Tumor mutation burden and recurrent tumors in hereditary lung cancer

Hsu, Yi Chiung; Chang, Gee Chen; Ho, Bing-Ching; Yuan, Shin Sheng; Li, Yu Cheng; Zeng, Jhih Wun; Yu, Sung-Liang; Li, Ker Chau; Yang, Pan Chyr; Chen, Hsuan Yu

doi:10.1002/cam4.2120

Cited by 19 publications

(13 citation statements)

References 46 publications

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“…After stratification of LUSC patients by smoking status, we observed no significant correlation between RAD18 expression or RAD18 CNV and mutational patterns in a tri-nucleotide setting (Figure 6H ; Supplementary Figures S5I, J and 6H ). We also confirmed previous indications that both LUAD and LUSC have prominent C→ A SNVs that are less abundant in non-smokers than smokers ( 53 ).…”

Section: Resultssupporting

confidence: 91%

Rad18 mediates specific mutational signatures and shapes the genomic landscape of carcinogen-induced tumorsin vivo

Lou

Yang

et al. 2021

NAR Cancer

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The E3 ubiquitin ligase Rad18 promotes a damage-tolerant and error-prone mode of DNA replication termed trans-lesion synthesis that is pathologically activated in cancer. However, the impact of vertebrate Rad18 on cancer genomes is not known. To determine how Rad18 affects mutagenesis in vivo, we have developed and implemented a novel computational pipeline to analyze genomes of carcinogen (7, 12-Dimethylbenz[a]anthracene, DMBA)-induced skin tumors from Rad18+/+ and Rad18−/− mice. We show that Rad18 mediates specific mutational signatures characterized by high levels of A(T)>T(A) single nucleotide variations (SNVs). In Rad18−/- tumors, an alternative mutation pattern arises, which is characterized by increased numbers of deletions >4 bp. Comparison with annotated human mutational signatures shows that COSMIC signature 22 predominates in Rad18+/+ tumors whereas Rad18−/− tumors are characterized by increased contribution of COSMIC signature 3 (a hallmark of BRCA-mutant tumors). Analysis of The Cancer Genome Atlas shows that RAD18 expression is strongly associated with high SNV burdens, suggesting RAD18 also promotes mutagenesis in human cancers. Taken together, our results show Rad18 promotes mutagenesis in vivo, modulates DNA repair pathway choice in neoplastic cells, and mediates specific mutational signatures that are present in human tumors.

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Section: Resultssupporting

confidence: 91%

Rad18 mediates specific mutational signatures and shapes the genomic landscape of carcinogen-induced tumorsin vivo

Lou

Yang

et al. 2021

NAR Cancer

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“…In specific cancer types and ethnic groups, the number of driver mutations is significantly positively correlated with cancer incidence rates ( 16 ). One lung cancer research identified that specific mutations could result in tumorigenesis or recurrence, and patients with a high burden of tumor-specific gene mutations had poor recurrence-free survival (RFS) ( 17 ). Another study showed that further validation and research on the elevated TMB and the potential impact of tumor-initiating mutations in clinically unfavorable prostate cancer could improve the outcomes of patients ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Tumor Mutation Burden Predicts Relapse in Papillary Thyroid Carcinoma With Changes in Genes and Immune Microenvironment

Guo

Chen

et al. 2021

Front. Endocrinol.

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BackgroundThe risk factors of papillary thyroid carcinoma (PTC) recurrence are meaningful for patients and clinicians. Tumor mutation burden (TMB) has been a biomarker for the effectiveness of immune checkpoint inhibitor (ICI) and prognosis in cancer. However, the role of TMB and its latent significance with immune cell infiltration in PTC are still unclear. Herein, we aimed to explore the effect of TMB on PTC prognosis.Material and MethodsRNA-seq and DNA-seq datasets of PTC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The Gene Ontology (GO) and gene set enrichment analysis (GSEA 4.0.1) were applied further to explore potential differences in PTC patients’ biological functions. The differentially expressed genes (DEGs) and immune microenvironment between the high and low TMB groups were determined.ResultsTMB had the highest AUC score than other clinical indicators in ROC analysis on recurrence-free survival, and a higher TMB score was related to a worse prognosis. Further, GSEA showed a higher level of oxidative phosphorylation (OXPHOS) in the high TMB group, and four genes correlated with recurrence-free survival rate were identified. The abundance of CD8+ T cells and M1 macrophages in the high TMB group was significantly lower than that in the low TMB group.ConclusionsOur study found that TMB was a better predictor variable at evaluating the risk of PTC recurrence. Moreover, TMB-related genes conferred dramatically correlated prognosis, which was worth exploring in guiding postoperative follow-up and predicting recurrence for PTC patients.

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“…The tumorigenesis of colon adenocarcinoma is commonly known as a multi-stage process, which involves a series of genetic changes interacting with the tumor microenvironment (TME) [14,15]. This study was conducted to analyze mutations in COAD samples from the TCGA dataset and ICGC dataset.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Biomarker MUC4 Mutations in Colon Adenocarcinoma Correlating with Tumor Microenvironment

Hui

Gao

2021

Preprint

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Background: Immunotherapy is a new strategy for Colorectal cancer (CRC) treatment. Tumor mutation burden (TMB) may act as an emerging biomarker for predicting responses to immunotherapy. Nevertheless, no studies investigate if these gene mutations correlate to TMB and tumor-infiltrating immune cells. Methods: Somatic mutation data for CRC samples were obtained from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) datasets. Then, we investigated the relationship between these mutant genes, TMB and overall survival outcomes. GSEA analysis was performed to explore the underlying mechanism of mutant gene. Finally, we further verified the connection between gene mutations and immune response.Results: We identified 17 common mutant genes shared by both two cohorts. Further analysis found that MUC4 mutation was strongly related to higher TMB and predicted a poorer prognosis. Moreover, functional enrichment analysis of samples with MUC4 mutation revealed that they were involved in regulating the natural killer cell mediated cytotoxicity signaling pathway. Significant changes in the proportion of the immune cells of CD8+ T cells, activated NK cells, M1 macrophages and resting memory CD4+ T cells were observed using the CIBERSORT algorithm. Conclusions: Our research revealed that MUC4 mutation significantly correlated with increased TMB, a worse prognosis and modulating the immune microenvironment, which may be considered a biomarker to predict the outcome of the immune response in colorectal cancer.

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Tumor mutation burden and recurrent tumors in hereditary lung cancer

Cited by 19 publications

References 46 publications

Rad18 mediates specific mutational signatures and shapes the genomic landscape of carcinogen-induced tumorsin vivo

Rad18 mediates specific mutational signatures and shapes the genomic landscape of carcinogen-induced tumorsin vivo

Tumor Mutation Burden Predicts Relapse in Papillary Thyroid Carcinoma With Changes in Genes and Immune Microenvironment

Prognostic Biomarker MUC4 Mutations in Colon Adenocarcinoma Correlating with Tumor Microenvironment

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