pediatric inspired protocols of the German Acute Lymphoblastic Leukemia Study Group (GMALL). Using random forest analyses of a well-defined patient subset with available WES/gene panel and DNA-methylation data, we established a 300-gene classifier which together with fusion calling and hotspot mutation calling reliably allocated samples to driver subtypes. Subgroup allocation was feasible for n=267 / 308 Ph-negative patients (86.7%) with Ph-like ALL (27.7%) being the most frequently observed subtype followed by DUX4 (14.6%), KMT2A (10.1%), PAX5-plus (9.7%), ZNF384 (9.0%), Near haploid - High hyperdiploid (NH-HeH, 6.0%), Low haploid - Near triploid (LH-NT, 6.0%) and TCF3-PBX1 (5.6%). With frequencies below 5% were observed: PAX5-alt, MEF2D, BCL2/MYC, ETV6-RUNX1, CEBP family member fusions and TCF3-HLF. The age distribution of these driver subtypes varied across our cohort (median age: 37 years, range: 16 - 81; left panel). Adult patients harboring ETV6-RUNX1 fusions (n=4) were 25 years or younger. NH-HeH, PAX5-plus and DUX4 ALL were also observed predominantly in younger patients (median ages: 24, 24, 30 years respectively; p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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