scholarly journals Inferring Homologous Recombination Deficiency of Ovarian Cancer From the Landscape of Copy Number Variation at Subchromosomal and Genetic Resolutions

2021 ◽  
Vol 11 ◽  
Author(s):  
Meng Zhang ◽  
Si-Cong Ma ◽  
Jia-Le Tan ◽  
Jian Wang ◽  
Xue Bai ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Copy Number Variation ◽  
Copy Number ◽  
The Cancer Genome Atlas ◽  
Homologous Recombination Deficiency ◽  
Number Variation ◽  
Cancer Genome Atlas ◽  
Tumor Types ◽  
Pan Cancer

BackgroundHomologous recombination deficiency (HRD) is characterized by overall genomic instability and has emerged as an indispensable therapeutic target across various tumor types, particularly in ovarian cancer (OV). Unfortunately, current detection assays are far from perfect for identifying every HRD patient. The purpose of this study was to infer HRD from the landscape of copy number variation (CNV).MethodsGenome-wide CNV landscape was measured in OV patients from the Australian Ovarian Cancer Study (AOCS) clinical cohort and >10,000 patients across 33 tumor types from The Cancer Genome Atlas (TCGA). HRD-predictive CNVs at subchromosomal resolution were identified through exploratory analysis depicting the CNV landscape of HRD versus non-HRD OV patients and independently validated using TCGA and AOCS cohorts. Gene-level CNVs were further analyzed to explore their potential predictive significance for HRD across tumor types at genetic resolution.ResultsAt subchromosomal resolution, 8q24.2 amplification and 5q13.2 deletion were predominantly witnessed in HRD patients (both p < 0.0001), whereas 19q12 amplification occurred mainly in non-HRD patients (p < 0.0001), compared with their corresponding counterparts within TCGA-OV. The predictive significance of 8q24.2 amplification (p < 0.0001), 5q13.2 deletion (p = 0.0056), and 19q12 amplification (p = 0.0034) was externally validated within AOCS. Remarkably, pan-cancer analysis confirmed a cross-tumor predictive role of 8q24.2 amplification for HRD (p < 0.0001). Further analysis of CNV in 8q24.2 at genetic resolution revealed that amplifications of the oncogenes, MYC (p = 0.0001) and NDRG1 (p = 0.0004), located on this fragment were also associated with HRD in a pan-cancer manner.ConclusionsThe CNV landscape serves as a generalized predictor of HRD in cancer patients not limited to OV. The detection of CNV at subchromosomal or genetic resolution could aid in the personalized treatment of HRD patients.

Analysis of TGCA data reveals genetic and epigenetic changes and biological function of MUC family genes in colorectal cancer

2019 ◽  
Vol 15 (35) ◽  
pp. 4031-4043 ◽  
Author(s):  
Zhipeng Jiang ◽  
Huashe Wang ◽  
Liang Li ◽  
Zehui Hou ◽  
Wei Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Copy Number Variation ◽  
Copy Number ◽  
Regulatory Networks ◽  
The Cancer Genome Atlas ◽  
Epigenetic Changes ◽  
Copy Number Variation Analysis ◽  
Number Variation ◽  
Cancer Genome Atlas ◽  
Drug Influence

Aim: Few studies focused on functions and regulatory networks of MUC family members in colorectal cancer based on comprehensive analysis of online database. Materials & methods: Copy number variation, methylation, pathway analysis and drug influence on MUC expression were analyzed based on The Cancer Genome Atlas and GTEx database. Results: Copy number variation analysis showed MUC heterozygous amplification and heterozygous deletion predominate. Methylation of MUC17, MUC12 and MUC4 were found related to gene expression. Function of MUC family genes mainly affects pathways such as apoptosis, cell cycle, DNA damage and EMT pathways. PLX4720, dabrafenib, gefitinib, afatinib and austocystin D can alter the expression of MUC gene. Conclusion: The genetic and epigenetic changes of MUC are related to the level of MUC expression in colorectal cancer.

scholarly journals Mitochondrial DNA copy number variation across human cancers

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ed Reznik ◽  
Martin L Miller ◽  
Yasin Şenbabaoğlu ◽  
Nadeem Riaz ◽  
Judy Sarungbam ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Copy Number Variation ◽  
Copy Number ◽  
The Cancer Genome Atlas ◽  
Mtdna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Number Variation ◽  
Somatic Alterations ◽  
Immunohistochemical Evidence ◽  
Tumor Types

Mutations, deletions, and changes in copy number of mitochondrial DNA (mtDNA), are observed throughout cancers. Here, we survey mtDNA copy number variation across 22 tumor types profiled by The Cancer Genome Atlas project. We observe a tendency for some cancers, especially of the bladder, breast, and kidney, to be depleted of mtDNA, relative to matched normal tissue. Analysis of genetic context reveals an association between incidence of several somatic alterations, including IDH1 mutations in gliomas, and mtDNA content. In some but not all cancer types, mtDNA content is correlated with the expression of respiratory genes, and anti-correlated to the expression of immune response and cell-cycle genes. In tandem with immunohistochemical evidence, we find that some tumors may compensate for mtDNA depletion to sustain levels of respiratory proteins. Our results highlight the extent of mtDNA copy number variation in tumors and point to related therapeutic opportunities.

