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

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: BCR-ABL1-like; RAS mutation; acute lymphoblastic leukemia.

FIGURE 1

Genetic and clinical characteristics of patients. Data are shown for 25 patients with BCR‐ABL1‐like ALL, 4 with ETV6‐RUNX1‐like ALL and 13 other B‐ALL. ABL1r, ABL1 rearrangement; FLT3r, FLT3 rearrangement; NCI, National Cancer Institute/Rome

FIGURE 2

Comparison of 5‐y EFS of BCR‐ABL1‐like ALL subgroup and non‐BCR‐ABL1‐like low and standard risk subgroup (A), and non‐BCR‐ABL1‐like high risk subgroup (B)