NOTCH2 mutation

Four of 10 patients were positive for PD-L1 and CD8+ T. By analyzing WES in three of these four patients, we notably identified the mutations of NOTCH1, FBXW7, and noncoding RNA intronic mutation in NOTCH2NLR in two of these three patients. This study may enable better selection of ICI therapy with CD8+ T-cell infiltration via PD-L1 expression for oral squamous cell carcinoma patients with mutations in Notch signaling pathway.

The patient was subsequently treated with 6 cycles of adriamycin chemotherapy. Computerized tomography scan after 3 cycles showed no residual disease. Published literature regarding dedifferentiated leiomyosarcoma is reviewed.

We then conducted univariate Cox Proportional Hazards analysis to investigate the prognostic significance of clinical and molecular features on time to first treatment (TTFT; most prevalent treatments: splenectomy, n=51; rituximab, n=20) and overall survival (OS)...To conclude, we demonstrate the potential clinical utility of epiCMIT score in SMZL patients, identifying that SMZL patients with high epiCMIT harbour specific genetic characteristics, and exhibit reduced treatment-free survival. EpiCMIT could be valuable in clinical practice, helping to identify those patients destined to progress and require closer monitoring.

Introduction: In the POLARIX study, polatuzumab vedotin in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) demonstrated prolonged progression-free survival (PFS) vs rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL; NCT03274492; Tilly et al. In this exploratory biomarker analysis, we recapitulated that pts with molecularly defined DLBCL subtypes, including EZB and MCD by LymphGen and DZsig+ by RNAseq, have poor outcomes with R-CHOP therapy. In pts with the EZB and MCD subtypes, Pola-R-CHP appeared to improve 2-year PFS compared with R-CHOP. Pts with GCB DLBCL who were DZsig+ significantly benefited from Pola-R-CHP vs R-CHOP.

In summary, we have developed a DNA methylation-based classifier that resolves 4 SBLPN subgroups with distinct molecular features, and reclassifies a subset of SMZL and HCL patients, adding further information to the updated WHO/ICC entities. We reveal distinct biological pathways operating in M-SBLPN subgroups that may aid targeted therapy approaches.

Introduction: In the POLARIX study (NCT03274492), polatuzumab vedotin in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) demonstrated prolonged progression-free survival (PFS) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL; Tilly et al. Our analyses demonstrated that the mutation landscape of ctDNA in DLBCL characterized by the AVENIO ctDNA NHL assay resembles that of tumor tissue determined by WES. Patients with molecular subtypes defined by WES or ctDNA had similar PFS outcomes. Overall, these findings support the use of plasma ctDNA as an alternative to tumor tissue for the genotyping of DLBCL.

Skin primary glomus tumors show frequent mutations in NOTCH2 and NOTCH3 , including gene fusions and novel truncating mutations. The presence of occasional BRAF and PDGFRB alterations raise the possibility of targeted therapies in clinically-advanced cases of this tumor type.

Furthermore, the NOTCH2-mediated tumorigenesis was mostly reversed after NF-κB inhibitor Bay11-7082 treatment. These findings identified the NOTCH2 P2113S mutation in ovarian carcinogenesis, and NOTCH2 P2113S is a potential target in treating OC.

73 patients had only one BTKi (ibrutinib (IBR), 64; acalabrutinib (ACA), 9). 12 pts had multiple BTKis, 8 with two drugs with IBR first followed by ACA (Nf3, 37.5%), vecabrutinib (Nf1, 12.5%), and PIR (Nf4, 50.0%); and 4 with three or more drugs... Our retrospective report summarizes mutations detected during BTKi treatment and shows that BTK L528W can occur during both covalent and non-covalent BTK inhibitor therapy. Four of six patients who progressed on PIR had T474 mutations. In addition, our results may suggest that activating mutations in RAS/RAF/MAPK pathway are related to BTKi resistance.

In this study, we conducted a comparative analysis of meningioma patients based on their smoking history, examining both their clinical trajectories and molecular changes. Meningiomas from current smokers were more likely to harbor NOTCH2 mutations, and AKT1 mutations were absent in current or past smokers. Moreover, both current and past smokers exhibited a mutational signature associated with DNA mismatch repair. Meningiomas from current smokers demonstrate downregulation of xenobiotic metabolic enzymes UGT2A1 and UGT2A2, which are downregulated in other smoking related cancers. Furthermore, current smokers exhibited downregulation xenobiotic metabolic gene sets, as well as enrichment in gene sets related to mitotic spindle, E2F targets, and G2M checkpoint, which are hallmark pathways involved in cell division and DNA replication control. In aggregate, our results demonstrate novel alterations in meningioma molecular biology in response to systemic carcinogens.

