Characterization of copy number alterations in a mouse model of fibrosis‐associated hepatocellular carcinoma reveals concordance with human disease

Abstract Genome-wide profiling of copy number alterations and DNA methylation in single cells could enable detailed investigation into the genomic and epigenomic heterogeneity of complex cell populations. However, current methods to do this require complex sample processing and cleanup steps, lack consistency, or are biased in their genomic representation. Here, we describe a novel single-tube enzymatic method, DNA Analysis by Restriction Enzyme (DARE), to perform deterministic whole genome amplification while preserving DNA methylation information. This method was evaluated on low amounts of DNA and single cells, and provides accurate copy number aberration calling and representative DNA methylation measurement across the whole genome. Single-cell DARE is an attractive and scalable approach for concurrent genomic and epigenomic characterization of cells in a heterogeneous population.

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Clinical implication of recurrent copy number alterations in hepatocellular carcinoma and putative oncogenes in recurrent gains on 1q

International Journal of Cancer ◽

10.1002/ijc.23901 ◽

2008 ◽

Vol 123 (12) ◽

pp. 2808-2815 ◽

Cited By ~ 60

Author(s):

Tae-Min Kim ◽

Seon-Hee Yim ◽

Seung-Hun Shin ◽

Hai-Dong Xu ◽

Yu-Chae Jung ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Implication ◽

Copy Number ◽

Copy Number Alterations

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Correlating Genomic Copy Number Alterations with Clinicopathologic Findings in A Case Series of Hepatocellular Carcinoma

10.21203/rs.3.rs-40266/v1 ◽

2020 ◽

Author(s):

Gang Peng ◽

Hongyan Chai ◽

Weizhen Ji ◽

Yufei Lu ◽

Shengming Wu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Copy Number ◽

Case Series ◽

Oligonucleotide Array ◽

Good Survival ◽

Survival Outcomes ◽

Copy Number Alterations ◽

Acgh Analysis ◽

Clinicopathologic Findings ◽

Grade Iii

Abstract Background: Oligonucleotide array comparative genomic hybridization (aCGH) analysis has been used for detecting somatic copy number alterations (CNAs) in various types of tumors. This study aimed to assess the clinical utility of aCGH for a case series of hepatocellular carcinoma (HCC) and to evaluate the correlation between CNAs and clinicopathologic findings.Methods: Survival outcomes from this case series were analyzed based on Barcelona-Clinic Liver Cancer Stage (BCLC), Edmondson-Steiner grade (E-S), and recurrence status. aCGH was performed on 75 HCC cases with paired DNA samples from tumor and adjacent nontumor tissues. Correlation of CNAs with clinicopathologic findings was analyzed by Wilcoxon rank test and clustering vs. K means. Results: The survival outcomes indicated that BCLC stages and recurrence status could be predictors and E-S grades could be a modifier for HCC. The most common CNAs involved gains of 1q and 8q and a loss of 16q (50%), losses of 4q and 17p and a gain of 5p (40%), and losses of 8p and 13q (30%). Correlation and clustering analyses noted that losses of 4q13.2q35.2 and 10q22.3q26.13 seen in cases of stage A, grade III and nonrecurrence were likely associated with good survival, while loss of 1p36.31p22.1 and gains of 2q11.2q21.2 and 20p13p11.1 seen in cases of stage C, grade III and recurrence were possibly associated with worst prognosis. Conclusions: These results indicated that aCGH analysis could be used to detect recurrent CNAs and involved key genes and pathways in patients with HCC. Further analysis on a large case series to validate the association of CNAs with clinicopathologic findings of HCC could provide information to interpret CNAs and predict prognosis.

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A comprehensive molecular characterization of the 8q22.2 region reveals the prognostic relevance of OSR2 mRNA in muscle invasive bladder cancer

PLoS ONE ◽

10.1371/journal.pone.0248342 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0248342

Author(s):

Daniel Uysal ◽

Karl-Friedrich Kowalewski ◽

Maximilian Christian Kriegmair ◽

Ralph Wirtz ◽

Zoran V. Popovic ◽

...