scholarly journals The Gasdermin E gene Potential as a Pan-Cancer Biomarker, While Discriminating between Different Tumor Types

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1810 ◽  
Author(s):  
Joe Ibrahim ◽  
Ken Op de Beeck ◽  
Erik Fransen ◽  
Marc Peeters ◽  
Guy Van Camp
Keyword(s):  
The Cancer Genome Atlas ◽  
Tumor Type ◽  
E Gene ◽  
Normal Tissues ◽  
Incidence And Mortality ◽  
Cancer Genome Atlas ◽  
Cancer Setting ◽  
Tumor Types ◽  
Methylation Patterns ◽  
Pan Cancer

Due to the elevated rates of incidence and mortality of cancer, early and accurate detection is crucial for achieving optimal treatment. Molecular biomarkers remain important screening and detection tools, especially in light of novel blood-based assays. DNA methylation in cancer has been linked to tumorigenesis, but its value as a biomarker has not been fully explored. In this study, we have investigated the methylation patterns of the Gasdermin E gene across 14 different tumor types using The Cancer Genome Atlas (TCGA) methylation data (N = 6502). We were able to identify six CpG sites that could effectively distinguish tumors from normal samples in a pan-cancer setting (AUC = 0.86). This combination of pan-cancer biomarkers was validated in six independent datasets (AUC = 0.84–0.97). Moreover, we tested 74,613 different combinations of six CpG probes, where we identified tumor-specific signatures that could differentiate one tumor type versus all the others (AUC = 0.79–0.98). In all, methylation patterns exhibited great variation between cancer and normal tissues, but were also tumor specific. Our analyses highlight that a Gasdermin E methylation biomarker assay, not only has the potential for being a methylation-specific pan-cancer detection marker, but it also possesses the capacity to discriminate between different types of tumors.

scholarly journals Duplication of chickendefensin7gene generated by gene conversion and homologous recombination

2016 ◽  
Vol 113 (48) ◽  
pp. 13815-13820 ◽  
Author(s):  
Mi Ok Lee ◽  
Susanne Bornelöv ◽  
Leif Andersson ◽  
Susan J. Lamont ◽  
Junfeng Chen ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Copy Number Variation ◽  
Gene Conversion ◽  
Copy Number ◽  
Computational Prediction ◽  
Gene Families ◽  
Duplication Event ◽  
Promoter Regions ◽  
Large Gene ◽  
Number Variation

Defensins constitute an evolutionary conserved family of cationic antimicrobial peptides that play a key role in host innate immune responses to infection. Defensin genes generally reside in complex genomic regions that are prone to structural variation, and defensin genes exhibit extensive copy number variation in humans and in other species. Copy number variation of defensin genes was examined in inbred lines of Leghorn and Fayoumi chickens, and a duplication ofdefensin7was discovered in the Fayoumi breed. Analysis of junction sequences confirmed the occurrence of a simple tandem duplication ofdefensin7with sequence identity at the junction, suggesting nonallelic homologous recombination betweendefensin7anddefensin6. The duplication event generated two chimeric promoters that are best explained by gene conversion followed by homologous recombination. Expression ofdefensin7was not elevated in animals with two genes despite both genes being transcribed in the tissues examined. Computational prediction of promoter regions revealed the presence of several putative transcription factor binding sites generated by the duplication event. These data provide insight into the evolution and possible function of large gene families and specifically, the defensins.

scholarly journals Higher prevalence of homologous recombination-deficiency in lung squamous carcinoma from African Americans

2019 ◽  
Author(s):  
Sanju Sinha ◽  
Khadijah A. Mitchell ◽  
Adriana Zingone ◽  
Elise Bowman ◽  
Neelam Sinha ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Copy Number ◽  
Squamous Carcinoma ◽  
The Cancer Genome Atlas ◽  
Multiple Cancer ◽  
Homologous Recombination Deficiency ◽  
Molecular Features ◽  
Incidence And Mortality ◽  
Cancer Types ◽  
Lung Squamous Carcinoma

AbstractTo improve our understanding of the longstanding disparities in incidence and mortality across multiple cancer types among minority populations, we performed a systematic comparative analysis of molecular features in tumors from African American (AA) and European American (EA) ancestry. Our pan-cancer analysis on the cancer genome atlas (TCGA) and a more focused analysis of genome-wide somatic copy number profiles integrated with tumor-normal RNA sequencing in a racially balanced cohort of 222 non-small cell lung cancers (NSCLC) reveals more aggressive genomic characteristics of AA tumors. In general, we find AA tumors exhibit higher genomic instability (GI), homologous recombination-deficiency (HRD) levels, and more aggressive molecular features such as chromothripsis across many cancer types, including lung squamous carcinoma (LUSC). GI and HRD levels are strongly correlated across AA tumors, indicating that HRD plays an important role in GI in these patients. The prevalence of germline HRD is higher in AA tumors, suggesting that the somatic differences observed have genetic ancestry origins. Finally, we identify AA-specific copy number-based arm, focal and gene level recurrent features in lung cancer, including a higher frequency of PTEN deletion and KRAS amplification and a lower frequency of CDKN2A deletion. These results highlight the importance of including minority and under-represented populations in genomics research and may have therapeutic implications.

