English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background  ARID1A is a member of the SWI/SNF chromatin remodeling complex. It functions as a tumor suppressor and several therapeutic targets in  ARID1A -mutated cancers are currently under development, including EZH2. A synthetic lethal relationship between ARID1A and EZH2 has been revealed in several tumor entities. Although genomic alterations of  ARID1A  have been described in various cancers, no study has examined correlations between  ARID1A  gene mutation and protein expression with clinicopathologic parameters and prognosis, particularly in liver fluke-related cholangiocarcinoma (Ov-CCA). Here, we investigated the clinical significance of  ARID1A  mutations and protein expression in CCA tissues and determined whether there is a correlation with EZH2 protein expression.    Methods  We evaluated ARID1A and EZH2 immunoreactivity using immunohistochemistry in 98 Ov-CCA with a wide range of clinicopathological features. Somatic mutations of  ARID1A  were analyzed using the ICGC sequencing data in 489 of Ov and non Ov-CCA and assessed prognostic values.    Results  While detecting a loss or reduction of ARID1A expression in 54 cases (55%) in Ov-CCA, ARID1A expression was associated with  ARID1A  mutations ( p  < 0.001, adjusted  p -value < 0.001). We observed that 12 of 13 tumors (92%) with loss of ARID1A expression had truncating mutations. There were nine of 13 tumors (69%) with loss of ARID1A expression and 25 of 41 tumors (61%) with low ARID1A expression exhibited distant metastasis ( p  = 0.028, adjusted  p -value = 0.168).  ARID1A  was predominantly mutated in Ov-CCA compared to non Ov-CCA (24% and 14% in Ov-CCA and non Ov-CCA, respectively,  p  = 0.027). There were 36 of 72 (50%) and 52 of 79 (66%) tumors with  ARID1A  mutation showed tumor stage IV and T3/T4, respectively. The significant mutual exclusivity and co-occurrence between  ARID1A  and  TP53/KRAS  mutations were not found in ICGC cohort. In addition, high EZH2 expression, a potential synthetic lethal target in  ARID1A -mutated tumors, was detected in 49 of 98 Ov-CCA (50%). Importantly, neither ARID1A expression nor  ARID1A  mutations correlated with EZH2 expression in this cohort.    Conclusion  We found that  ARID1A  inactivation, by somatic mutation or by loss of expression, frequently occurs in Ov-CCA. Reduction of ARID1A expression and/or somatic mutation was shown to be associated with CCA progression. These findings suggest that ARID1A may serve as a prognostic biomarker, and thus may be a promising therapeutic target for CCA.

ARID1A alterations and their clinical significance in cholangiocarcinoma