scholarly journals Abnormal Expressions of DNA Glycosylase Genes NEIL1, NEIL2, and NEIL3 Are Associated with Somatic Mutation Loads in Human Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Kazuya Shinmura ◽  
Hisami Kato ◽  
Yuichi Kawanishi ◽  
Hisaki Igarashi ◽  
Masanori Goto ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Human Cancer ◽  
Promoter Hypermethylation ◽  
The Cancer Genome Atlas ◽  
Expression Level ◽  
Dna Glycosylases ◽  
Potent Inducer ◽  
Nucleotide Mutation ◽  
Cancer Types ◽  
Using Data

The effects of abnormalities in the DNA glycosylases NEIL1, NEIL2, and NEIL3 on human cancer have not been fully elucidated. In this paper, we found that the median somatic total mutation loads and the median somatic single nucleotide mutation loads exhibited significant inverse correlations with the median NEIL1 and NEIL2 expression levels and a significant positive correlation with the median NEIL3 expression level using data for 13 cancer types from the Cancer Genome Atlas (TCGA) database. A subset of the cancer types exhibited reduced NEIL1 and NEIL2 expressions and elevated NEIL3 expression, and such abnormal expressions of NEIL1, NEIL2, and NEIL3 were also significantly associated with the mutation loads in cancer. As a mechanism underlying the reduced expression of NEIL1 in cancer, the epigenetic silencing ofNEIL1through promoter hypermethylation was found. Finally, we investigated the reason why an elevated NEIL3 expression level was associated with an increased number of somatic mutations in cancer and found that NEIL3 expression was positively correlated with the expression of APOBEC3B, a potent inducer of mutations, in diverse cancers. These results suggested that the abnormal expressions of NEIL1, NEIL2, and NEIL3 are involved in cancer through their association with the somatic mutation load.

scholarly journals Landscape of Microsatellite Instability Across 39 Cancer Types

2017 ◽  
pp. 1-15 ◽  
Author(s):  
Russell Bonneville ◽  
Melanie A. Krook ◽  
Esko A. Kautto ◽  
Jharna Miya ◽  
Michele R. Wing ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Human Cancer ◽  
The Cancer Genome Atlas ◽  
Repair System ◽  
Multiple Cancer ◽  
External Data ◽  
Mismatch Repair System ◽  
Cancer Types ◽  
Genomic Microsatellites

Purpose Microsatellite instability (MSI) is a pattern of hypermutation that occurs at genomic microsatellites and is caused by defects in the mismatch repair system. Mismatch repair deficiency that leads to MSI has been well described in several types of human cancer, most frequently in colorectal, endometrial, and gastric adenocarcinomas. MSI is known to be both predictive and prognostic, especially in colorectal cancer; however, current clinical guidelines only recommend MSI testing for colorectal and endometrial cancers. Therefore, less is known about the prevalence and extent of MSI among other types of cancer. Methods Using our recently published MSI-calling software, MANTIS, we analyzed whole-exome data from 11,139 tumor-normal pairs from The Cancer Genome Atlas and Therapeutically Applicable Research to Generate Effective Treatments projects and external data sources across 39 cancer types. Within a subset of these cancer types, we assessed mutation burden, mutational signatures, and somatic variants associated with MSI. Results We identified MSI in 3.8% of all cancers assessed—present in 27 of tumor types—most notably adrenocortical carcinoma (ACC), cervical cancer (CESC), and mesothelioma, in which MSI has not yet been well described. In addition, MSI-high ACC and CESC tumors were observed to have a higher average mutational burden than microsatellite-stable ACC and CESC tumors. Conclusion We provide evidence of as-yet-unappreciated MSI in several types of cancer. These findings support an expanded role for clinical MSI testing across multiple cancer types as patients with MSI-positive tumors are predicted to benefit from novel immunotherapies in clinical trials.

scholarly journals Identifying and characterizing lincRNA genomic clusters reveals its cooperative functions in human cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hanxiao Zhou ◽  
Yue Gao ◽  
Xin Li ◽  
Shipeng Shang ◽  
Peng Wang ◽  
...  
Keyword(s):  
Human Cancer ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Computational Method ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Pathophysiological Mechanism ◽  
Multiple Cancer ◽  
Cancer Types ◽  
Genomic Clusters

