ARID1A Variations in Cholangiocarcinoma: Clinical Significances and Molecular Mechanisms.

Shankun Zhao,Weizhou Wu,Jie Zhu,Pan Wang,Hao Jiang,Yichao Wang,Youwen Xu

doi:10.3389/fonc.2021.693295

Shankun Zhao, Weizhou Wu + Show 5 more

Open Access

https://doi.org/10.3389/fonc.2021.693295

Copy DOI

Abstract

Cholangiocarcinoma (CCA), a high mortality malignant carcinoma characterized by advanced disease and frequent recurrence, constitutes a major challenge for treatment and prognosis. AT-rich interaction domain 1A (ARID1A) variation is a distinct genetic entity in CCA, getting mounting concerns recently. Here, we comprehensively reviewed the clinical significance and molecular mechanisms of ARID1A alterations in CCA. Based on the independent data derived from 29 relevant studies, the variation rate of ARID1A in intrahepatic and extrahepatic CCA is reported at 6.9–68.2% and 5–55%, respectively. Most of the included studies (28/29, 96.6%) suggest that ARID1A serves as a tumor suppressor in CCA. ARID1A variation may be an important prognostic indicator to predict disease mortality, metastasis, and recurrence in patients with CCA. Multifactorial molecular mechanisms are involved in the relationship between ARID1A variations and the pathogenesis and pathophysiology of CCA, including disruption of the cell cycle, chromatin remodeling, oxidative stress damage, DNA hypermethylation, and the interaction of multiple genes being affected. This review describes that ARID1A variation might be a potential diagnostic and prognostic biomarker for CCA. Future diagnoses and treatments targeting ARID1A hint towards a precision medicine strategy in the management of CCA.

Highlights

Cholangiocarcinoma (CCA) is the second most frequently diagnosed primary liver malignancy, accounting for 10–20% of primary hepatic carcinomas, and representing 3% of all gastrointestinal tumors [1]
This review has shown AT-rich interaction domain 1A (ARID1A) variations in CCA cases are diverse in different studies, ranging from 5 to 68.2%
Excepting for one study indicating the carcinogenic functions for ARID1A, the remaining 28 included studies suggest that ARID1A is a tumor suppressor in CCA

Summary

INTRODUCTION

Cholangiocarcinoma (CCA) is the second most frequently diagnosed primary liver malignancy, accounting for 10–20% of primary hepatic carcinomas, and representing 3% of all gastrointestinal tumors [1]. The differences in ARID1A mutation rates and expression level that observed between different studies could be due to multiple factors, including distinct demographic characteristics (sample size, race, and regions), different types (ICC, ECC, or combined) and disease states (early or advanced CCA), specific anti-ARID1A antibodies and measurements for assessing the ARID1A expression (immunohistochemistry, targeted sequencing analysis, tissue microarrays, western blot, quantitative real-time reverse transcription PCR, and chromatin immunoprecipitation), and various co-present or targeted proteins being affected by ARID1A. This schematic diagram summarizes that multifactorial mechanisms that are potentially involved in the ARID1A-driven CCA development, including opposing functions in cell cycle arrest, chromatin remodeling and chromosome organization, oxidative stress damage, DNA hypermethylation, downregulation of IDH, and the interaction of multiple genes (i.e., TP53, ALDH1A1, and Beclin-1 target) that enhance cellular proliferation and antiapoptotic processes. Further comprehensive researches are still warranted to better elucidate the underlying mechanisms of CCA development initiated by ARID1A variations

Limitations and Perspectives

Findings

CONCLUSIONS