ALL-351: NRAS, KRAS, JAK2, CRLF2, TP53 Mutations in Adult ALL patients

Abstract

Context Testing for NRAS, KRAS, JAK2, CRLF2 and TP53 mutations in adult ALL patients and studying of molecular pathways are critical for understanding the biology of ALL. Objective Assessment of mutations in NRAS, KRAS, JAK2, CRLF2, TP53 genes and analysis of signaling pathways in de novo adult ALL patients. Design NRAS, KRAS, JAK2, CRLF2, TP53 mutations were studied B-ALL (Ph+/Ph−). TP53 gene mutations were investigated in B-ALL (Ph+/Ph−) and T-ALL patients.TP53 gene was also evaluated in non-tumor cells of 5 patients to exclude germline mutations. Gene expression profiling was performed for 5 B-ALL patients. Setting Sanger sequencing of hot-spot regions NRAS, KRAS, JAK2, CRLF2 and TP53 (exons 2-10) was conducted. PanCancer Pathways Panel by NanoString was used for gene expression analysis. KEGG pathway analysis for overexpressed genes (of the 13 canonical pathways) was carried out using the DAVID tool. Patients or other participants The study included 95 B-ALL patients, m:f (39:45), median age 31 years; 64 T-ALL, m:f (44:20), median age 27 years, 27 Ph+ ALL, m:f (10:17), median age 33 years. 109 patients treated by protocol ALL-2016 ( NCT03462095 ), 50 patients – by ALL-2009 ( NCT01193933 ), 23 – by ALL-2012 (for Ph«+»ALL) and 4 – by other protocols. Median follow-up 20.8 months. Results NRAS (9.7%), KRAS (12.9%), JAK2 (3.16%) mutations was detected only in B-ALL patients. CRLF2 mutations mutation was not detected. NRAS, KRAS, JAK2 mutations didn't impact disease outcome in B-ALL patients treated by ALL-2009, ALL-2016 protocols. TP53 mutations more often were detected in B-ALL patients (11.2%) compared with T (3.1%) and Ph+ (7.4%). They were associated with poorer OS (TP53-WT – 66.9% vs 48% TP53 mut, p=0.094) and a lower incidence of CR (TP53-WT – 90.6% vs 70.4% TP53 mut, p = 0.033). In 4 out of 5 patients, TP53 mutations were detected in non-tumor cells what considers leukemia as a manifestation of Li-Fraumeni syndrome. The most significant pathways affected were pathways in cancer (p = 6.7E-33) and cell cycle (p = 3.3E-31). Conclusions TP53 mutations are associated with unfavorable prognosis. Most TP53 mutations are of hereditary origin. NRAS, KRAS, JAK2 mutations did not affect the disease outcome. Pathway analysis provides a useful tool for understanding the ALL biology, and we plan to continue it and recruit more patients. The reported study was funded by RFBR, project number 19-31-27001.