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Genes Chromosomes Cancer. 2019 Oct;58(10):723-730. doi: 10.1002/gcc.22765. Epub 2019 May 27.

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

Author information

1
Center for Genetic Epidemiology, Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, California.
2
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California.
3
Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec, Canada.
4
Department of Neurosurgery, Duke University, Durham, North Carolina.
5
Children's Health and Discovery Institute, Duke University, Durham, North Carolina.
6
Department of Neurological Surgery, University of California San Francisco, San Francisco, California.
7
School of Public Health, University of California, Berkeley, Berkeley, California.
8
University Hospital Magdeburg, Institute of Human Genetics, Magdeburg, Germany.
9
Department of Pediatrics, University of California San Francisco, San Francisco, California.
10
Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California San Diego, San Diego, California.
11
Rady Children's Hospital San Diego, San Diego, California.
12
Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, California.
13
Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.

Abstract

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.

KEYWORDS:

ALL; FLT3; GAB2; acute lymphoblastic leukemia; germline mutations; high hyperdiploidy

PMID:
31102422
PMCID:
PMC6684857
[Available on 2020-10-01]
DOI:
10.1002/gcc.22765
[Indexed for MEDLINE]

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