Identification of Deleterious <i>NOTCH</i> Mutation as Novel Predictor to Efficacious Immunotherapy in NSCLC

Zhang, Kai; Hong, Xiaohua; Song, Zhengbo; Xu, Yu; Li, Chengcheng; Wang, Guoqiang; Zhang, Yuzi; Zhao, Xiaochen; Zhao, Zhengyi; Zhao, Jing; Huang, Mengli; Huang, Depei; Qi, Chuang; Gao, Chan; Cai, Shangli; Gu, Fei; Hu, Yue; Xu, C.; Wang, Wenxian; Lou, Zhenkun; Zhang, Yong; Liu, Li

doi:10.1158/1078-0432.ccr-19-3976

Cited by 80 publications

(63 citation statements)

References 44 publications

(45 reference statements)

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“…Somatic frame shift mutations of common tumor suppressor genes (NOTCH1 and SMARC4) were frequently observed in HPV-negative anti-PD-1/PD-L1 responders [112]. Furthermore, a more recent study identified NOTCH1-3 LOF mutations as novel biomarkers predicting improved response to immune checkpoint inhibitor treatment in lung cancer patients [113]. Taken together, these studies suggest that NOTCH1 mutation may be an important biomarker to predict response to immune checkpoint inhibitors.…”

Section: Immunotherapymentioning

confidence: 92%

NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma

Shah

Huang

et al. 2020

Cells

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Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated in HNSCC. Clearer understanding of NOTCH1 signaling in HNSCCs is crucial to clinically targeting this pathway. Structural characterization of NOTCH1 mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1’s role as a tumor suppressor in this cancer. Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type NOTCH1 further supports a tumor suppressor function. Additionally, the loss of NOTCH1 signaling can drive HNSCC tumorigenesis and clinical aggressiveness. Our recent data suggest that NOTCH1 controls genes involved in early differentiation that could have different phenotypic consequences depending on the cancer’s genetic background, including acquisition of pseudo-stem cell-like properties. The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors. The latter is being tested in a clinical trial, and if validated, it may lead to the development of the first biomarker-driven targeted therapy for HNSCC.

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Section: Immunotherapymentioning

confidence: 92%

NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma

Shah

Huang

et al. 2020

Cells

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“…Targeting NOTCH1 may therefore affect cell proliferation and survival, and provide an immune-responsive tumor microenvironment, thus improving the efficacy of immunotherapy (56). Another study uncovered a marked association between mutations in NOTCH1/2/3 and improved outcomes in EGFR-and ALK-wild-type patients with NSCLC treated with immune checkpoint inhibitors (57). In addition, deleterious NOTCH mutations exhibited an improved effect compared with non-deleterious mutations (57).…”

Section: Discussionmentioning

confidence: 99%

“…Another study uncovered a marked association between mutations in NOTCH1/2/3 and improved outcomes in EGFR-and ALK-wild-type patients with NSCLC treated with immune checkpoint inhibitors (57). In addition, deleterious NOTCH mutations exhibited an improved effect compared with non-deleterious mutations (57). However, the underlying mechanism remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological and molecular characteristics of patients with hypermutant lung cancer: A retrospective cohort study

Zhang

Wang

et al. 2021

Oncol Lett

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Tumor mutation burden (TMB) is an independent indicator used to select patients sensitive to immunotherapy. The present study aimed to investigate the clinicopathological and molecular characteristics of patients with hypermutant lung cancer to identify an economical, simple and complementary method for predicting TMB and immunotherapy responses. In total, 1,000 patients with lung cancer were randomly selected, and their samples were submitted to next-generation sequencing, with their TMB status reviewed. The threshold of hypermutation was set to 17.24 mutations (muts)/Mb. The proportion of smokers was higher in the hypermutant cohort (n=67) compared with in the non-hypermutant cohort (n=933; 85.1 vs. 46.6%; P<0.0001). Compared with in the non-hypermutant cohort, the proportion of squamous cell carcinoma cases and small cell lung cancer cases was higher in the hypermutant cohort (22.4 vs. 13.1% and 6.0 vs. 2.6%, respectively). In addition, compared with in the non-hypermutant cohort, mutations in the low-density lipoprotein receptor-related protein 1B were more frequently observed in the hypermutant cohort (67.2 vs. 14.3%; P<0.0001). A similar trend was obtained for all genes tested, except for the EGFR gene. Furthermore, in the hypermutant cohort, the prevalence of microsatellite instability was extremely high (9.0%). The mutation frequency in DNA damage response (DDR) genes was notably higher in the hypermutant cohort, where several DDR-associated genes were enriched, compared with in the non-hypermutant cohort. The enrichment analysis revealed a strong association between mutations in Notch signaling and high TMB. To the best of our knowledge, the present study is the first to comprehensively investigate the clinical and genetic characteristics of patients with hypermutant lung cancer in a Chinese population. The results of the current study suggested that hypermutant lung cancer exerted distinctive clinical and genetic features, which may be used as complementary indicators for screening patients sensitive to immunotherapy.

