High incidence of RAS pathway mutations among sentinel genetic lesions of Korean pediatric BCR‐ABL1‐like acute lymphoblastic leukemia

Abstract

Abstract Introduction Recent advances in genetic analysis have led to the discovery of novel genetic subtypes of precursor B‐cell acute lymphoblastic leukemia (B‐ALL) with prognostic relevance. In this study, we studied a cohort of pediatric B‐ALL patients to retrospectively determine the incidence of patients harboring novel genetic subtypes, as well as their outcome. Methods B‐ALL patients (N = 190) diagnosed in a single Korean hospital were included in the study. Patients' medical records were reviewed for data on established genetic abnormalities and outcome. CRLF2 expression was analyzed by quantitative RT‐PCR. Anchored multiplex PCR‐based enrichment was used to detect fusions and point mutations in 81 ALL‐related genes. Results Incidence of established recurrent genetic subtypes was as follows: high hyperdiploidy (21.6%), ETV6‐RUNX1 (21.6%), BCR‐ABL1 (7.9%), KMT2A rearrangement (7.4%) TCF3‐PBX1/TCF3‐HLF (7.4%), and hypodiploidy (1.1%). Incidence of new genetic subtypes was as follows: BCR‐ABL1‐like (13.2%), ETV6‐RUNX1‐like (2.1%), EWSR1‐ZNF384 (1.1%), and iAMP21 (1.1%). Median age at diagnosis of BCR‐ABL1‐like ALL was 6.8 years. According to type of genetic abnormality, BCR‐ABL1‐like ALL was divided into ABL class (12%), CRLF2 class (8%), JAK‐STAT class (12%), and RAS class (68%). The 5‐year event‐free survival (EFS) of BCR‐ABL1‐like patients was significantly inferior to non‐BCR‐ABL1‐like low‐ and standard‐risk patients (71.5 ± 9.1% vs 92.5 ± 3.2%, P = .001) and comparable to non‐BCR‐ABL1‐like high (75.2 ± 6.2%) and very high‐risk patients (56.8 ± 7.4%). All four ETV6‐RUNX1‐like patients survived event‐free. Conclusion Analogous to previous studies, incidence of BCR‐ABL1‐like ALL in our cohort was 13.2% with outcome comparable to high and very high‐risk patients. A significantly high number of RAS class mutations was a distinct feature of our BCR‐ABL1‐like ALL group.

Keywords

• acute lymphoblastic leukemia
• BCR-ABL1-like
• RAS mutation