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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.

SUBMITTER: Li Z

PROVIDER: S-EPMC8695434 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Although knowledge of the genetics of diffuse large B-cell lymphoma (DLBCL) has been increasing, little is known about the characteristics and prognostic significance of cytogenetic abnormalities and the clinical utility of cytogenetic studies performed on bone marrow (BM) specimens. To investigate the significance of isolated cytogenetic aberrations in the absence of histologic BM involvement, we assessed the implication of cytogenetic staging and prognostic stratification by a retrospective multicenter analysis of newly diagnosed DLBCL patients. METHODS: We analyzed cytogenetic and clinical data from 1585 DLBCL patients whose BM aspirates had been subjected to conventional karyotyping for staging. If available, interphase fluorescence in situ hybridization (FISH) data were also collected from patients. RESULTS: Histologic BM involvement were found in 259/1585 (16.3%) patients and chromosomal abnormalities were detected in 192 (12.1%) patients (54 patients with single abnormalities and 138 patients with 2 or more abnormalities). Isolated cytogenetic aberrations (2 or more abnormalities) without histologic involvement were found in 21 patients (1.3%). Two or more cytogenetic abnormalities were associated with inferior overall survival (OS) compared with a normal karyotype or single abnormality in both patients with histologic BM involvement (5-year OS, 16.5% vs. 52.7%; P < 0.001) and those without BM involvement (31.8% vs. 66.5%; P < 0.001). This result demonstrated that BM cytogenetic results have a significant prognostic impact that is independent of BM histology. The following abnormalities were most frequently observed: rearrangements involving 14q32, 19q13, 19p13, 1p, 3q27, and 8q24; del(6q); dup(1q); and trisomy 18. In univariate analysis, several specific abnormalities including abnormalities at 16q22-q24, 6p21-p25, 12q22-q24, and -17 were associated with poor prognosis. Multivariate analyses performed for patients who had either chromosomal abnormalities or histologic BM involvement, revealed IPI high risk, = 2 cytogenetic abnormalities, and several specific chromosomal abnormalities, including abnormalities at 19p13, 12q22-q24, 8q24, and 19q13 were significantly associated with a worse prognosis. CONCLUSIONS: We suggest that isolated cytogenetic aberrations can be regarded as BM involvement and cytogenetic evaluation of BM improves staging accuracy along with prognostic information for DLBCL patients.

Project description:BackgroundNeutrophil-to-lymphocyte ratio (NLR) has been investigated as a prognostic marker in patients with diffuse large B-cell lymphoma (DLBCL); however, the results remain controversial. This study aimed to explore the association between NLR and survival outcomes and clinicopathological factors in DLBCL.MethodsRelevant studies were retrieved by searching PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) databases. The last search was updated on February 17, 2017. Hazard ratios (HRs) and odds ratios (ORs) and their 95% confidence intervals (CIs) were used as effective measures in the meta-analysis. Random-effects models and fixed-effects models were used for analyses. Meta-regression was performed. Publication bias was assessed using Begg's test. Stata version 12.0 was used for all analyses.ResultsA total of 9 studies with 2297 patients were included in the meta-analysis. The pooled results showed that NLR was a significant indicator for poor overall survival (OS) (HR = 1.84, 95% CI = 1.52-2.22, p<0.001) and poor progression-free survival (PFS) (HR = 1.64, 95% CI = 1.36-1.98, p<0.001). NLR remained a significant biomarker for OS and PFS regardless of location, sample size or cut-off value. In addition, high NLR was also associated with Ann Arbor stage (OR = 2.09, 95% CI = 1.14-3.81, p = 0.017), lactate dehydrogenase level (OR = 2.74, 95% CI = 1.16-6.46, p = 0.021), extranodal disease (OR = 1.63, 95% CI = 1.06-2.52, p = 0.027), and International Prognostic Index score (OR = 2.44, 95% CI = 1.03-5.08, p = 0.043). However, NLR was found to have no significant association with sex (OR = 0.89, 95% CI = 0.71-1.11, p = 0.29), age (OR = 1.18, 95% CI = 0.94-1.48, p = 0.152), European Cooperative Oncology Group performance status score (OR = 1.78, 95% CI = 0.71-4.46, p = 0.217), or presence of B symptoms (OR = 1.56, 95% CI = 0.7-3.48, p = 0.278).ConclusionIn conclusion, our meta-analysis demonstrated that NLR has a strong association with worse OS and PFS in patients with DLBCL. NLR could be recommended as an inexpensive prognostic biomarker in DLBCL.

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

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