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“…Speci c somatic mutations, such as TET1 mutation, NOTCH mutation as well as TP53 and KRAS comutation, have been proven to be the promising biomarkers for ICI response [7][8][9]. However, sex biases, often ignored in the in the eld of immunotherapy, might exist in the speci c genetic alterations.…”

Section: Introductionmentioning

confidence: 99%

The Association of Sex-biased ATRX Mutation in Female Gastric Cancer Patients With Enhanced Immunotherapy-related Anticancer Immunity  

Ge¹,

Fan

Du³

et al. 2020

Preprint

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Background: Genetic alterations have been proven to be the promising biomarkers for ICI response. However, sex biases in genetic alterations have been often ignored in the field of immunotherapy, which might specially influence the anticancer immunity and immunotherapy efficacy in male or female patients. Here, we have systematically evaluated the effect of the sex biases in somatic mutation of gastric cancer (GC) patients on the anticancer immunity and clinical benefit to immunotherapy. Methods: Genomic and transcriptomic data of gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). We also obtained the genomic and clinical data of a MSKCC ICI-treated cohort from cbioportal database. GC male and female-derived tumor somatic mutation profiles were compared by maftools R package. Single sample gene set enrichment analysis (ssGSEA) was conducted to calculate the score of the anticancer immunity indicators including IFN-γ signaling, cytolytic activity (CYT) and antigen presenting machinery (APM). Results: ATRX was found to mutate more frequently in female GC patients compared to male patients (FDR = 0.0108). Female GC patients with ATRX mutation manifested significantly more MSI-high subtypes, increased TMB and PDL1 expression as well as higher scores of IFN-γ signaling, CYT and APM. Gene set enrichment analysis (GSEA) has shown that ATRX mutation might enhance the immunogenicity and anticancer immunity through affecting DNA damage repair pathways. In the ICI-treated cohort from MSKCC, GC patients with ATRX mutation were associated with prolonged overall survival. When stratifying the entire ICI-treated cohort by sex, female patients with ATRX mutation obtained significantly better survival benefits than that of ATRX mutant male patients (Female patients, HR of ATRX MT vs WT = 0.636, 95%CI = 0.455-0.890, P = 0.023; Male patients, HR of ATRX MT vs WT = 0.929, 95%CI = 0.596-1.362, P = 0.712). Conclusions: ATRX mutation might serve as a potential predictive biomarker for favorable clinical benefit to ICI in female GC patients. ATRX mutation could be applied in combination with other biomarkers of ICI response to better identify the female GC patients who will derive greater benefits from ICI therapy.

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Identification of Deleterious NOTCH Mutation as Novel Predictor to Efficacious Immunotherapy in NSCLC

Cited by 80 publications

References 44 publications

NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma

NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma

Clinicopathological and molecular characteristics of patients with hypermutant lung cancer: A retrospective cohort study

The Association of Sex-biased ATRX Mutation in Female Gastric Cancer Patients With Enhanced Immunotherapy-related Anticancer Immunity

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Identification of Deleterious NOTCH Mutation as Novel Predictor to Efficacious Immunotherapy in NSCLC

Cited by 80 publications

References 44 publications

NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma

NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma

Clinicopathological and molecular characteristics of patients with hypermutant lung cancer: A retrospective cohort study

The Association of Sex-biased ATRX&nbsp;Mutation in Female Gastric Cancer Patients With Enhanced Immunotherapy-related Anticancer Immunity&nbsp;&nbsp;

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The Association of Sex-biased ATRX Mutation in Female Gastric Cancer Patients With Enhanced Immunotherapy-related Anticancer Immunity