Up to 40% of DLBCL patients display refractory disease or relapse after standard chemotherapy treatment (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), leading to significant morbidity and mortality. Targeting CHOP-resistant DLBCL tumors with the Phase 3 clinical trial molecules nirogacestat, a selective g-secretase inhibitor, and ipatasertib, a pan-AKT inhibitor, synergistically promotes DLBCL death. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in KLHL6- or NOTCH2-mutated DLBCL.

Through genetic analysis of prostate cancer, it was possible to analyze numerous gene mutations, and to find clinically significant mutations. Several genes, such as BRCA2, NOTCH2 and TP53 gene mutations have been found to be associated with advanced prostate cancer. The prognosis of prostate cancer can be predicted by genetic analysis, and the better prognosis can be expected through the application of a proper targeted therapy for each pathway alterations.

Additionally, co-treatment with FHD-286 and venetoclax, decitabine or OTX015, as compared to each drug alone or vehicle control, significantly reduced AML burden and improved the overall survival of the NSG mice, without inducing significant toxicity. Taken together, these findings highlight the promise of FHD-286 treatment alone and in rational combinations in exerting significant anti-AML efficacy against cellular models of AML, especially those with MLL-r, mtNPM1 or chromosome 3q26 lesions and EVI1 overexpression.

NGS-detected mutations may be of therapeutic interest. Herein, we detected 3 EZH2 and 8 CREBBP mutations that might be eligible for targeted therapies.

With high efficacy and manageable tolerability, zanubrutinib plus salvage chemotherapy may be a potential treatment option for R/R DLBCL. CAR-T cell therapy may be a priority strategy for these poor responders to BTKi-based treatment.

Arbo represents a NOTCH2 mutated model that is useful in MCL as well as other lymphomas with such mutation. We plan to deposit Arbo at the ATCC to be available for the research community.

Based on these observations, and clinical efficacy of the combination of venetoclax and decitabine/azacitidine, we determined the in vitro lethal activity of co-treatment with FHD-286 and venetoclax or decitabine against AML cell lines and PD AML cells. Additionally, co-treatment with FHD-286 and venetoclax or decitabine or OTX015, as compared to each drug alone or vehicle control, significantly reduced the AML burden and improved median and overall survival of the immune-depleted mice, without inducing significant toxicity. Taken together, these findings highlight the promise of FHD-286 treatment alone and in rational combinations in exerting significant anti-AML efficacy against cellular models of AML, especially those with MLL-r, mtNPM1 or chromosome 3q26 lesions and EVI1 overexpression.

We present here a refined classification of DLBCL genetic subgroups that combines previously described classification algorithms and extends it to allow classification of more tumors into additional subgroups that preserve the major divisions of existing systems. This represents an important advancement that will facilitate further understanding of genomic complexity in this disease.

These results suggest that DZNep may have potential as a novel therapeutic agent for DFLBL therapy. This agent may serve as a novel molecular agent to be applied to GCB DLBCL.

Our results confirm the relevance of mutations in B-cell receptor/nuclear factor-κB signaling and immune escape pathways in IVLBCL and identify novel driver alterations. The similar mutational profile in tumors with extravascular dissemination suggests that these cases may also be considered in the spectrum of IVLBCL.

Clear cell AFX and PDS seem to share fundamental molecular driver events. Their molecular profle is also similar to that described in more common variants. Whilst no unique mutational profle was identi-fed in our cases, presence of the genetic abnormalities described herein may increase the level of confdence in diagnosing these lesions.

On the widest case-series so far published focusing on LPL and SMZL immunohistochemical diagnosis at onset on BMB, we demonstrated that MNDA expression significantly support the diagnosis of SMZL. This observation may be of particular help in cases where the MYD88 p.Leu265Pro mutational status and/or SMZL-related genetic aberrations are unavailable.

