Mutations predictive of hyperactive Ras signaling correlate with inferior survival across high-risk pediatric acute leukemia.

Autor:	Ney GM; Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA., Anderson B; Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA., Bender J; Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA., Kumar-Sinha C; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Wu YM; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Vats P; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Cieslik M; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Robinson DR; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Li Q; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Chinnaiyan AM; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Mody R; Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Jazyk:	angličtina
Zdroj:	Translational pediatrics [Transl Pediatr] 2020 Feb; Vol. 9 (1), pp. 43-50.
DOI:	10.21037/tp.2019.12.03
Abstrakt:	Background: Cancer remains the number one cause of disease-related mortality in children, and despite advances in the molecular understanding of leukemia and targeted therapies, refractory leukemia remains a leading cause of death. It therefore is essential to further define features, e.g., FLT3 alterations and KMT2A rearrangements, associated with inferior survival early to augment or alter therapeutic strategies to improve outcomes. Methods: To gain insights into the genetic drivers predictive of aggressive clinical behavior among pediatric leukemia patients, we performed comprehensive integrative clinical sequencing (ICS), including paired tumor/normal DNA sequencing and RNA-seq, for pediatric patients who presented at our institution over a period of five years with acute lymphoblastic or myelogenous leukemia (ALL and AML; n=43) and high-risk clinical features (high white blood cell count, extramedullary disease, or refractory and/or relapsed disease). Results: We found that RAS - and Ras-pathway aberrations, including N-RAS , NF1 and PTPN11 , are frequent somatic mutations and, importantly, associated with decreased event free and overall survival (OS) (P=0.04, median event free survival 22.8 vs. 5.6 months; P=0.04, median OS 124 vs. 22.5 months). Conclusions: We thus propose that hyperactive Ras signaling confers inferior survival in high-risk pediatric acute leukemia and that Ras pathways should be molecularly characterized to inform clinical decision making and to identify patients for experimental clinical trials and RAS-targeted therapy. Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare. (2020 Translational Pediatrics. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu