NOTCH4 regulates colorectal cancer proliferation, invasiveness, and determines clinical outcome of patients

Zhang, Zixi; Bu, Xin; Yang, Jingyi; Zhu, Shaojun; He, Shuixiang; Zheng, Jun; Wang, Weizhong; Chu, Dake

doi:10.1002/jcp.26619

Cited by 15 publications

(12 citation statements)

References 39 publications

(58 reference statements)

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“…To date, four Notch receptors (Notch 1, Notch 2, Notch 3, and Notch 4) have been identified in mammals [ 5 ]. Notch signaling critically affects the tumorigenesis and proliferation control of cells in the gastrointestinal tract [ 6 ]. It is interesting to note that Notch signaling acts as an oncogenic event in some cancers and a cancer suppressor in others.…”

Section: Introductionmentioning

confidence: 99%

Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy

Long

Wang

et al. 2021

BMC Med

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Background Immune checkpoint inhibitor (ICI) therapy elicits durable antitumor responses in patients with many types of cancer. Genomic mutations may be used to predict the clinical benefits of ICI therapy. NOTCH homolog-4 (NOTCH4) is frequently mutated in several cancer types, but its role in immunotherapy is still unclear. Our study is the first to study the association between NOTCH4 mutation and the response to ICI therapy. Methods We tested the predictive value of NOTCH4 mutation in the discovery cohort, which included non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, esophagogastric cancer, and bladder cancer patients, and validated it in the validation cohort, which included non-small cell lung cancer, melanoma, renal cell carcinoma, colorectal cancer, esophagogastric cancer, glioma, bladder cancer, head and neck cancer, cancer of unknown primary, and breast cancer patients. Then, the relationships between NOTCH4 mutation and intrinsic and extrinsic immune response mechanisms were studied with multiomics data. Results We collected an ICI-treated cohort (n = 662) and found that patients with NOTCH4 mutation had better clinical benefits in terms of objective response rate (ORR: 42.9% vs 25.9%, P = 0.007), durable clinical benefit (DCB: 54.0% vs 38.1%, P = 0.021), progression-free survival (PFS, hazard ratio [HR] = 0.558, P < 0.001), and overall survival (OS, HR = 0.568, P = 0.006). In addition, we validated the prognostic value of NOTCH4 mutation in an independent ICI-treated cohort (n = 1423). Based on multiomics data, we found that NOTCH4 mutation is significantly associated with enhanced immunogenicity, including a high tumor mutational burden, the expression of costimulatory molecules, and activation of the antigen-processing machinery, and NOTCH4 mutation positively correlates activated antitumor immunity, including infiltration of diverse immune cells and various immune marker sets. Conclusions Our findings indicated that NOTCH4 mutation serves as a novel biomarker correlated with a better response to ICI therapy.

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Section: Introductionmentioning

confidence: 99%

Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy

Long

Wang

et al. 2021

BMC Med

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“…As a biomarker in many tumors, NOTCH4 established significant roles in cell growth, invasion and apoptosis. Zhang et al (28) revealed that suppressing the expression of NOTCH4 could inhibit the PCa progression and epithelialmesenchymal transition by stimulating NF-κB. Regarding MAL (29), it was reported that low expression of MAL was associated with poor failure-free survival and it might serve as an independent prognostic signature when estimating the tumor immune infiltrate in classical Hodgkin lymphoma.…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of a six immune-related gene signature for prediction of biochemical recurrence in localized prostate cancer following radical prostatectomy

et al. 2021

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Background: Prostate cancer (PCa) is the second lethal heterogeneous cancer among males worldwide, and approximately 20% of PCa patients following radical prostatectomy (RP) will undergo biochemical recurrence (BCR). This study is aimed to identify the immune-related gene signature that can predict BCR in localized PCa following RP. Methods: Expression profile of genes together with clinical parameters from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus database (GEO) and the immune-related genes from the Molecular Signatures Database v4.0 were applied to construct and validate the gene signature. The Cox regression analyses were conducted to identify the candidate genes and establish the gene signature. To estimate the prognostic power of the risk score, the time-dependent receiver operating characteristic (ROC) analysis and Harrell's index of concordance (C-index) were utilized. We also established a nomogram to forecast the probability of patients' survival.Results: A total of 268 patients from the TCGA and 77 patients from GSE70770 and six immune-related genes (SCIN, THY1, TBX1, NOTCH4, MAL, BNIP3L) were eventually selected. The Kaplan-Meier analysis demonstrated that patients in the low-risk group had a significantly longer recurrence-free survival (RFS) compared to those in the high-risk group. In the multivariate Cox model, the signature was identified as an independent prognostic factor, which was significantly associated with RFS (TCGA: HR =5.232, 95% CI:

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“…Accumulating evidence has illustrated the specificity of NOTCH4 for different cancers and has suggested the potential for NOTCH4 to be used as a marker for the diagnosis and prognosis of cancers. Zhang et al15 reported that NOTCH4 might be an independent marker of relapse and prognosis in colorectal cancer patients, because overexpression of NOTCH4 in colorectal cancer cell lines suppressed tumor cell proliferation, migration, and invasion, while it induced apoptosis. Consistent with colorectal cancer, previous results demonstrated that high expression of NOTCH4 in ovarian cancer is correlated with a better prognosis 27,28.…”

Section: Discussionmentioning

confidence: 99%

“…As one of the main signaling pathways of cancer stem cells, the NOTCH signaling pathway plays an important role in the maintenance of self-renewal, multidirectional differentiation, and apoptosis of various cancer stem cells and thus participates in the regulation of cancer stem cells 13. Deregulation or mutation of NOTCH receptors, ligands, and signaling regulators is implicated in the occurrence, development, and progression of several human solid tumors, for example, breast cancer,14 colon cancer,15 and liver cancer,16 as well as NSCLC 17. Previous reports have demonstrated that NOTCH signaling is activated aberrantly and plays a critical role in the initiation, progression, and metastasis of NSCLC 18…”

Section: Introductionmentioning

confidence: 99%

<p>Association between single nucleotide polymorphisms of <em>NOTCH</em> signaling pathway-related genes and the prognosis of NSCLC</p>

Lin

Liu

et al. 2019

CMAR

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Objective In this study, we analyzed the association between genetic variants of genes in the NOTCH signaling pathway and the prognosis of non-small-cell lung cancer (NSCLC) in the Chinese population. We also explored the interaction between genetic and epidemiological factors for the test group. Methods We performed genotyping of 987 NSCLC patients. Then, we used Cox proportional hazard models to analyze the associations between single-nucleotide polymorphisms (SNPs) and the prognosis of NSCLC. We employed Stata software to test the heterogeneity of associations between subgroups, and we analyzed the additive and multiplicative interactions between SNPs and epidemiologic factors. Results This work revealed the important prognostic and predictive value of rs915894 in the NOTCH4 gene, which may be regarded as a promising prognosis biomarker of NSCLC. Cox regression analysis indicated that the C allele of rs915894 is associated with longer survival and decreased risk of death in NSCLC (codominant model: adjusted HR =0.83, 95% CI =0.70–0.99; dominant model: adjusted HR =0.83, 95% CI =0.71–0.98). Additional stepwise regression analysis suggested that this SNP is an independently favorable factor for the prognosis of NSCLC (dominant model: adjusted HR =0.85, 95% CI =0.72–0.99). This protective effect is more pronounced for patients who are not smokers, have a history of other lung diseases, or have a family history of cancer. We also detected statistically significant additive and multiplicative interactions between rs915894 and smoking, rs915894 and history of lung diseases, and rs915894 and family history of cancer, which all affect NSCLC survival. Conclusion This study demonstrated that rs915894 in NOTCH 4 may be a genetic marker for NSCLC prognosis in the Chinese population and that rs915894 may have an interactive relationship with epidemiologic factors.

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NOTCH4 regulates colorectal cancer proliferation, invasiveness, and determines clinical outcome of patients

Cited by 15 publications

References 39 publications

Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy

Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy

Identification and validation of a six immune-related gene signature for prediction of biochemical recurrence in localized prostate cancer following radical prostatectomy

<p>Association between single nucleotide polymorphisms of <em>NOTCH</em> signaling pathway-related genes and the prognosis of NSCLC</p>

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