Low <em>ARID1A</em> Expression is Associated with Poor Prognosis in Hepatocellular Carcinoma
AT-rich interactive domain 1A (<i>ARID1A</i>) is one of the most frequently mutated genes in hepatocellular carcinoma (HCC), but its clinical significance is not clarified. We aimed to evaluate the clinical significance of low <i>ARID1A</i> expression in HCC. By analyzing the...
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MDPI AG
2020-09-01
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| author | Sun Young Yim Sang Hee Kang Ji-Hyun Shin Yun Seong Jeong Bo Hwa Sohn Soon Ho Um Ju-Seog Lee |
| author_facet | Sun Young Yim Sang Hee Kang Ji-Hyun Shin Yun Seong Jeong Bo Hwa Sohn Soon Ho Um Ju-Seog Lee |
| author_sort | Sun Young Yim |
| collection | DOAJ |
| description | AT-rich interactive domain 1A (<i>ARID1A</i>) is one of the most frequently mutated genes in hepatocellular carcinoma (HCC), but its clinical significance is not clarified. We aimed to evaluate the clinical significance of low <i>ARID1A</i> expression in HCC. By analyzing the gene expression data of liver from <i>Arid1a</i>-knockout mice, hepatic <i>Arid1a</i>-specific gene expression signature was identified (<i>p</i> < 0.05 and 0.5-fold difference). From this signature, a prediction model was developed to identify tissues lacking <i>Arid1a</i> activity and was applied to gene expression data from three independent cohorts of HCC patients to stratify patients according to <i>ARID1A</i> activity. The molecular features associated with loss of <i>ARID1A</i> were analyzed using The Cancer Genome Atlas (TCGA) multi-platform data, and Ingenuity Pathway Analysis (IPA) was done to uncover potential signaling pathways associated with <i>ARID1A</i> loss. <i>ARID1A</i> inactivation was clinically associated with poor prognosis in all three independent cohorts and was consistently related to poor prognosis subtypes of previously reported gene signatures (highly proliferative, hepatic stem cell, silence of Hippo pathway, and high recurrence signatures). Immune activity, indicated by significantly lower IFNG6 and cytolytic activity scores and enrichment of regulatory T-cell composition, was lower in the <i>ARID1A</i>-low subtype than <i>ARID1A</i>-high subtype. Ingenuity pathway analysis revealed that direct upstream transcription regulators of the <i>ARID1A</i> signature were genes associated with cell cycle, including <i>E2F</i> group, <i>CCND1,</i> and <i>MYC,</i> while tumor suppressors such as <i>TP53, SMAD3,</i> and <i>CTNNB1</i> were significantly inhibited. <i>ARID1A</i> plays an important role in immune activity and regulating multiple genes involved in HCC development. Low-<i>ARID1A</i> subtype was associated with poor clinical outcome and suggests the possibility of <i>ARID1A</i> as a prognostic biomarker in HCC patients. |
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| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
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| spelling | doaj.art-c7ef06793d804f8a9be36b7c81fc33de2023-11-20T12:03:11ZengMDPI AGCells2073-44092020-09-0199200210.3390/cells9092002Low <em>ARID1A</em> Expression is Associated with Poor Prognosis in Hepatocellular CarcinomaSun Young Yim0Sang Hee Kang1Ji-Hyun Shin2Yun Seong Jeong3Bo Hwa Sohn4Soon Ho Um5Ju-Seog Lee6Department of Internal Medicine, Korea University College of Medicine, Seoul 136-701, KoreaDepartment of Surgery, Korea University College of Medicine, Seoul 136-701, KoreaDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Internal Medicine, Korea University College of Medicine, Seoul 136-701, KoreaDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USAAT-rich interactive domain 1A (<i>ARID1A</i>) is one of the most frequently mutated genes in hepatocellular carcinoma (HCC), but its clinical significance is not clarified. We aimed to evaluate the clinical significance of low <i>ARID1A</i> expression in HCC. By analyzing the gene expression data of liver from <i>Arid1a</i>-knockout mice, hepatic <i>Arid1a</i>-specific gene expression signature was identified (<i>p</i> < 0.05 and 0.5-fold difference). From this signature, a prediction model was developed to identify tissues lacking <i>Arid1a</i> activity and was applied to gene expression data from three independent cohorts of HCC patients to stratify patients according to <i>ARID1A</i> activity. The molecular features associated with loss of <i>ARID1A</i> were analyzed using The Cancer Genome Atlas (TCGA) multi-platform data, and Ingenuity Pathway Analysis (IPA) was done to uncover potential signaling pathways associated with <i>ARID1A</i> loss. <i>ARID1A</i> inactivation was clinically associated with poor prognosis in all three independent cohorts and was consistently related to poor prognosis subtypes of previously reported gene signatures (highly proliferative, hepatic stem cell, silence of Hippo pathway, and high recurrence signatures). Immune activity, indicated by significantly lower IFNG6 and cytolytic activity scores and enrichment of regulatory T-cell composition, was lower in the <i>ARID1A</i>-low subtype than <i>ARID1A</i>-high subtype. Ingenuity pathway analysis revealed that direct upstream transcription regulators of the <i>ARID1A</i> signature were genes associated with cell cycle, including <i>E2F</i> group, <i>CCND1,</i> and <i>MYC,</i> while tumor suppressors such as <i>TP53, SMAD3,</i> and <i>CTNNB1</i> were significantly inhibited. <i>ARID1A</i> plays an important role in immune activity and regulating multiple genes involved in HCC development. Low-<i>ARID1A</i> subtype was associated with poor clinical outcome and suggests the possibility of <i>ARID1A</i> as a prognostic biomarker in HCC patients.https://www.mdpi.com/2073-4409/9/9/2002<i>ARID1A</i>hepatocellular carcinomagenomicsprognosis |
| spellingShingle | Sun Young Yim Sang Hee Kang Ji-Hyun Shin Yun Seong Jeong Bo Hwa Sohn Soon Ho Um Ju-Seog Lee Low <em>ARID1A</em> Expression is Associated with Poor Prognosis in Hepatocellular Carcinoma Cells <i>ARID1A</i> hepatocellular carcinoma genomics prognosis |
| title | Low <em>ARID1A</em> Expression is Associated with Poor Prognosis in Hepatocellular Carcinoma |
| title_full | Low <em>ARID1A</em> Expression is Associated with Poor Prognosis in Hepatocellular Carcinoma |
| title_fullStr | Low <em>ARID1A</em> Expression is Associated with Poor Prognosis in Hepatocellular Carcinoma |
| title_full_unstemmed | Low <em>ARID1A</em> Expression is Associated with Poor Prognosis in Hepatocellular Carcinoma |
| title_short | Low <em>ARID1A</em> Expression is Associated with Poor Prognosis in Hepatocellular Carcinoma |
| title_sort | low em arid1a em expression is associated with poor prognosis in hepatocellular carcinoma |
| topic | <i>ARID1A</i> hepatocellular carcinoma genomics prognosis |
| url | https://www.mdpi.com/2073-4409/9/9/2002 |
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