scholarly journals Mitochondrial DNA Copy Number Variation Across Human Cancers

2015 ◽  
Author(s):  
Ed Reznik ◽  
Martin Miller ◽  
Yasin Senbabaoglu ◽  
Nadeem Riaz ◽  
William Lee ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Copy Number Variation ◽  
Copy Number ◽  
Large Scale ◽  
Tumor Type ◽  
Mtdna Copy Number ◽  
Tissue Samples ◽  
Mitochondrial Dna Copy Number ◽  
Number Variation ◽  
Tumor Types

In cancer, mitochondrial dysfunction, through mutations, deletions, and changes in copy number of mitochondrial DNA (mtDNA), contributes to the malignant transformation and progression of tumors. Here, we report the first large-scale survey of mtDNA copy number variation across 21 distinct solid tumor types, examining over 13,000 tissue samples profiled with next-generation sequencing methods. We find a tendency for cancers, especially of the bladder and kidney, to be significantly depleted of mtDNA, relative to matched normal tissue. We show that mtDNA copy number is correlated to the expression of mitochondrially-localized metabolic pathways, suggesting that mtDNA copy number variation reflect gross changes in mitochondrial metabolic activity. Finally, we identify a subset of tumor-type-specific somatic alterations, including IDH1 and NF1 mutations in gliomas, whose incidence is strongly correlated to mtDNA copy number. Our findings suggest that modulation of mtDNA copy number may play a role in the pathology of cancer.

scholarly journals Copy number gain of CMTM6 increases the expression of PD-L1 in undifferentiated pleomorphic sarcoma

2021 ◽  
Author(s):  
Shin Ishihara ◽  
Takeshi Iwasaki ◽  
Kenichi Kohashi ◽  
Yuichi Yamada ◽  
Yu Toda ◽  
...  
Keyword(s):  
Copy Number ◽  
Transmembrane Domain ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
The Cancer Genome Atlas ◽  
Gene Copy ◽  
Undifferentiated Pleomorphic Sarcoma ◽  
Pleomorphic Sarcoma ◽  
Number Variation ◽  
Cancer Genome Atlas

Abstract Background Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometime strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained still unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6. Materials and methods Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data. Results TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had worse prognosis for overall survival. Conclusions CMTM6 expression was significantly correlated with PD-L1 expression. CMTM6 expression induced strong PD-L1 expression (≥ 50%). CMTM6 copy number gain promoted CMTM6 expression and increased PD-L1 expression in UPS.

scholarly journals Pan-cancer driver copy number alterations identified by joint expression/CNA data analysis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Gaojianyong Wang ◽  
Dimitris Anastassiou
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
The Cancer Genome Atlas ◽  
Copy Number Alterations ◽  
Multiple Cancer ◽  
Cancer Driver ◽  
Large Gene ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Pan Cancer

Abstract Analysis of large gene expression datasets from biopsies of cancer patients can identify co-expression signatures representing particular biomolecular events in cancer. Some of these signatures involve genomically co-localized genes resulting from the presence of copy number alterations (CNAs), for which analysis of the expression of the underlying genes provides valuable information about their combined role as oncogenes or tumor suppressor genes. Here we focus on the discovery and interpretation of such signatures that are present in multiple cancer types due to driver amplifications and deletions in particular regions of the genome after doing a comprehensive analysis combining both gene expression and CNA data from The Cancer Genome Atlas.

Multiomics analysis identifies key genes and pathways related to N6-methyladenosine RNA modification in ovarian cancer

Epigenomics ◽  
2021 ◽  
Author(s):  
Haoya Xu ◽  
Xianli Li ◽  
Shengtan Wang ◽  
Feifei Li ◽  
Jian Gao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Target Genes ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Rna Modification ◽  
Pathway Enrichment Analysis ◽  
Pathway Enrichment ◽  
Number Variation ◽  
Cancer Genome Atlas ◽  
Patient Prognosis

Aims: To explore the pathways and target genes related to N6-methyladenosine (m6A) methylation in ovarian cancer and their effect on patient prognosis. Methods & materials: The Cancer Genome Atlas was used to screen genes related to m6A regulators in terms of gene expression, mutation and copy number variation. These genes were subjected to pathway enrichment analysis. Prognosis-related genes were screened and involved in risk signature construction. Immunohistochemistry was used for verification. Results: We obtained 1408 genes dysregulated in parallel to m6A regulators, which were mainly involved in the platelet activation pathway. The m6A-related signature was constructed based on the expression of four prognosis-related genes ( RPS6KA2, JUNB, HNF4A and P2RX1). Conclusion: This work provides new insights into the mechanism of m6A methylation in ovarian cancer.

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