Mutation, methylation, and gene expression profiles in dup(1q)-positive pediatric B-cell precursor acute lymphoblastic leukemia

Rebeqa Gunnarsson,Anders Castor,Andrea Biloglav,Kajsa Paulsson,Thoas Fioretos,Mikael Behrendtz,Kristina B Lundin-Ström,Anders Lundmark,Sebastian Dilorenzo,Bertil Johansson,Anders Isaksson,Henrik Lilljebjörn,Per Wahlberg,Marianne Rissler,Linda Olsson

doi:10.1038/s41375-018-0092-2

Abstract

High-throughput sequencing was applied to investigate the mutation/methylation patterns on 1q and gene expression profiles in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) with/without (w/wo) dup(1q). Sequencing of the breakpoint regions and all exons on 1q in seven dup(1q)-positive cases revealed non-synonymous somatic single nucleotide variants (SNVs) in BLZF1, FMN2, KCNT2, LCE1C, NES, and PARP1. Deep sequencing of these in a validation cohort w (n = 17)/wo (n = 94) dup(1q) revealed similar SNV frequencies in the two groups (47% vs. 35%; P = 0.42). Only 0.6% of the 36,259 CpGs on 1q were differentially methylated between cases w (n = 14)/wo (n = 13) dup(1q). RNA sequencing of high hyperdiploid (HeH) and t(1;19)(q23;p13)-positive cases w (n = 14)/wo (n = 52) dup(1q) identified 252 and 424 differentially expressed genes, respectively; only seven overlapped. Of the overexpressed genes in the HeH and t(1;19) groups, 23 and 31%, respectively, mapped to 1q; 60-80% of these encode nucleic acid/protein binding factors or proteins with catalytic activity. We conclude that the pathogenetically important consequence of dup(1q) in BCP ALL is a gene-dosage effect, with the deregulated genes differing between genetic subtypes, but involving similar molecular functions, biological processes, and protein classes.

Highlights

IntroductionThe high frequency of 1q gain strongly suggests that it plays an important pathogenetic role in tumorigenesis in general, perhaps by conferring a proliferative advantage, as indicated by a study of growth patterns of dup(1q)-positive and -negative chronic lymphocytic leukemia clones in nude mice[16]
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Gain of 1q through a duplication or an unbalanced translocation (both are here denoted “dup(1q)”) is found by chromosome banding analysis in ~5% of pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) cases [1, 2], but the frequency increases quite substantially if single nucleotide polymorphism array (SNP-A) analyses are performed[3, 4]
Such a proliferative advantage is a possible explanation for the worse prognosis of Wilms' tumors and multiple myelomas with 1q gains[8, 17, 18]

Summary

Introduction

The high frequency of 1q gain strongly suggests that it plays an important pathogenetic role in tumorigenesis in general, perhaps by conferring a proliferative advantage, as indicated by a study of growth patterns of dup(1q)-positive and -negative chronic lymphocytic leukemia clones in nude mice[16]. Such a proliferative advantage is a possible explanation for the worse prognosis of Wilms' tumors and multiple myelomas with 1q gains[8, 17, 18]

Methods

Results

Conclusion