10. Comprehensive genomic characterization of pediatric B-ALL

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Genomic alterations in B-ALL are essential for disease diagnosis, prognosis, and treatment. We performed integrated genomic analysis on 136 pediatric B-ALL patients using the CHOP Comprehensive Hematological Cancer NGS Panel along with conventional cytogenetic studies. The panel interrogates 118 cancer genes for sequence and copy number variants (CNV) and 110 genes for known and novel fusions. Clinically significant genomic changes were identified in 89.7% of patients. Fusion genes or gene rearrangements were detected in 52.9% of the patients, 20% of them were never reported before. ETV6-RUNX1 (27.8%) was the most common fusion, followed by Ph+/Ph-like fusions (26.4%), KMT2A-rearrangements (15.3%), TCF3-PBX1 (8.3%), and TCF3-HLF (2.8%). Many fusions were cryptic and were missed by conventional cytogenetics or even by FISH. One hundred thirty-three mutations were observed in these patients with most of the mutations in genes involving RAS-pathway (31.9%), followed by PTPN11 (8.2%), PAX5 (7.4%), CREBBP (6.7%), TP53 (5.2%), and JAK2 (4.4%). RAS mutations are common in both primary and relapsed cases, while TP53 mutations were only observed in relapsed cases. CNVs were detected in 86.2% of the patients including hyperdiploidy (18.5%), iAMP21 (3.8%), hypodipolidy/near-haploidy (3.1%), and cryptic deletions involving IKZF1, CDKN2A/B, or ETV6 (73.1%). Three patients with normal cytogenetics were found to carry Ph-like ALL-associated alterations by NGS assay. These genomic alterations have significantly impacted patient care, especially in cases of Ph-like ALL. Our comprehensive NGS testing has provided critical evidence for both precision diagnoses and therapeutic decisions.