Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children.
Adam J de SmithGeneviève LavoieKyle M WalshSumeet AujlaErica EvansHelen M HansenIvan SmirnovAlice Y KangMartin ZenkerJohn J CeremsakElliot StieglitzIvo S MuskensWilliam RobertsRoberta McKean-CowdinCatherine MetayerPhilippe P RouxJoseph L WiemelsPublished in: Genes, chromosomes & cancer (2019)
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.
Keyphrases
- end stage renal disease
- acute lymphoblastic leukemia
- newly diagnosed
- ejection fraction
- chronic kidney disease
- signaling pathway
- pi k akt
- prognostic factors
- cell proliferation
- squamous cell carcinoma
- patient reported outcomes
- acute myeloid leukemia
- bone marrow
- dna methylation
- dna repair
- risk assessment
- immune response
- risk factors
- dna damage
- transcription factor
- inflammatory response
- binding protein
- tyrosine kinase
- hiv infected
- hypertrophic cardiomyopathy