IDENTIFY THE MOST COMMONLY MUTATED GENES IN CHRONIC LYMPHOCYTIC LEUKEMIA AND THE SIGNIFICANCE ON PROGNOSIS

Abstract

Introduction: The prognosis of chronic lymphocytic leukemia (CLL) varies widely individually. The clinical staging systems by Rai and Binet, cytogenetics/FISH, and mutational status of IGHV have been commonly used as clinical prognostic factors for CLL patients. The advent of molecular panels by next-generation sequencing might provide additional markers to predict the outcome of CLL patients. In this study, we evaluate gene mutation profiles as well as IGVH mutation status for its application to predicting survival outcomes among these CLL patients. Methods: We performed next-generation sequencing (NGS) sequencing in 196 clinically characterized CLL samples in OSU James Cancer Hospital and analyzed the IGVH mutation status of 172 patients from the same cohort. In addition, clinic-pathological data include age, gender, immunophenotyping, and cytogenetics/FISH. Results: 50 genes in the NGS mutation panel and IGVH mutation status are explored for a sequencing-based prediction model. Five genes (TP53, NOTCH1, SF3B1, and RAS including KRAS and BRAF) are identified as the most commonly mutated genes in the order of frequencies from 24.1%, 14.2%, 13.4%, and 11.6%, respectively. There are 66.9% unmutated IGVH genes but has no significant correlation between the outcomes (p = 0.48). However, the patients with unmutated IGVH have a substantial correlation to mutated TP53 and NOTCH1, but not SF3B1 and RAS mutations. The outcome in this cohort is significantly correlated to the pathogenic mutations present among these four genes (p < 0.001, n = 139, Cochran’s Q test). However, both Kaplan-Meier and Cox Regression survival analyses reveal that mutated RAS (BRAF and KRAS) is the only one that has a significant correlation to a favorable survival outcome. Keywords: chronic lymphocytic leukemia (CLL), genomics, epigenomics, and other -omics, risk models No conflicts of interests pertinent to the abstract.