The acquisition of molecular drivers in pediatric therapy-related myeloid neoplasms

Jason R Schwartz,Xiaolong Chen,Samuel W Brady,Scott Newman,Yanling Liu,Michael F Walsh,Michael P Walsh,Gang Wu,Jamie L Maciaszek,Huiyun Wu,Jeffrey E Rubnitz,Xiaotu Ma,Lindsey Montefiori ,Kim E Nichols,Cristyn Branstetter,Jinghui Zhang,Guangchun Song,Tanja A Grüber ,Jing Ma,Ryan Hiltenbrand,Stanley Pounds,Charles G Mullighan,Priyadarshini Kumar,Jennifer L Kamens ,J Robert Michael,John Easton,Tamara Westover,Jeffery M Klco

doi:10.1038/s41467-021-21255-8

Abstract

Pediatric therapy-related myeloid neoplasms (tMN) occur in children after exposure to cytotoxic therapy and have a dismal prognosis. The somatic and germline genomic alterations that drive these myeloid neoplasms in children and how they arise have yet to be comprehensively described. We use whole exome, whole genome, and/or RNA sequencing to characterize the genomic profile of 84 pediatric tMN cases (tMDS: n = 28, tAML: n = 56). Our data show that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements are frequent somatic drivers, and we identify cases with aberrant MECOM expression secondary to enhancer hijacking. Unlike adults with tMN, we find no evidence of pre-existing minor tMN clones (including those with TP53 mutations), but rather the majority of cases are unrelated clones arising as a consequence of cytotoxic therapy. These studies also uncover rare cases of lineage switch disease rather than true secondary neoplasms.

Highlights

Pediatric therapy-related myeloid neoplasms occur in children after exposure to cytotoxic therapy and have a dismal prognosis
In the fourth case (SJ016473), the hypermutation status appears to be driven by variants with variant allele frequency (VAF) < 0.2 (Supplementary Fig. 2b), and the corresponding driver alteration could have escaped detection due to limited depth
Here we show the results of our comprehensive sequencing of pediatric therapy-related myeloid neoplasms (tMN) which reveals that KMT2Ar are the most common driver alterations in our pediatric tMN cohort along with Ras/MAPK pathway mutations

Summary

Introduction

Pediatric therapy-related myeloid neoplasms (tMN) occur in children after exposure to cytotoxic therapy and have a dismal prognosis. Unlike adults with tMN, we find no evidence of pre-existing minor tMN clones (including those with TP53 mutations), but rather the majority of cases are unrelated clones arising as a consequence of cytotoxic therapy. These studies uncover rare cases of lineage switch disease rather than true secondary neoplasms. Using a comprehensive sequencing approach, we show that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements are frequent somatic drivers in pediatric tMN, and we find that in some cases aberrant MECOM expression is secondary to enhancer hijacking. Using samples from serial timepoints, we find no evidence of pre-existing minor tMN clones (including those with TP53 mutations) like in adults with tMN5–7, but rather the majority of cases are unrelated clones arising as a consequence of cytotoxic therapy

Methods

Results

Conclusion