Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children

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.

Pediatric acute lymphoblastic leukemia

“…[26][27][28] Finally, germline genomic analysis has identified additional susceptibility variants in sporadic hyperdiploid B-ALL (NBN, ETV6, FLT3, SH2B3, and CREBBP), Down syndrome-associated B-ALL (IKZF1, NBN, RTEL1), and T-ALL (Fanconi-BRCA pathway mutations). [29][30][31]…”

B-ALL Complexity: Is Targeted Therapy Still A Valuable Approach for Pediatric Patients?

“…Hyperdiploidy is observed in approximately 25% of childhood B-ALL and is associated with a favorable outcome. Ras pathway alterations and epigenetic modifications are frequent events in high-hyperdiploid ALL [8], as well as CEBPE, ARID5B, PIP4K2A, and BMI1 genetic mutations [19][20][21], that are present in 50% of hyperdiploid patients [8]. Moreover, specific mutations of KRAS that lead to downstream phosphorylation of extracellular signal-regulated kinase (ERK) were found in hyperdiploid patients [8], suggesting that Ras/MEK/ERK network inhibition could be a good therapeutic target in high-hyperdiploid childhood B-ALL.…”

“…Finally, recurrent germline GRB2-associated-binding protein (GAB) 2 mutations were identified in high-hyperdiploid patients and could be evaluated as a putative novel predisposition factor to B-ALL development [21]. Interestingly, GAB2 is an upstream activator of Ras/MEK/ERK and PI3K/Akt/mTOR signaling pathways, though to bind SHP2 and the p85 regulatory subunit of PI3K [22].…”

Increased Risk of Chronic Myeloid Leukemia Following Gastric Conditions IndicatingHelicobacter pyloriInfection: A Case–Control Study

“…It has been demonstrated both in vitro, and recently in murine-knockout models, that BCR-ABL1 leukemogenesis is dependent on GAB2 (36,37). Germline GAB2 mutations have further been linked to childhood leukemia development (38). Meanwhile, Helicobacter pylori uses its virulence factor cytotoxin-associated gene A (CagA) to mimic GAB2 function in the cells it infects (39,40).…”