Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children.

Published

Journal Article

High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD-ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer-relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥ 20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11-encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P = 4.4 × 10-3 ), an observation that was replicated in ALL patients from the TARGET project (P = .034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS-independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD-ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene.

Full Text

Duke Authors

Cited Authors

  • de Smith, AJ; Lavoie, G; Walsh, KM; Aujla, S; Evans, E; Hansen, HM; Smirnov, I; Kang, AY; Zenker, M; Ceremsak, JJ; Stieglitz, E; Muskens, IS; Roberts, W; McKean-Cowdin, R; Metayer, C; Roux, PP; Wiemels, JL

Published Date

  • October 2019

Published In

Volume / Issue

  • 58 / 10

Start / End Page

  • 723 - 730

PubMed ID

  • 31102422

Pubmed Central ID

  • 31102422

Electronic International Standard Serial Number (EISSN)

  • 1098-2264

Digital Object Identifier (DOI)

  • 10.1002/gcc.22765

Language

  • eng

Conference Location

  • United States