Ibrutinib, as a single agent, has demonstrated limited activity in DLBCL with mutant MYD88 and wildtype CD79 . In this study, we identified 3 patients with mutant MYD88 and wildtype CD79A/B (8.1%), among whom 2 harbored MYD88 L265P variants and 1 had MYD88 S219C mutation. Conclusion The utility of mutational profiling may facilitate the identification of potential drug targets, which in turns may represent new therapeutic possibilities.

Additionally, a dose dependent decrease in the expression of CD23 was observed by flow cytometry following treatment with gliotoxin.To determine the dependence of Arbo on B-cell receptor (BCR) signaling for survival, we cultured the cells with increasing concentrations of the BTK inhibitor ibrutinib for 48h. Inhibition of cell growth was observed in a dose-dependent manner resulting in an IC50 of 0.4 µM.In conclusion, Arbo is a novel blastoid MCL cell line with a NOTCH2 mutation that is fully characterized and will be made available to the research community.Supported by a grant from the Ladies Leukemia League, Inc., of the Gulf South Region.

Notch2-mutant non-neuroendocrine cells highly express innate immune signaling genes including STING and were sensitive to STING agonists. This work identifies a Notch-independent mechanism to promote non-neuroendocrine plasticity and suggests that therapeutic approaches to activate STING could be selectively beneficial for SCLCs with NOTCH2 mutations.

Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, and an important therapeutic consideration for desmoid tumor.

The level of CD47 expression does not appear to predict OS in patients with DLBCL treated with R-CHOP. This study demonstrates that conventional immunohistochemical methods can readily identify DLBCL with high CD47 expression, and these patients may benefit from the use of anti-CD47 therapy.

No abstract available

Here we analysed clinico-biological features in 373 DLBCL patients homogeneously treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), in order to identify variables associated with early failure to treatment (EF), defined as primary refractoriness or relapse within 12 months from diagnosis. Mutations in NOTCH2, gains in 5p15·33 (TERT), 12q13 (CDK2), 12q14·1 (CDK4) and 12q15 (MDM2) showed predictive importance for EF independently from R-IPI. GEP studies showed that EF cases were significantly enriched in sets related to cell cycle regulation and inflammatory response, while cases in response showed over-representation of gene sets related to extra-cellular matrix and tumour microenvironment.

These data make NOTCH signaling an appealing target for drug discovery in SMZL; however, prior efforts attempting to manipulate this pathway failed to demonstrate meaningful clinical benefit, or their safety profile prevented further development. In this review, we discuss the current knowledge of NOTCH implications in the pathogenesis and as a potential druggable target in SMZL.

Patients with two or more score points have a median survival of <5 years. Watch and wait strategy is appropriate in low-risk and asymptomatic patients, whereas treatment of symptomatic patients ranges from splenectomy to rituximab monotherapy or associated with chemotherapy.

There was a negative correlation between EGFR and NOTCH2 mutations (correlation coefficient, -0.078; P=0.027). Thus, the present study highlights the importance of NOTCH2 mutations and might provide novel therapeutic options for patients with NSCLC who do not harbor EGFR mutations.

Restoration of PTEN expression can be achieved with an EZH2 inhibitor (UNC1999), a γ-secretase inhibitor (Compound E), or knockdown of EZH2 or NOTCH. These findings elucidate a mechanism of transcriptional repression of PTEN induced by NOTCH1 or NOTCH2 alterations, and identifies actionable signaling pathways responsible for driving a large subset of poor-prognosis breast cancers.

Overall, novel mutations were identified and differences between mutation patterns in localized and metastatic SCCs were found. These findings may have clinical applications.

Overall survival was 82% at 10 years and not influenced by TP53 aberration. Our present findings suggest that most t(CDK6)+ neoplasms correspond to a particular subgroup of indolent marginal zone B-cell lymphomas with distinctive features.

This is a case of AV-SMZL in which a cancer panel test successfully detected genetic alterations that are potentially associated with its pathogenesis. These findings suggest that genetic analysis is useful for making diagnoses as well as for determining treatment strategies in AV-SMZL.

Our results also suggest the ineffectiveness for distinguishing clonal hematopoietic mutations of low variant allele frequency (≤0.1%) from tumor-derived mutations using conventional next-generation sequencing of blood cell DNA. However, an error correction model with an ultralow error rate and high coverage depth is required for blood cell DNA sequencing, which is difficult and costly to achieve with current technologies.