Abstract Background Emerging evidence has revealed that some long intergenic non-coding RNAs (lincRNAs) are likely to form clusters on the same chromosome, and lincRNA genomic clusters might play critical roles in the pathophysiological mechanism. However, the comprehensive investigation of lincRNA clustering is rarely studied, particularly the characterization of their functional significance across different cancer types. Methods In this study, we firstly constructed a computational method basing a sliding window approach for systematically identifying lincRNA genomic clusters. We then dissected these lincRNA genomic clusters to identify common characteristics in cooperative expression, conservation among divergent species, targeted miRNAs, and CNV frequency. Next, we performed comprehensive analyses in differentially-expressed patterns and overall survival outcomes for patients from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) across multiple cancer types. Finally, we explored the underlying mechanisms of lincRNA genomic clusters by functional enrichment analysis, pathway analysis, and drug-target interaction. Results We identified lincRNA genomic clusters according to the algorithm. Clustering lincRNAs tended to be co-expressed, highly conserved, targeted by more miRNAs, and with similar deletion and duplication frequency, suggesting that lincRNA genomic clusters may exert their effects by acting in combination. We further systematically explored conserved and cancer-specific lincRNA genomic clusters, indicating they were involved in some important mechanisms of disease occurrence through diverse approaches. Furthermore, lincRNA genomic clusters can serve as biomarkers with potential clinical significance and involve in specific pathological processes in the development of cancer. Moreover, a lincRNA genomic cluster named Cluster127 in DLK1-DIO3 imprinted locus was discovered, which contained MEG3, MEG8, MEG9, MIR381HG, LINC02285, AL132709.5, and AL132709.1. Further analysis indicated that Cluster127 may have the potential for predicting prognosis in cancer and could play their roles by participating in the regulation of PI3K-AKT signaling pathway. Conclusions Clarification of the lincRNA genomic clusters specific roles in human cancers could be beneficial for understanding the molecular pathogenesis of different cancer types.

scholarly journals Epigenetic silencing of lncRNA MORT in 16 TCGA cancer types

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 211 ◽  
Author(s):  
Lukas Vrba ◽  
Bernard W. Futscher
Keyword(s):  
Dna Methylation ◽  
Mammary Epithelial Cells ◽  
Human Cancer ◽  
Large Fraction ◽  
Cell Types ◽  
Mammary Epithelial ◽  
The Cancer Genome Atlas ◽  
Human Mammary Epithelial ◽  
Cancer Types

We have previously described a hominid-specific long non-coding RNA, MORT (also known as ZNF667-AS1, Gene ID: 100128252), which is expressed in all normal cell types, but epigenetically silenced during cancer-associated immortalization of human mammary epithelial cells.  Initial analysis of The Cancer Genome Atlas (TCGA) showed that 15 of 17 cancer types, which represent the 10 most common cancers in women and men, display DNA methylation associated MORT silencing in a large fraction of their tumors.  In this study we analyzed MORT expression and DNA methylation state in the remaining 16 TCGA cancer types not previously reported.  Seven of the 16 cancer types showed DNA methylation linked MORT silencing in a large fraction of their tumors.  These are carcinomas (cervical cancer, and cancers of esophagus, stomach, and bile duct), and the non-epithelial tumors mesothelioma, sarcoma, and uterine carcinosarcoma.  Together with the findings from our previous report, MORT expression is silenced by aberrant DNA methylation in 22 of 33 of TCGA cancer types.  These 22 cancers include most carcinoma types, blood derived cancers and sarcomas.  In conclusion, results suggest that the MORT gene is one of the most common epigenetic aberrations seen in human cancer.  Coupled with the timing of MORT gene silencing during in vitro epithelial cell immortalization and its occurrence early in the temporal arc of human carcinogenesis, this provides strong circumstantial evidence for a tumor suppressor role for MORT.

scholarly journals RNF125 Modulates Tumor Immunity by Promoting Ubiquitination of PD-L1

2021 ◽  
Author(s):  
Yumeng Peng ◽  
Huan Yang ◽  
Zihui Li ◽  
Huilong Li ◽  
Xiaolin Qiu ◽  
...  
Keyword(s):  
Tumor Immunity ◽  
Human Cancer ◽  
Ring Finger ◽  
Ring Domain ◽  
The Cancer Genome Atlas ◽  
Comprehensive Treatment ◽  
Cancer Genome Atlas ◽  
Using Data ◽  
The Stability ◽  
L1 Protein

