NOTCH1 is recurrently mutated in chronic lymphocytic leukemia (CLL), most commonly as a two base-pair frameshift deletion (c.7541_7542delCT). This mutated allele encodes a truncated form of the receptor (P2514fs*4) lacking the C-terminal PEST degradation domain, and results in increased NOTCH1 signaling duration. NOTCH1 mutation has been associated with poor clinical outcomes in CLL. We sought to validate a highly sensitive and quantitative droplet digital PCR (ddPCR) assay for the NOTCH1 delCT mutation which we anticipated would perform well as compared to Sanger sequencing and allele-specific PCR. Performance characteristics of this assay were tested on 126 samples from an unselected CLL cohort, and a separate cohort of 85 samples from patients with trisomy 12 CLL. The delCT mutation was detected at allele frequencies as low as 0.024% and found 25% of unselected cases and 55% of trisomy 12 cases were positive at the 0.024% detection threshold. Mutational burdens ≥1% were found to be significantly associated with shorter overall survival (OS) in patients with trisomy 12+ disease in multivariate analysis (median OS 9.1 vs. 13 years with hazard ratio of 2.34; p=0.031). Mutational burdens <1% correlated with shorter OS in univariate, but not multivariate analyses. These results suggest ddPCR testing for NOTCH1 delCT mutation may prove useful for risk stratification and/or disease monitoring in certain subsets of patients with CLL.Copyright © 2020. Published by Elsevier Inc.
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