Clinical Features and Prognostic Significance of NOTCH1 Mutations in Diffuse Large B-Cell Lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of large lymphoid B cell malignancy with distinct clinical and genetic features. Recently, NOTCH1 mutations were identified in DLBCL cases by Next-generation sequencing (NGS), but the clinical features and prognostic impact were not systematically studied. Here, NOTCH1 genes in 161 DLBCL samples were sequenced by NGS. The prognostic value of NOTCH1 mutations was assessed in the context of clinical and laboratory factors, such as international prognostic index (IPI), cell-of-origin classification, double expression of BCL2 and c-MYC. The combined data from three Western cohorts were used to validate these results. As a result, NOTCH1 mutations were found in 17(10.6%) patients, and three patients had a hotspot mutation of c.7541_7542delCT. The presence of NOTCH1 mutations was significantly associated with poor complete response and progression free survival(PFS), which was independent of established clinical and laboratory parameters. In addition, 30 (1.92%) of 1562 patients treated with R-CHOP regimen in those combined Western cohorts had NOTCH1 mutations. Meta-analysis of the Western cohorts confirmed that NOTCH1 mutations were also associated with poor PFS and OS. In conclusion, DLBCL patients with the NOTCH1 mutations have worse PFS and OS, and the NOTCH1 mutations can be used as an independent predictor for patients with DLBCL.

Identification of CXCR4 Upregulation in Diffuse Large B-Cell Lymphoma Associated with Prognostic Significance and Clinicopathological Characteristics

“…JAK-STAT signaling pathways were associated with pathogenesis of ABC-DLBCL [ 22 ]. DLBCL patients with the NOTCH1 mutations have worse PFS and OS [ 23 ]. These results are consistent with previous studies showing that the CXCR4/CXCL12 axis can mediate tumorigenicity by activating various intracellular signaling transduction pathways and downstream effectors [ 24 – 28 ].…”

Analysis of Notch1 protein expression in methotrexate-associated lymphoproliferative disorders

“… 29 Recent research has indicated that mutations in NOTCH1 are present in approximately 10% of DLBCL cases. 27 It has also been suggested that Notch1 might function as a driver in the pathogenesis of certain DLBCL cases. 28 To date, there are no published studies that have examined immunostaining of the NICD domain of Notch1 specifically in DLBCL.…”

Resistance to PSEN1-selective γ-secretase inhibitors in T-cell acute lymphoblastic leukemia

“…1,2 3 Mammals have four NOTCH receptors (NOTCH1, NOTCH2, NOTCH3, NOTCH4) with slightly different structures/functions and distinct subcellular localizations. 1 While all NOTCH receptors play some role in cancer development, this is most clear for NOTCH1, which is frequently mutated or overexpressed in breast cancer 4 , lung cancer 5 , aggressive desmoid tumors 6 and in hematological cancers, such as T-cell acute lymphoblastic leukemia (T-ALL) 7 , chronic lymphocytic leukemia (CLL) 8 , diffuse large B-cell lymphoma (DLBCL) 9 and mantle cell lymphoma (MCL) 10 . The majority of T-ALL cases harbor activating NOTCH1 mutations and therefore NOTCH1 has been actively investigated as a major target for therapy in this rare leukemia.…”