Abstract In recent years, the incidence of tumors has been increasing, and the overall cure rate by traditional treatment methods does not exceed 20%. One of the most effective and promising strategies for comprehensive treatment of tumors is immunotherapy, such as treatment with the PD-1/PD-L1 antibody. Here, we showed that ring finger protein 125 (RNF125), an E3 ligase in the RING domain family, could interact with PD-L1 to reduce the stability of PD-L1 protein. In addition, RNF125 downregulated the expression of PD-L1 by promoting its ubiquitination at K48, whereas a mutation in the RING domain of RNF125 disrupted this function. A significant positive correlation between RNF125 and genes involved with tumor immunity was determined in cancer samples, as determined using data from The Cancer Genome Atlas (TCGA). Furthermore, we elucidated the effects of RNF125 on the occurrence and development of tumors in mice. Analyses of wild-type and RNF125 knockout mice transplanted with MC-38 cells revealed enhanced MC-38 tumor growth in KO mice. These data indicated that RNF125 could participate in tumor immunity by promoting the K48-linked ubiquitination of PD-L1 to affect the occurrence and development of tumors, providing a potential target for enhancing therapeutic efficacy for human cancer treatment.

scholarly journals Prognostic power of molecular and clinical data across cancer types

2020 ◽  
Author(s):  
Xinsen Xu ◽  
Wei Wang ◽  
Min He ◽  
Linhua Yang ◽  
Wei Chen ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Clinical Data ◽  
Clinical Decision Making ◽  
Human Cancer ◽  
Clinical Decision ◽  
Molecular Data ◽  
The Cancer Genome Atlas ◽  
Low Grade ◽  
Cancer Types ◽  
Prognostic Power

Abstract Background Precision medicine holds promise in prognostication of human cancer. By analyzing the Cancer Genome Atlas (TCGA) data, we evaluated the prognostic power of molecular and clinical data across 33 cancer types.Methods The clinical and molecular data of more than 11,000 patients were obtained from the TCGA database. Top features associated with overall survival were identified. Concordance index of each data type was calculated to investigate the prognostic power. The performance differences among clinical data, molecular data and combination data (integration of molecular data with clinical data) were evaluated.Results The prognostic power of combination data was significantly higher than the molecular data in 108 of 163 comparisons. However, it was only significantly higher than the clinical data in 27 of 163 comparisons. The clinical data seemed to be the most informative prognostic variable in almost half cancer types (14/33). Deeper insights into the low grade glioma models showed that integration of clinical data with molecular data yielded better prognostic modelling than either data used alone. From the pan-cancer level, the combination data was shown to be the most informative prognostic predictor when the sample size was large. In addition, mutation data also showed significant prognostic value.Conclusions Molecular markers complement the traditional diagnostic approaches in the pursuit of precision medicine. The combination of reliable clinical data, multidimensional genomic measurements and mature bioinformatics algorithms may confer more robust prognostic value that will inform clinical decision making.

scholarly journals Comprehensive Characterization of Integrin Subunit Genes in Human Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Kaisa Cui ◽  
Xiaohan Wu ◽  
Liang Gong ◽  
Surui Yao ◽  
Shengbai Sun ◽  
...  
Keyword(s):  
Human Cancer ◽  
Gene Expression Omnibus ◽  
Tnm Staging ◽  
The Cancer Genome Atlas ◽  
Cancer Type ◽  
Integrin Subunit ◽  
Dna Hypomethylation ◽  
Systematic Assessment ◽  
Human Cancers ◽  
Cancer Types