Keyword(s):

Bladder Cancer ◽

In Silico ◽

Copy Number ◽

In Silico Analysis ◽

Copy Number Alterations ◽

Muscle Invasive Bladder Cancer ◽

Mrna Gene ◽

Muscle Invasive ◽

Silico Analysis

Technological advances in molecular profiling have enabled the comprehensive identification of common regions of gene amplification on chromosomes (amplicons) in muscle invasive bladder cancer (MIBC). One such region is 8q22.2, which is largely unexplored in MIBC and could harbor genes with potential for outcome prediction or targeted therapy. To investigate the prognostic role of 8q22.2 and to compare different amplicon definitions, an in-silico analysis of 357 patients from The Cancer Genome Atlas, who underwent radical cystectomy for MIBC, was performed. Amplicons were generated using the GISTIC2.0 algorithm for copy number alterations (DNA_Amplicon) and z-score normalization for mRNA gene overexpression (RNA_Amplicon). Kaplan-Meier survival analysis, univariable, and multivariable Cox proportional hazard ratios were used to relate amplicons, genes, and clinical parameters to overall (OS) and disease-free survival (DFS). Analyses of the biological functions of 8q22.2 genes and genomic events in MIBC were performed to identify potential targets. Genes with prognostic significance from the in silico analysis were validated using RT-qPCR of MIBC tumor samples (n = 46). High 8q22.2 mRNA expression (RNA-AMP) was associated with lymph node metastases. Furthermore, 8q22.2 DNA and RNA amplified patients were more likely to show a luminal subtype (DNA_Amplicon_core: p = 0.029; RNA_Amplicon_core: p = 0.01). Overexpression of the 8q22.2 gene OSR2 predicted shortened DFS in univariable (HR [CI] 1.97 [1.2; 3.22]; p = 0.01) and multivariable in silico analysis (HR [CI] 1.91 [1.15; 3.16]; p = 0.01) and decreased OS (HR [CI] 6.25 [1.37; 28.38]; p = 0.0177) in RT-qPCR data analysis. Alterations in different levels of the 8q22.2 region are associated with manifestation of different clinical characteristics in MIBC. An in-depth comprehensive molecular characterization of genomic regions involved in cancer should include multiple genetic levels, such as DNA copy number alterations and mRNA gene expression, and could lead to a better molecular understanding. In this study, OSR2 is identified as a potential biomarker for survival prognosis.

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Amplification of the EGFR and CCND1 Are Coordinated and Play Important Roles in the Progression of Oral Squamous Cell Carcinomas

Cancers ◽

10.3390/cancers11060760 ◽

2019 ◽

Vol 11 (6) ◽

pp. 760 ◽

Cited By ~ 6

Author(s):

Huei-Tzu Chien ◽

Sou-De Cheng ◽

Chun-Ta Liao ◽

Hung-Ming Wang ◽

Shiang-Fu Huang

Keyword(s):

Squamous Cell ◽

Tumor Suppressor Genes ◽

Copy Number ◽

Clinical Stage ◽

Copy Number Alterations ◽

Suppressor Genes ◽

Common Cancer ◽

Genome Wide

Oral squamous cell carcinoma (OSCC) is a common cancer in Taiwan and worldwide. To provide some clues for clinical management of OSCC, 72 advanced-stage OSCCs were analyzed using two microarray platforms (26 cases with Affymetrix 500 K and 46 cases with Affymetrix SNP 6.0). Genomic identification of significant targets in cancer analyses were used to identify significant copy number alterations (CNAs) using a q-value cutoff of 0.25. Among the several significant regions, 12 CNAs were common between these two platforms. Two gain regions contained the well-known oncogenes EGFR (7p11.2) and CCND1 (11q13.3) and several known cancer suppressor genes, such as FHIT (3p14.2–p12.1), FAT1 (4q35.1), CDKN2A (9p21.3), and ATM (11q22.3–q24.3), reside within the 10 deletion regions. Copy number gains of EGFR and CCND1 were further confirmed by fluorescence in situ hybridization and TaqMan CN assay, respectively, in 257 OSCC cases. Our results indicate that EGFR and CCND1 CNAs are significantly associated with clinical stage, tumor differentiation, and lymph node metastasis. Furthermore, EGFR and CCND1 CNAs have an additive effect on OSCC tumor progression. Thus, current genome-wide CNA analysis provides clues for future characterization of important oncogenes and tumor suppressor genes associated with the behaviors of the disease.

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