Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster III
Hematology Disease Topics & Pathways:
AML, Diseases, Pediatric, Technology and Procedures, Study Population, Myeloid Malignancies, Clinically relevant, RNA sequencing
A total of 1831 non-synonymous mutations that were predicted somatic and/or associated to pediatric cancer were identified in 972 genes, including 1597 single nucleotide variants (SNV), 210 insertion/deletion (indels) and 24 internal tandem duplications (ITD), with a median of 6 mutations per case (ranging 0 to 15). Among these abnormalities, 7 aberrations occurred in more than 5% of cases in current cohort, including mutations in KIT (n=54, 18.5%), FLT3 (n=46, 15.8%), NRAS (n=28, 9.6%), CEBPA (n=23, 7.9%), ASXL2 (n=20, 6.8%), KRAS (n=16, 5.5%) and CSF3R (n=15, 5.1%). 444 potential driver variations were identified affecting 66 genes by a combined strategy of mutation pathogenicity and hotspot analysis. Each patient carried a median of one driver mutations per case (ranging 0 to 7). In addition, RNA-seq identified 227 fusions involving 99 genes in 203 out of 292 patients (69.5%), and CBL exon8/9 deletion in 12 patients (4.1%). The most prevalent fusions detected in current cohort included RUNX1-RUNX1T1 (n=82, 28.1%), KMT2A rearrangements (n=45, 15.4%) and NUP98 rearrangements (n=17, 5.8%). Furthermore, novel gene rearrangements were identified in current study, including PTPRA-FUS, ZEB2-ATIC, MSI2-UBE3C (n=1 each).
Distinct genomic aberration profile was revealed while comparing our results to the mutation profile characterized in Children's Oncology Group (COG)-National Cancer Institute (NCI) TARGET AML initiative representing the Western pediatric AML cohort. A total of 16 recurrently mutated genes were identified with significantly (two-sided fisher exact test) different mutation frequency. Among these, 7 genes mutated more frequently in Chinese patients, including KIT (18.5% vs 12.8% in Chinese and Western cohort, respectively. p=0.027), ASXL2 (6.8% vs 3.6%, p=0.043), CSF3R (5.1% vs 2.4%, p=0.044), JAK2 (3.4% vs 0.0%, p<0.001), DNM2 (2.7% vs 0.0%, p<0.001), KDM6A (2.1% vs 0.0%, p<0.001) and KMT2C (1.7% vs 0.0%, p=0.003). On the other hand, mutations in FLT3 (15.8% vs 33.0%, p<0.001), NRAS (9.6 vs 30.9%, p<0.001), KRAS (5.5% vs 12.8%, p<0.001), WT1 (2.4% vs 13.6%, p<0.001), NPM1 (2.4% vs 10.3%, p<0.001), PTPN11 (3.8% vs 8.1%, p=0.016), TET2 (1.0% vs 5.2%, p=0.001), CBL sequence mutation (0.0% vs 3.0%, p<0.001) and IKZF1 (0.3% vs 2.7%, p=0.018) were occurred less frequently in Chinese patients. Notably, the RAS signaling pathway as a whole was significantly less frequently mutated in Chinese patients (35.6% vs 71.0%, p<0.001). Furthermore, distinct associations between mutations and FAB subtypes were also observed. For example, NF1 mutations were significantly enriched with subtype M5 in Chinese patients (p=0.003), which was previously reported as co-mutated with CBFB-MYH11 fusion with associated with subtype M4.
Survival analysis revealed key genomic aberrations associated with patient prognosis. Variants significantly (log-rank test) associated with better event free survival rate included mutations in CEBPA (p=0.023), NPM1 (p=0.026) and GATA2 (p=0.016). On the other hand, CBFA2T3-GLIS2 (p=0.028), nucleoporin gene family related fusions (including NUP98, NUP214 and NUP153, p<0.001), FUS related fusions (p=0.030), mutations in RUNX1 (p<0.001) and FLT3 (p=0.003) were associated with worse prognosis. A revised risk stratification model was proposed based on these associations observed.
Characterized a first comprehensive genomic landscape of Chinese pediatric AML, our results reveal a distinct mutation profile as compared to the Western cohort, in terms of both mutation frequency and patterns of mutation co-occurrence. These findings further reveal the complexity of pediatric AML and highlight the importance of tailored risk stratification for Chinese patients in clinical management.
Disclosures: No relevant conflicts of interest to declare.
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