Although integrin subunit genes (ITGs) have been reported to be associated with some human cancer types, a systematic assessment of ITGs across human cancers is lacking. Hence, we performed comprehensive analyses to investigate mRNA expression, copy number variation (CNV), DNA methylation, mutation, and clinical landscapes of ITGs in more than 8000 cancer patients from The Cancer Genome Atlas (TCGA) dataset. Landscapes of ITGs were established across 20 human cancer types. We observed that ITGs are extensively dysregulated with heterogeneity in different system cancer types, part of which are driven by CNV, DNA hypomethylation or mutation. Furthermore, dysregulated prognosis-related ITGs were systematically identified in each cancer type, including ITGA11 in stomach adenocarcinoma (STAD). The models based on dysregulated ITGs with clinical relevance and TNM staging indexes are good indicators in STAD and head and neck squamous cell carcinoma. Finally, ITGA11 is overexpressed and associated with poor survival in STAD cases from the TCGA and additionally Gene Expression Omnibus cohorts. Functionally, ITGA11 knockdown inhibits malignant phenotypes in STAD cell lines AGS and MKN45, demonstrating the oncogenic role of ITGA11 in STAD. Together, this study highlights the important roles of ITGs in tumorigenesis as potential prognostic biomarkers, and provide an effective resource that identifies cancer-related genes of ITGs in human cancers.

scholarly journals Comprehensive characterization and clinical relevance of the SWI/SNF copy number aberrations across human cancers

Hereditas ◽  
2021 ◽  
Vol 158 (1) ◽  
Author(s):  
Zhiwei Xing ◽  
Buhuan Ma ◽  
Weiting Sun ◽  
Yimin Sun ◽  
Caixia Liu
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Therapy Resistance ◽  
The Cancer Genome Atlas ◽  
Dna Damage And Repair ◽  
Human Cancers ◽  
Oncogenic Pathways ◽  
Cancer Types ◽  
Tcga Dataset ◽  
The Impact

Abstract Background Alterations in genes encoding chromatin regulatory proteins are prevalent in cancers and may confer oncogenic properties and molecular changes linked to therapy resistance. However, the impact of copy number alterations (CNAs) of the SWItch/Sucrose NonFermentable (SWI/SNF) complex on the oncogenic and immunologic properties has not been systematically explored across human cancer types. Methods We comprehensively analyzed the genomic, transcriptomic and clinical data of The Cancer Genome Atlas (TCGA) dataset across 33 solid cancers. Results CNAs of the SWI/SNF components were identified in more than 25% of all queried cancers, and tumors harboring SWI/SNF CNAs demonstrated a worse overall survival (OS) than others in several cancer types. Mechanistically, the SCNA events in the SWI/SNF complex are correlated with dysregulated genomic features and oncogenic pathways, including the cell cycle, DNA damage and repair. Notably, the SWI/SNF CNAs were associated with homologous recombination deficiency (HRD) and improved clinical outcomes of platinum-treated ovarian cancer. Furthermore, we observed distinct immune infiltrating patterns and immunophenotypes associated with SWI/SNF CNAs in different cancer types. Conclusion The CNA events of the SWI/SNF components are a key process linked to oncogenesis, immune infiltration and therapeutic responsiveness across human cancers.

scholarly journals A network-based drug repositioning infrastructure for precision cancer medicine through targeting significantly mutated genes in the human cancer genomes

2016 ◽  
Vol 23 (4) ◽  
pp. 681-691 ◽  
Author(s):  
Feixiong Cheng ◽  
Junfei Zhao ◽  
Michaela Fooksa ◽  
Zhongming Zhao
Keyword(s):  
Drug Repositioning ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
The Cancer Genome Atlas ◽  
Sequencing Data ◽  
Underlying Assumption ◽  
Cancer Genomes ◽  
Cancer Types ◽  
Druggable Targets ◽  
Integrative Network

Abstract Objective Development of computational approaches and tools to effectively integrate multidomain data is urgently needed for the development of newly targeted cancer therapeutics. Methods We proposed an integrative network-based infrastructure to identify new druggable targets and anticancer indications for existing drugs through targeting significantly mutated genes (SMGs) discovered in the human cancer genomes. The underlying assumption is that a drug would have a high potential for anticancer indication if its up-/down-regulated genes from the Connectivity Map tended to be SMGs or their neighbors in the human protein interaction network. Results We assembled and curated 693 SMGs in 29 cancer types and found 121 proteins currently targeted by known anticancer or noncancer (repurposed) drugs. We found that the approved or experimental cancer drugs could potentially target these SMGs in 33.3% of the mutated cancer samples, and this number increased to 68.0% by drug repositioning through surveying exome-sequencing data in approximately 5000 normal-tumor pairs from The Cancer Genome Atlas. Furthermore, we identified 284 potential new indications connecting 28 cancer types and 48 existing drugs (adjusted P < .05), with a 66.7% success rate validated by literature data. Several existing drugs (e.g., niclosamide, valproic acid, captopril, and resveratrol) were predicted to have potential indications for multiple cancer types. Finally, we used integrative analysis to showcase a potential mechanism-of-action for resveratrol in breast and lung cancer treatment whereby it targets several SMGs (ARNTL, ASPM, CTTN, EIF4G1, FOXP1, and STIP1). Conclusions In summary, we demonstrated that our integrative network-based infrastructure is a promising strategy to identify potential druggable targets and uncover new indications for existing drugs to speed up molecularly targeted cancer therapeutics.

