RAS pathway mutations as a predictive biomarker for treatment adaptation in pediatric B-cell precursor acute lymphoblastic leukemia

• Published in: Leukemia Vol. 32; no. 4; pp. 931 - 940
• Main Authors: Jerchel, I S, Hoogkamer, A Q, Ariës, I M, Steeghs, E M P, Boer, J M, Besselink, N J M, Boeree, A, van de Ven, C, de Groot-Kruseman, H A, de Haas, V, Horstmann, M A, Escherich, G, Zwaan, C M, Cuppen, E, Koudijs, M J, Pieters, R, den Boer, M L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2018; Nature Publishing Group
• Subjects: 631/67/1990/283/2125; 631/67/69; Acute lymphoblastic leukemia; Adolescent; Animals; B-Lymphocytes - metabolism; Biological markers; Biomarkers; Biomarkers, Tumor - genetics; Cancer Research; Care and treatment; Cell Line, Tumor; Chemoresistance; Chemotherapy; Child; Child, Preschool; Childhood leukemia; Critical Care Medicine; Diagnosis; Female; Gene mutation; Gene sequencing; Genetic aspects; Hematology; Humans; Infant; Infant, Newborn; Inhibitors; Intensive; Internal Medicine; Leukemia; Lymphatic leukemia; Lymphocytes B; Male; Medicine; Medicine & Public Health; MEK inhibitors; Mice; Mice, Inbred NOD; Mutation; Mutation - genetics; Mutation Rate; Oncogene Proteins, Fusion - genetics; Oncology; Original; original-article; Patients; Pediatrics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursors; Prednisolone; Prognosis; ras Proteins - genetics; Runx1 protein; Signal Transduction - genetics; Subgroups; Vincristine
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.303

RAS pathway mutations have been linked to relapse and chemotherapy resistance in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, comprehensive data on the frequency and prognostic value of subclonal mutations in well-defined subgroups using highly sensitive and quantitative methods are lacking. Targeted deep sequencing of 13 RAS pathway genes was performed in 461 pediatric BCP-ALL cases at initial diagnosis and in 19 diagnosis-relapse pairs. Mutations were present in 44.2% of patients, with 24.1% carrying a clonal mutation. Mutation frequencies were highest in high hyperdiploid, infant t(4;11)-rearranged, BCR-ABL1 -like and B-other cases (50–70%), whereas mutations were less frequent in ETV6-RUNX1 -rearranged, and rare in TCF3-PBX1 - and BCR-ABL1 -rearranged cases (27–4%). RAS pathway-mutated cells were more resistant to prednisolone and vincristine ex vivo . Clonal, but not subclonal, mutations were linked to unfavorable outcome in standard- and high-risk-treated patients. At relapse, most RAS pathway mutations were clonal (9 of 10). RAS mutant cells were sensitive to the MEK inhibitor trametinib ex vivo , and trametinib sensitized resistant cells to prednisolone. We conclude that RAS pathway mutations are frequent, and that clonal, but not subclonal, mutations are associated with unfavorable risk parameters in newly diagnosed pediatric BCP-ALL. These mutations may designate patients eligible for MEK inhibitor treatment.