Abstract
Early detection improves survival and increases curative probability in hepatocellular carcinoma (HCC). Peripheral blood mononuclear cells (PBMCs) can provide an inexpensive, less-invasive and highly accurate method. The objective of this study is to find the potential marker for HCC screening, utilizing gene expression of the PBMCs. Data from the NCBI GEO database of gene expression in HCC patients and healthy donor's PBMCs was collected. As a result, GSE 49515 and GSE 58208 were found. Using both, a statistical significance test was conducted in each gene expression of each data set which resulted in 187 genes. We randomized three selected genes (FLNA, CAP1, and CLU) from the significant p-value group (p-values < 0.001). Then, a total of 76 healthy donors, 153 HCC, 20 hepatic fibrosis, 20 non-alcoholic fatty liver were collected. Quantitative RT-PCR (qRT-PCR) was performed in cDNA from all blood samples from the qRT-PCR, The Cycle threshold (Ct) value of FLNA, CLU, CAP1 of HCC group (28.47 ± 4.43, 28.01 ± 3.75, 29.64 ± 3.90) were lower than healthy group (34.23 ± 3.54, 32.90 ± 4.15, 32.18 ± 5.02) (p-values < 0.0001). The accuracy, sensitivity and specificity of these genes as a screening tool were: FLNA (80.8%, 88.0%, 65.8%), CLU (63.4%, 93.3%, 31.3%), CAP1 (67.2%, 83.3%, 39.1%). The tests were performed in two and three gene combinations. Results demonstrated high accuracy of 86.2%, sensitivity of 85% and specificity of 88.4% in the FLNA and CLU combination. Furthermore, after analyzed using hepatic fibrosis and non-alcoholic fatty liver as a control, the FLNA and CLU combination is shown to have accuracy of 76.9%, sensitivity of 77.6% and specificity of 75%. Also, we founded that our gene combination performs better than the current gold standard for HCC screening. We concluded that FLNA and CLU combination have high potential for being HCC novel markers. Combined with current tumor markers, further research of the gene’s expression might help identify more potential markers and improve diagnosis methods.
Highlights
Abbreviations AFP Alpha-Fetoprotein antigen presenting cells (APCs) Antigen Presenting Cells AP-1 Activator protein 1 cAMP Cyclic adenosine monophosphate CAP1 Cyclase Associated Actin Cytoskeleton Regulatory Protein 1 CLU Clusterin cancer stage (Ct) Cycle threshold cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) Cytotoxic T-Lymphocytes-Associated protein 4 FLNA Filamin A glyceraldehyde 3-phosphate dehydrogenase (GAPDH) Glyceraldehyde 3-phosphate dehydrogenase GEO Gene Expression Omnibus
We focused on the usability of peripheral white blood cells (WBCs), especially peripheral blood mononuclear cells (PBMCs) as a biomarker for liver c ancers[17]
Gender data shows that our samples had more males than females (Table 2); The Hepatocellular carcinoma (HCC) group has 124 males to 29 females, the Healthy group has 45 males to 31 females, the hepatic fibrosis (HF) group has 16 males to 4 females, and the non-alcoholic fatty liver (NAFL) group has 18 males to 2 females
Summary
Abbreviations AFP Alpha-Fetoprotein APCs Antigen Presenting Cells AP-1 Activator protein 1 cAMP Cyclic adenosine monophosphate CAP1 Cyclase Associated Actin Cytoskeleton Regulatory Protein 1 CLU Clusterin Ct Cycle threshold CTLA-4 Cytotoxic T-Lymphocytes-Associated protein 4 FLNA Filamin A GAPDH Glyceraldehyde 3-phosphate dehydrogenase GEO Gene Expression Omnibus. The AFP blood test produces a wide variation of results with sensitivity ranging from 32 to 79.5% and specificity ranging from 29.4 to 98.5%5–7. Ultrasound test sensitivity for the detection of HCC ranges from 29 to 100%, whereas its specificity ranges from 94 to 100%. This means both AFP and ultrasound performance as screening/diagnosis markers are not very satisfactory[8]. There are multiple studies regarding the change in gene expression in circulating white blood cells of the cancer patient[9,10,11]. The objective of this study is to find the high-performance novel markers for HCC screening, utilizing gene expression of PBMCs (Fig. 1b)
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