scholarly journals A Potential Biomarker of Combination of Tumor Mutation Burden and Copy Number Alteration for Efficacy of Immunotherapy in KRAS-Mutant Advanced Lung Adenocarcinoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Luochengling Xiang ◽  
Xiao Fu ◽  
Xiao Wang ◽  
Wenyuan Li ◽  
Xiaoqiang Zheng ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Copy Number Alteration ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Potential Biomarker

scholarly journals Identification of Tumor Mutation Burden, Microsatellite Instability, and Somatic Copy Number Alteration derived 9-gene Signatures to Predict Clinical Outcomes in STAD

2021 ◽  
Author(s):  
Chuanzhi Chen ◽  
Yi Chen ◽  
Xin Jin ◽  
Yongfeng Ding ◽  
Junjie Jiang ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Copy Number ◽  
Copy Number Alteration ◽  
External Validation ◽  
The Cancer Genome Atlas ◽  
Roc Curve Analysis ◽  
Predictive Tool ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Somatic Copy Number Alteration

Abstract Background: Genomic features including tumor mutation burden (TMB), microsatellite instability (MSI) and somatic copy number alteration (SCNA), had been demonstrated to be involved with the tumor microenvironment (TME) and outcome of gastric cancer (GC). Methods: We obtained profiles of TMB, MSI and SCNA by processing 405 GC data from The Cancer Genome Atlas (TCGA), then conducted a comprehensive analysis though “iClusterPlus”. Another independent Gene Expression Omnibus (GEO) contained specimens from 109 GC patients was designed as an external validation. Results: Two subgroups were generated, with distinguished prognosis, somatic mutation burden, copy number changes and immune landscape. We revealed that Cluster1 was marked by a better prognosis, accompanied by higher TMB, MSIsensor score, TMEscore, and lower SCNA burden. Based on these clusters, we screened 196 differentially expressed genes (DEGs), which were subsequently projected into univariate Cox survival analysis. Thus, we constructed a 9-gene immune risk score (IRS) model using lasso penalized logistic regression. Moreover, the prognostic prediction of IRS was verified by receiver operating characteristic (ROC) curve analysis and nomogram plot.Conclusions: Our works suggested that the 9‐gene‐signature prediction model, which derived from TMB, MSI, SCNA was a promising predictive tool for clinical outcome in GC patients. This novel methodology may help clinicians uncover the underlying mechanisms and guide future treatment strategies.

scholarly journals Molecular Subtyping and Prognostic Assessment Based on Tumor Mutation Burden in Patients with Lung Adenocarcinomas

2019 ◽  
Vol 20 (17) ◽  
pp. 4251 ◽  
Author(s):  
Changzheng Wang ◽  
Han Liang ◽  
Cong Lin ◽  
Fuqiang Li ◽  
Guoyun Xie ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Disease Free Survival ◽  
Sequencing Data ◽  
Mutational Signatures ◽  
Driver Genes ◽  
Molecular Subtyping ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Potential Biomarker ◽  
Lung Adenocarcinomas

The distinct molecular subtypes of lung cancer are defined by monogenic biomarkers, such as EGFR, KRAS, and ALK rearrangement. Tumor mutation burden (TMB) is a potential biomarker for response to immunotherapy, which is one of the measures for genomic instability. The molecular subtyping based on TMB has not been well characterized in lung adenocarcinomas in the Chinese population. Here we performed molecular subtyping based on TMB with the published whole exome sequencing data of 101 lung adenocarcinomas and compared the different features of the classified subtypes, including clinical features, somatic driver genes, and mutational signatures. We found that patients with lower TMB have a longer disease-free survival, and higher TMB is associated with smoking and aging. Analysis of somatic driver genes and mutational signatures demonstrates a significant association between somatic RYR2 mutations and the subtype with higher TMB. Molecular subtyping based on TMB is a potential prognostic marker for lung adenocarcinoma. Signature 4 and the mutation of RYR2 are highlighted in the TMB-High group. The mutation of RYR2 is a significant biomarker associated with high TMB in lung adenocarcinoma.