scholarly journals Integrative genomic analyses of APOBEC-mutational signature, expression and germline deletion of APOBEC3 genes, and immunogenicity in multiple cancer types

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhishan Chen ◽  
Wanqing Wen ◽  
Jiandong Bao ◽  
Krystle L. Kuhs ◽  
Qiuyin Cai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Cell ◽  
Expression Level ◽  
Multiple Cancer ◽  
Association Analyses ◽  
Mutational Signature ◽  
Immunological Mechanisms ◽  
Cancer Types ◽  
Using Data ◽  
Relationship Of

Abstract Background Although APOBEC-mutational signature is found in tumor tissues of multiple cancers, how a common germline APOBEC3A/B deletion affects the mutational signature remains unclear. Methods Using data from 10 cancer types generated as part of TCGA, we performed integrative genomic and association analyses to assess inter-relationship of expressions for isoforms APOBEC3A and APOBEC3B, APOBEC-mutational signature, germline APOBEC3A/B deletions, neoantigen loads, and tumor infiltration lymphocytes (TILs). Results We found that expression level of the isoform uc011aoc transcribed from the APOBEC3A/B chimera was associated with a greater burden of APOBEC-mutational signature only in breast cancer, while germline APOBEC3A/B deletion led to an increased expression level of uc011aoc in multiple cancer types. Furthermore, we found that the deletion was associated with elevated APOBEC-mutational signature, neoantigen loads and relative composition of T cells (CD8+) in TILs only in breast cancer. Additionally, we also found that APOBEC-mutational signature significantly contributed to neoantigen loads and certain immune cell abundances in TILs across cancer types. Conclusions These findings reveal new insights into understanding the genetic, biological and immunological mechanisms through which APOBEC genes may be involved in carcinogenesis, and provide potential genetic biomarker for the development of disease prevention and cancer immunotherapy.

scholarly journals Pan-Cancer Analysis Reveals Distinct Metabolic Reprogramming in Different Epithelial–Mesenchymal Transition Activity States

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1778
Author(s):  
Ji-Yong Sung ◽  
Jae-Ho Cheong
Keyword(s):  
Energy Metabolism ◽  
Epithelial Mesenchymal Transition ◽  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas ◽  
Cancer Type ◽  
Mesenchymal Transition ◽  
Significant Difference ◽  
Cancer Types ◽  
Using Data ◽  
Patient Prognosis

Epithelial–mesenchymal transition (EMT) is critical for cancer development, invasion, and metastasis. Its activity influences metabolic reprogramming, tumor aggressiveness, and patient survival. Abnormal tumor metabolism has been identified as a cancer hallmark and is considered a potential therapeutic target. We profiled distinct metabolic signatures by EMT activity using data from 9452 transcriptomes across 31 different cancer types from The Cancer Genome Atlas. Our results demonstrated that ~80 to 90% of cancer types had high carbohydrate and energy metabolism, which were associated with the high EMT group. Notably, among the distinct EMT activities, metabolic reprogramming in different immune microenvironments was correlated with patient prognosis. Nine cancer types showed a significant difference in survival with the presence of high EMT activity. Stomach cancer showed elevated energy metabolism and was associated with an unfavorable prognosis (p < 0.0068) coupled with high expression of CHST14, indicating that it may serve as a potential drug target. Our analyses highlight the prevalence of cancer type-dependent EMT and metabolic reprogramming activities and identified metabolism-associated genes that may serve as potential therapeutic targets.

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