Namjan Achira, Techasen Anchalee, Loilome Watcharin, Sa-Ngaimwibool Prakasit, Jusakul Apinya
Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.
Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand.
PeerJ. 2020 Dec 3;8:e10464. doi: 10.7717/peerj.10464. eCollection 2020.
ARID1A is a member of the SWI/SNF chromatin remodeling complex. It functions as a tumor suppressor and several therapeutic targets in -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 have been described in various cancers, no study has examined correlations between 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 mutations and protein expression in CCA tissues and determined whether there is a correlation with EZH2 protein expression.
We evaluated ARID1A and EZH2 immunoreactivity using immunohistochemistry in 98 Ov-CCA with a wide range of clinicopathological features. Somatic mutations of were analyzed using the ICGC sequencing data in 489 of Ov and non Ov-CCA and assessed prognostic values.
While detecting a loss or reduction of ARID1A expression in 54 cases (55%) in Ov-CCA, ARID1A expression was associated with mutations ( < 0.001, adjusted -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 ( = 0.028, adjusted -value = 0.168). was predominantly mutated in Ov-CCA compared to non Ov-CCA (24% and 14% in Ov-CCA and non Ov-CCA, respectively, = 0.027). There were 36 of 72 (50%) and 52 of 79 (66%) tumors with mutation showed tumor stage IV and T3/T4, respectively. The significant mutual exclusivity and co-occurrence between and mutations were not found in ICGC cohort. In addition, high EZH2 expression, a potential synthetic lethal target in -mutated tumors, was detected in 49 of 98 Ov-CCA (50%). Importantly, neither ARID1A expression nor mutations correlated with EZH2 expression in this cohort.
We found that 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是SWI/SNF染色质重塑复合体的成员。它作为一种肿瘤抑制因子发挥作用，目前正在开发针对多种突变癌症的几个治疗靶点，包括EZH2。在多个肿瘤实体中已揭示ARID1A与EZH2之间存在合成致死关系。尽管已在各种癌症中描述了基因改变，但尚无研究探讨基因突变和蛋白表达与临床病理参数及预后之间的相关性，尤其是在肝吸虫相关胆管癌（Ov-CCA）中。在此，我们研究了CCA组织中ARID1A突变和蛋白表达的临床意义，并确定其与EZH2蛋白表达是否存在相关性。
我们使用免疫组织化学评估了98例具有广泛临床病理特征的Ov-CCA中ARIDlA和EZH2的免疫反应性。利用ICGC测序数据对489例Ov-CCA和非Ov-CCA中的ARID1A体细胞突变进行了分析，并评估了其预后价值。
在Ov-CCA的54例（55%）病例中检测到ARID1A表达缺失或降低，ARID1A表达与ARID1A突变相关（P<0.001，校正P值<0.001）。我们观察到，13例ARID1A表达缺失的肿瘤中有12例（92%）发生了截短突变。13例ARID1A表达缺失肿瘤中有9例（69%），41例ARID1A低表达肿瘤中有25例（61%）出现远处转移（P=0.028，校正P值=0.168）。与非Ov-CCA相比，ARID1A在Ov-CCA中主要发生突变（Ov-CCA和非Ov-CCA中分别为2l%和14%，P=0.027）。72例（50%）发生ARID1A突变的肿瘤中有36例处于肿瘤IV期，79例（66%）发生ARID1A突变的肿瘤中有52例为T3/T4期。在ICGC队列中未发现ARID1A与EZH2突变之间存在显著的相互排斥和共发生情况。此外，在98例Ov-CCA中有四十九例（50%）检测到EZH2高表达，EZH2是ARID1A突变肿瘤中的一个潜在合成致死靶点。重要的是，在该队列中，ARID1A表达和ARID1A突变均与EZH2表达无关。
我们发现，通过体细胞突变或表达缺失导致的ARID1A失活在Ov-CCA中频繁发生。ARID1A表达降低和/或体细胞突变与CCA进展相关。这些发现表明，ARID1A可能作为一种预后生物标志物，因此可能是CCA的一个有前景的治疗靶点。
