The pattern of gene copy number alteration (CNAs) in hepatocellular carcinoma: an in silico analysis

Abstract Background Hepatocellular carcinoma (HCC) is the most common type of liver cancer that occurs predominantly in patients with previous liver conditions. In the absence of an ideal screening modality, HCC is usually diagnosed at an advanced stage. Recent studies show that loss or gain of genomic materials can activate the oncogenes or inactivate the tumor suppressor genes to predispose cells toward carcinogenesis. Here, we evaluated both the copy number alteration (CNA) and RNA sequencing data of 361 HCC samples in order to locate the frequently altered chromosomal regions and identify the affected genes. Results Our data show that the chr1q and chr8p are two hotspot regions for genomic amplifications and deletions respectively. Among the amplified genes, YY1AP1 (chr1q22) possessed the largest correlation between CNA and gene expression. Moreover, it showed a positive correlation between CNA and tumor grade. Regarding deleted genes, CHMP7 (chr8p21.3) possessed the largest correlation between CNA and gene expression. Protein products of both genes interact with other cellular proteins to carry out various functional roles. These include ASH1L, ZNF496, YY1, ZMYM4, CHMP4A, CHMP5, CHMP2A and CHMP3, some of which are well-known cancer-related genes. Conclusions Our in-silico analysis demonstrates the importance of copy number alterations in the pathology of HCC. These findings open a door for future studies that evaluate our results by performing additional experiments.

Download Full-text

Identification of factors regulating the gene expression of alcohol dehydrogenases in hepatocellular carcinoma

10.21203/rs.3.rs-810174/v1 ◽

2021 ◽

Author(s):

Jinghe Xie ◽

Yaqi Qiu ◽

Shuai Zhang ◽

Keqing Ma ◽

Yimeng Ou ◽

...

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Dna Methylation ◽

Copy Number ◽

Gene Copy Number ◽

Copy Number Variations ◽

The Cancer Genome Atlas ◽

Gene Copy ◽

Excessive Alcohol Consumption ◽

Alcohol Dehydrogenases

Abstract Background Excessive alcohol consumption has been documented to increase the risk of liver hepatocellular carcinoma (HCC) development. Accordingly, a broad interest pointed to alcohol dehydrogenases (ADHs), which display essential roles in alcohol metabolism. Despite the relevance of ADHs expression and the prognosis of HCC has been estimated, so far, limited research concerning the factors that are responsible for the regulation of ADHs expression has been reported. Methods In this study, using The Cancer Genome Atlas (TCGA) and RegNetwork database, we predicted potential factors consisting of DNA methylation, gene copy number variations, transcription factors (TFs) and microRNAs (miRNAs) that might impact ADHs gene expression in HCC. Results We found that DNA methylation induced the down-regulated expression of ADH1B. Of note, our results implicated that gene copy number variation might not have effects on ADHs expression. Regarding TFs, we speculated that NFYA modulated ADH1C, E2F1 and TFAP2A regulated ADH6 expression based on their expression and prognostic value. Moreover, miR-185 and miR-561 might elicit the repression of ADH4, and miR-105 might impair ADH6 expression. Conclusion This study revealed that multiple factors, including DNA methylation, TFs and microRNAs, affect the expression of ADH family members, which provided new insights into discovering promising HCC-suppressive targets.

Download Full-text

In silico analysis suggests disruption of interactions between HAMP from hepatocytes and SLC40A1 from macrophages in hepatocellular carcinoma

BMC Medical Genomics ◽

10.1186/s12920-021-00977-0 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Liang Hu ◽

Chao Wu

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

In Silico ◽

Large Scale ◽

Expression Profiles ◽

Gene Expression Profiles ◽

In Silico Analysis ◽

Hepatocyte Proliferation ◽

Upregulated Genes ◽

Silico Analysis

Abstract Background Identification of factors associated with proliferation in the hepatocellular carcinoma (HCC) microenvironment aids in understanding the mechanisms of disease progression and provides druggable targets. Gene expression profiles of individual cells in HCC and para-carcinoma tissues can be effectively obtained using the single-cell RNA sequencing (scRNA-Seq) technique. Here, we aimed to identify proliferative hepatocytes from HCC and para-carcinoma tissues, detect differentially expressed genes between the two types of proliferative hepatocytes, and investigate their potential roles in aberrant proliferation. Results Two respective gene signatures for proliferative cells and hepatocytes were established and used to identify proliferative hepatocytes from HCC and para-carcinoma tissues based on scRNA-Seq data. Gene expression profiles between the two types of proliferative hepatocytes were compared. Overall, 40 genes were upregulated in proliferative hepatocytes from para-carcinoma tissue, whereas no upregulated genes were detected in those from HCC tissue. Twelve of the genes, including HAMP, were specifically expressed in the liver tissue. Based on previous reports, we found that HAMP modulates cell proliferation through interaction with its receptor SLC40A1. Comprehensive analysis of cells in HCC and para-carcinoma tissues revealed that: (1) HAMP is specifically expressed in hepatocytes and significantly downregulated in malignant hepatocytes; (2) a subset of macrophages expressing SLC40A1 and genes reacting to various infections is present in para-carcinoma but not in HCC tissue. We independently validated the findings with scRNA-Seq and large-scale tissue bulk RNA-Seq/microarray analyses. Conclusion HAMP was significantly downregulated in malignant hepatocytes. In addition, a subset of macrophages expressing SLC40A1 and genes reacting to various infections was absent in HCC tissue. These findings support the involvement of HAMP-SLC40A1 signaling in aberrant hepatocyte proliferation in the HCC microenvironment. The collective data from our in silico analysis provide novel insights into the mechanisms underlying HCC progression and require further validation with wet laboratory experiments.

