Mapping of the mutational landscape of juvenile myelomonocytic leukemia patients by whole exome sequencing

Abstract

Background and Aim - Juvenile Myelomonocytic Leukemia(JMML) is a rare myelodysplastic/myeloproliferative neoplasm. The RAS-pathway related genes are most commonly mutated in JMML. Other secondary mutations/alternative pathways are also thought to be involved in the pathogenesis. This study was prospectively done to map the mutational landscape of newly diagnosed and treatment naive JMML patients. Method - The mutational profile of 38 JMML patients was analysed by whole-exome-sequencing. The DNA from the blood/bone-marrow sample (for somatic mutations) and the buccal swab (for germline mutations) was isolated and sequenced on the Illumina platform at 250x and 100x respectively. Results - Out of the 38 patients, somatic mutations were found in 34 (89%). These were as follows: PTPN11(n=12) was the most altered gene, followed by NRAS(n=9), KRAS(n=6), NF1(n=4) and CBL(n=3). The germline mutations were detected in 11 patients out of 36 patients (31%) ((NF1=3, KRAS=1, NRAS=2, PTPN11=1, CBL=3, SETBP1=1). Thirteen patients had more than one co-existing somatic mutation in genes known to play a role in hematopoiesis or known to be associated with malignancies. The patients with PTPN11 somatic mutations most commonly had another mutation: PTPN11-SETBP1 (n=4); PTPN11-TP53 (n=1); PTPN11-JAK3 (n=1); PTPN11-ASXL1-EZH2(n=1), PTPN11-SETBP1-ETV-6 (n=1). Other co-existing mutation combinations were NF1-NOTCH1(n=1), NF1-ZRSR2 (n=1), NRAS-CBL (n=1), NRAS-FLT3-ITD-EP300 (n=1) and KRAS-SUSD2 (n=1).