Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children

Area of Science:

• Genetics
• Oncology
• Pediatric Hematology

Background:

• High hyperdiploidy (HD) is the most common subtype of childhood acute lymphoblastic leukemia (ALL).
• A higher incidence of HD-ALL is observed in patients with congenital cancer syndromes.
• The role of germline predisposition in HD-ALL etiology requires further investigation.

Purpose of the Study:

• To assess the frequency of predisposing germline mutations in childhood HD-ALL patients.
• To identify novel genes associated with HD-ALL predisposition.
• To investigate the functional impact of identified mutations on cellular pathways.

Main Methods:

• Targeted sequencing of cancer-relevant genes in 57 HD-ALL patients.
• Analysis of mutation frequency in the Exome Aggregation Consortium (ExAC) and TARGET project datasets.
• Functional characterization of GAB2 mutations in HEK293 cells.

Main Results:

• Confirmed germline mutations in NBN, ETV6, and FLT3 in 5.3% of patients.
• Identified putative predisposing mutations in SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9 in 10.5% of patients.
• Found significantly higher frequency of rare, damaging GAB2 mutations in HD-ALL patients (2.6%) compared to controls (0.28%).
• Demonstrated that a GAB2 frameshift mutation (P621fs) altered SHP2 binding and downstream signaling, potentially promoting leukemogenesis via RAS-independent effects.

Conclusions:

• Rare, high-penetrance germline mutations significantly contribute to HD-ALL etiology.
• GAB2 is identified as a putative novel gene predisposing to childhood ALL.
• These findings highlight the importance of genetic screening in pediatric leukemia.