Download Full-text

The pattern of gene copy number variations (CNVs) in hepatocellular carcinoma; in silico analysis

10.21203/rs.3.rs-20514/v1 ◽

2020 ◽

Author(s):

Hossein Ansari ◽

Arman Shahrisa ◽

Maryam Tahmaseby ◽

Zahra Mohammadi ◽

Vinicio Carloni ◽

...

Keyword(s):

Tumor Suppressor ◽

In Silico ◽

Copy Number ◽

In Silico Analysis ◽

Multivesicular Body ◽

Copy Number Variations ◽

Molecular Networks ◽

Gene Copy ◽

Body Protein ◽

Silico Analysis

Abstract Cancer-associated death is the second leading cause of death worldwide. Study of the involved molecular networks of cancers can identify the potential target for early diagnosis, efficient therapies, and predictive prognosis of patients with cancer. Copy number variations are one type of DNA mutations which has been connected with human cancers. The CNVs can be used to find the regions of the genome involved in cancer phenotypes. This study is aimed to perform genome-wide chromosomal CNVs in HCC samples to find hotspot regions of disease using in silico analysis. The obtained data showed that gain of chromosome 1q and loss of 8p were frequently observed in target cancerous tissues. All the gains and losses were associated with tumor grade and metastasis. However, the amplification of YY1AP1 (Yin Yang-1 Associated Protein 1) and deletion of CHMP7 (Charged Multivesicular Body Protein 7) were observed in most of patients. These expression levels of YY1AP1 and CHMP7 were also upregulated and downregulated in cancerous samples respectively. Additionally, these two genes interact with critical oncogene and tumor suppressor genes like MDM2 (Mouse double minute 2 homolog) and VHL (von Hippel-Lindau tumor suppressor) showing the potential of these genes in HCC pathogenesis. Based on the observed data we suggest the 1q and 8p as candidate regions for HCC for researches especially YY1AP1 and CHMP7 loci.

Download Full-text

Insulin-like Growth Factor Receptor 1 (IGF1R) Gene Copy Number Is Associated With Survival in Operable Non–Small-Cell Lung Cancer: A Comparison Between IGF1R Fluorescent In Situ Hybridization, Protein Expression, and mRNA Expression

Journal of Clinical Oncology ◽

10.1200/jco.2009.24.6611 ◽

2010 ◽

Vol 28 (13) ◽

pp. 2174-2180 ◽

Cited By ~ 89

Author(s):

Rafal Dziadziuszko ◽

Daniel T. Merrick ◽

Samir E. Witta ◽

Adelita D. Mendoza ◽

Barbara Szostakiewicz ◽

...

Keyword(s):

Gene Expression ◽

Growth Factor ◽

Protein Expression ◽

Squamous Cell ◽

Copy Number ◽

Gene Copy Number ◽

Growth Factor Receptor ◽

Gene Copy ◽

Cell Versus

PurposeThe purpose of this study was to characterize insulin-like growth factor-1 receptor (IGF1R) protein expression, mRNA expression, and gene copy number in surgically resected non–small-cell lung cancers (NSCLC) in relation to epidermal growth factor receptor (EGFR) protein expression, patient characteristics, and prognosis.Patients and MethodsOne hundred eighty-nine patients with NSCLC who underwent curative pulmonary resection were studied (median follow-up, 5.3 years). IGF1R protein expression was evaluated by immunohistochemistry (IHC) with two anti-IGF1R antibodies (n = 179). EGFR protein expression was assessed with PharmDx kit. IGF1R gene expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 114 corresponding fresh-frozen samples. IGF1R gene copy number was assessed by fluorescent in situ hybridization using customized probes (n = 181).ResultsIGF1R IHC score was higher in squamous cell carcinomas versus other histologies (P < .001) and associated with stage (P = .03) but not survival (P = .46). IGF1R and EGFR protein expression showed significant correlation (r = 0.30; P < .001). IGF1R gene expression by qRT-PCR was higher in squamous cell versus other histologies (P = .006) and did not associate with other clinical features nor survival (P = .73). Employing criteria previously established for EGFR copy number, patients with IGF1R amplification/high polysomy (n = 48; 27%) had 3-year survival of 58%, patients with low polysomy (n = 87; 48%) had 3-year survival of 47% and patients with trisomy/disomy (n = 46; 25%) had 3-year survival of 35%, respectively (P = .024). Prognostic value of high IGF1R gene copy number was confirmed in multivariate analysis.ConclusionIGF1R protein expression is higher in squamous cell versus other histologies and correlates with EGFR expression. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number harbors positive prognostic value.

Download Full-text