scholarly journals Paired analysis of tumor mutation burden for lung adenocarcinoma and associated idiopathic pulmonary fibrosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yasuto Yoneshima ◽  
Eiji Iwama ◽  
Shingo Matsumoto ◽  
Taichi Matsubara ◽  
Testuzo Tagawa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Adenocarcinoma ◽  
Genetic Alterations ◽  
Driver Mutations ◽  
Somatic Variant ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
And Oxidative Stress

AbstractGenetic alterations underlying the development of lung cancer in individuals with idiopathic pulmonary fibrosis (IPF) have remained unclear. To explore whether genetic alterations in IPF tissue contribute to the development of IPF-associated lung cancer, we here evaluated tumor mutation burden (TMB) and somatic variants in 14 paired IPF and tumor samples from patients with IPF-associated lung adenocarcinoma. We also determined TMB for 22 samples of lung adenocarcinoma from patients without IPF. TMB for IPF-associated lung adenocarcinoma was significantly higher than that for matched IPF tissue (median of 2.94 vs. 1.26 mutations/Mb, P = 0.002). Three and 102 somatic variants were detected in IPF and matched lung adenocarcinoma samples, respectively, with only one pair of specimens sharing one somatic variant. TMB for IPF-associated lung adenocarcinoma was similar to that for lung adenocarcinoma samples with driver mutations (median of 2.94 vs. 2.51 mutations/Mb) and lower than that for lung adenocarcinoma samples without known driver mutations (median of 2.94 vs. 5.03 mutations/Mb, P = 0.130) from patients without IPF. Our findings suggest that not only the accumulation of somatic mutations but other factors such as inflammation and oxidative stress might contribute to the development and progression of lung cancer in patients with IPF.

Exploration of Tumor Mutation Burden Combined with Immune Infiltrates in the Prognosis of Lung Adenocarcinoma

2021 ◽  
Author(s):  
Zhenyu Zhao ◽  
Boxue He ◽  
Qidong Cai ◽  
Pengfei Zhang ◽  
Xiong Peng ◽  
...  
Keyword(s):  
High Risk ◽  
Lung Adenocarcinoma ◽  
Clinical Application ◽  
Risk Group ◽  
High Risk Group ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Immune Signature ◽  
Immune Infiltration ◽  
Mutation Burden

Abstract Background: Lung adenocarcinoma (LUAD) accounts for a majority of cancer-related deaths worldwide annually. A recent study shows that immunotherapy is an effective method of LUAD treatment, and tumor mutation burden (TMB) was associated with the immune microenvironment and affected the immunotherapy. Exploration of the gene signature associated with tumor mutation burden and immune infiltrates in predicting prognosis in lung adenocarcinoma in this study, we explored the correlation of TMB with immune infiltration and prognosis in LUAD.Materials and Methods: In this study, we firstly got mutation data and LUAD RNA-Seq data of the LUAD from The Cancer Genome Atlas (TCGA), and according to the TMB we divided the patients into high/low-TMB levels groups. The gene ontology (GO) pathway enrichment analysis and KOBAS-Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis were utilized to explore the molecular function of the differentially expressed genes (DEGs) between the two groups. The function enrichment analyses of DEGs were related to the immune pathways. Then, the ESTIMATE algorithm, CIBERSORT, and ssGSEA analysis were utilized to identify the relationship between TMB subgroups and immune infiltration. According to the results, Venn analysis was utilized to select the immune-related genes in DEGs. Univariate and Lasso Cox proportional hazards regression analyses were performed to construct the signature which positively associated with the immune infiltration and affected the survival. Finally, we verified the correlation between the signature and immune infiltration. Result: The exploration of the immune infiltration suggested that high-TMB subgroups positively associated with the high level of immune infiltration in LUAD patients. According to the TMB-related immune signature, the patients were divided into High/Low-risk groups, and the high-risk group was positively associated with poor prognostic. The results of the PCA analysis confirmed the validity of the signature. We also verified the effectiveness of the signature in GSE30219 and GSE72094 datasets. The ROC curves and C-index suggested the good clinical application of the TMB-related immune signature in LUAD prognosis. Another result suggested that the patients of the high-risk group were positively associated with higher TMB levels, PD-L1expression, and immune infiltration levels.Conclusion: In conclusion, our signature provides potential biomarkers for studying aspects of the TMB in LUAD such as TMB affected immune microenvironment and prognosis. This signature may provide some biomarkers which could improve the biomarkers of PD-L1 immunotherapy response and were inverted for the clinical application of the TMB in LUAD. LUAD male patients with higher TMB-levels and risk scores may benefit from immunotherapy. The high-risk patients along with higher PD-L1 expression of the signature may suitable for immunotherapy and improve their survival by detecting the TMB of LUAD.

