RAS Pathway Alterations in Pediatric AML Patients

Abstract

Listen

Translate article

RAS pathway alterations are highly prevalent in hematologic malignancies1,2, often involving gain of function KRAS, NRAS or HRAS mutations and have been linked to tumorigenesis and associated with poorer prognosis in different cancer entities3-5. In adult myeloid leukemia, RAS mutations are one of the most common mutations, yet show no clear prognostic value6. In a study of the Japanese pediatric AML cohort, NRAS mutations were associated with a favorable outcome, the effect of KRAS mutations could not be analyzed due to the limited patient size7. Here we report the outcome of 372 pediatric AML patients of the German AML-BFM study between 2016 and 2021 that were characterized by morphology, multicolor flow cytometry, classical cytogenetics and mutation analysis via panel sequencing. In total, 27% (n=102) of the patients showed a RAS pathway alteration, involving n=32 patients (9%) with a KRAS mutation and n=75 (20%) with a NRAS mutation. Notably, no HRAS mutation was detected in our cohort. Age distribution did not differ between the groups (Fig. A). Interestingly, the KRAS cohort consisted mostly of male patients (72%, p=0,0087), while the overall cohort was balanced (48,7% male patients). NRAS and KRAS mutations were strong predictors of therapy response and early death. Only 1/75 (1,3%) of all patients harboring a NRAS mutations showed poor response to induction therapy compared to patients without a NRAS mutation (10,10%, p=0,01). KRAS mutations on the opposite were strongly associated with non-response (21,9%; p<0,01) and subsequent early deaths (n=6/32; p=0,001) compared to patients without KRAS mutations (3,2%). Of note, only 1/75 (1,3%) of patients with NRAS mutation and 17/372 (4,6%) of all AML patients suffered early deaths. Risk stratification taking into account re-stratification after poor therapy response showed a significant higher proportion of high-risk patients in the KRAS-mutated cohort (43,8 %) compared to 20% in the patients with NRAS mutations (p=0,0022). KRAS mutations correlated with KMT2A-MLLT1 (15,6%; p=0,01) translocations, which were significantly rarer in patients without KRAS mutations (3,5%). NRAS mutations occurred frequently with CBFA2T3-RUNX1 (14,7%; p=0,0002) and CBFB-MYH11 translocations (12%; p=0,0068%) as well as KIT mutations (12%; p=0,026). Existence of RAS mutations showed overall no significant impact on event-free survival (EFS=69,6% ±4,8%) and overall survival (OS=82,8% ±4,2%) compared to RAS wildtype (EFS=66,4% ±3,1% ; OS=76,5% ±2,9%) (Fig. B). Multivariate analysis comparing outcome for several subgroups also showed no significant differences. In summary, we show worse therapy response and increased early death rates in patients with KRAS mutations, while NRAS mutations are associated with better therapy response. These findings warrant further analyses and longer follow-up on the cohort to determine long-term significances of RAS pathway alterations in pediatric AML patients. 1.de Luca, A., Maiello, M. R., D'Alessio, A., Pergameno, M. & Normanno, N. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets16 Suppl 2, (2012). 2.Hobbs, G. A., Der, C. J. & Rossman, K. L. RAS isoforms and mutations in cancer at a glance. Journal of Cell Science129, 1287-1292 (2016). 3.Hsu, H. C. et al. Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients. Oncotarget7, 22257 (2016). 4.Vauthey, J., Zimmitti, G., Kopetz, S., ... J. S.-A. of & 2013, undefined. RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases. ncbi.nlm.nih.gov. 5.Dinu, D. et al. Prognostic significance of KRAS gene mutations in colorectal cancer - preliminary study. Journal of Medicine and Life7, 581 (2014). 6.Neubauer, A. et al. Patients With Acute Myeloid Leukemia and RAS Mutations Benefit Most From Postremission High-Dose Cytarabine: A Cancer and Leukemia Group B Study. Journal of Clinical Oncology26, 4603 (2008). 7.Kaburagi, T. et al. Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia. Haematologica107, 583-592 (2022). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal