Landscape of NOTCH1 mutations and co-occurring biomarker alterations in chronic lymphocytic leukemia

NOTCH1 is one of the most frequently mutated genes in chronic lymphocytic leukemia and has emerged as a marker of poor prognosis. In addition to coding NOTCH1 mutations involving exon 34, non-coding NOTCH1 mutations involving the 3′ UTR have been described in a limited number of chronic lymphocytic leukemia (CLL) patients and were associated with adverse outcomes. In this study, 1574 CLL patients were assessed using targeted sequencing with a 29 gene panel and the results were correlated with prognostic characteristics. NOTCH1 mutations were detected in 252 (16%) patients, including both coding (220/252, 14%), non-coding (24/252, 1.5%) and a mixture of coding and non-coding (8/252, 0.5%) NOTCH1 mutations. NOTCH1 mutations were more commonly seen in patients with unmutated IGHV, ZAP70 positivity and CD38 positivity. Mixed NOTCH1 mutations were also more commonly seen in patients with unmutated IGHV and ZAP70. There was no association between mixed NOTCH1 mutations and CD38 expression in this cohort. The most common cytogenetic alteration detected in patients with coding and mixed NOTCH1 mutations was trisomy 12, whereas del13q was the most common cytogenetic alteration detected in patients with non-coding NOTCH1 mutation. The most common gene mutations co-occurring with coding NOTCH1 mutations were: TP53 (23.2%), SF3B1 (16.4%) and SPEN (10%). The most common gene mutations co-occurring with non-coding NOTCH1 mutations were: SF3B1 11(34.4%), ATM 4(12.5%) and TP53 4(12.5%). CLL patients with clonal coding and non-coding NOTCH1 mutations had a significantly shorter time-to-first treatment than patients with wild type NOTCH1 (4.3 vs 10.0 years and 0.9 vs 10.0 years respectively, p < 0.05). Similarly, CLL patients with subclonal coding NOTCH1 mutations had a significantly shorter time-to-first treatment than patients with wild type NOTCH1 (5.6 vs 10.0 years, p < 0.05). CLL patients with subclonal non-coding NOTCH1 mutations also had a shorter time-to-first treatment than patients with wild type NOTCH1 mutations, however, the difference was not significant (5.1 vs 10.0 years, p = 0.15). These data confirm that both coding and non-coding NOTCH1 mutations carry adverse prognostic impact and need to be included in sequencing assays performed for the prognostic workup of CLL patients.