scholarly journals The prognostic value of tumor mutation burden in EGFR-mutant advanced lung adenocarcinoma, an analysis based on cBioPortal data base

2019 ◽  
Vol 11 (11) ◽  
pp. 4507-4515 ◽  
Author(s):  
Xiao-Dong Jiao ◽  
Xi He ◽  
Bao-Dong Qin ◽  
Ke Liu ◽  
Ying Wu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Data Base ◽  
Prognostic Value ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Egfr Mutant

Common driver mutations and smoking history affect tumor mutation burden in lung adenocarcinoma

2018 ◽  
Vol 230 ◽  
pp. 181-185 ◽  
Author(s):  
Masayuki Nagahashi ◽  
Seijiro Sato ◽  
Kizuki Yuza ◽  
Yoshifumi Shimada ◽  
Hiroshi Ichikawa ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Smoking History ◽  
Driver Mutations ◽  
Tumor Mutation Burden ◽  
Mutation Burden

Characterization of genomic alterations as biomarkers of immune checkpoint inhibitor (ICI) response in metastatic urothelial carcinoma (mUC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 400-400
Author(s):  
Matthew Labriola ◽  
Jason Zhu ◽  
Rajan Gupta ◽  
Shannon McCall ◽  
Jennifer Jackson ◽  
...  
Keyword(s):  
Clinical Information ◽  
Personal Genome ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Potential Biomarker ◽  
Wide Range ◽  
Metastatic Urothelial Carcinoma ◽  
Underlying Mechanisms ◽  
Fgfr3 Mutations

400 Background: ICIs have expanded therapeutic options for mUC patients (pts); however, biomarkers such as PD-L1 have not served as reliable predictors of treatment efficacy. High tumor mutation burden (TMB) has been previously described as a potential biomarker for predicting ICI response in several indications, but its utility is still being explored in mUC. Here, we compare the genomic landscapes and clinical outcomes of mUC pts following ICI therapy using an investigational solid tissue-based next-generation sequencing assay to assess TMB and identify genetic correlates of ICI response. Methods: 20 pts with mUC treated with ICIs at Duke Cancer Institute were identified. Tumor samples were retrospectively evaluated with a Personal Genome Diagnostics Assay for somatic variants across > 500 genes, as well as TMB and microsatellite status. Tumor samples were also stained for PD-L1 status using the Dako 22C3 IHC assay. Deidentified clinical information was extracted from the medical record and tumor response was evaluated using RECIST 1.1 criteria. Results: Pts were grouped by overall response following ICI therapy as either responders (“R”, n = 6) or non-responders (“NR”, n = 13). Pts exhibited a wide range of TMB scores (0.7 to 30.4 mutations/Mb), with a mean TMB score of 9.60 vs. 3.87 mut/Mb in R vs NR groups, respectively; however, this difference was not statistically significant ( p = 0.284). 18 pts were evaluated for PD-L1 status, with only 2 positive samples (one in each group). Rs had significantly more mutations in histone methylation genes (KDM6A, KMT2C, and KMT2D), (67% vs 15% in NRs, p = 0.0039). FGFR3 mutations were also more frequent in R vs NR (67% vs 5%, p = 0.0339). Finally, there was a higher frequency of mutations in TP53 and BRCA1 in the NRs. Conclusions: In this mUC cohort, neither TMB nor PD-L1 correlated with response to ICI therapy. Histone modifying genes and FGFR3 mutations were more frequent in responders, whereas BRCA1 and TP53 mutations were enriched in non-responders, warranting future prospective studies to understand underlying mechanisms of ICI response and resistance in mUC.

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