Analysis of RAS gene mutations in adverse events during first induction chemotherapy in childhood acute lymphoblastic leukemia.

ABSTRACT

Background: The rat sarcoma virus (RAS) pathway controls cell proliferation, differentiation, and apoptosis, which have been implicated in the pathogenesis of various hematological malignancies. Prognostic importance of RAS gene mutation, relatively frequently in childhood acute lymphoblastic leukemia (ALL), has been debated. We aimed to study RAS gene mutation profile and prognosis in 93 children with newly diagnosed ALL. Methods: We retrospectively analyzed clinical characteristics, treatment, and outcomes of 93 ALL children during first induction chemotherapy in Anhui Provincial Children's Hospital under the Chinese Children's Leukemia Group-acute lymphoblastic leukemia 2018 (CCLG-ALL-2018). All genomic DNA samples were obtained from bone marrow mononuclear cells upon new diagnosis. RAS gene mutation was performed by polymerase chain reaction (PCR). All children were stratified into standard-, medium-, and high-risk groups, and then treated with risk-based regimens according to CCLG-ALL-2018 protocol. Results: Of 93 ALL children, 26 (27.9%) were positive for RAS mutation, among whom 19 had N-RAS mutation, 8 had K-RAS mutation, and 1 had a double mutation. The ETV6/RUNX1 fusion gene was the most common genetic alteration (n=16, 17.2%). The most common adverse events during first induction chemotherapy were coagulation abnormalities (n=76, 81.7%), followed by fever (n=71, 76.3%) and alanine transaminase (ALT) elevation (n=34, 36.6%). Compared with negative RAS mutation group, the risk of hyperbilirubinemia was significantly reduced in RAS mutation group (P=0.018), and there was no significant difference in any other adverse events. The average duration of agranulocytosis during first induction chemotherapy was 6 days, and the average duration of agranulocytosis in RAS mutation group and RAS negative group was 6 and 5 days, with no significant difference. Multivariate linear regression analysis showed that in RAS mutation group, when body mass index (BMI) exceeded the median value of this ALL population (BMI >15.38), the risk of agranulocytosis was significantly increased (P=0.003). Conclusions: Newly diagnosed ALL in children with RAS mutation is less likely to be associated with fusion gene expression. RAS mutation increases the risk of agranulocytosis duration during first induction chemotherapy, lowers BMI and reduces the risk of hyperbilirubinemia in ALL children.