Prognostic role of ARID1A negative expression in gastric cancer

Mai Ashizawa,Daisuke Ujiie,Tomoyuki Momma,Akiteru Goto,Wataru Sakamoto,Shinji Ohki,Tomohiro Kikuchi,Takahiro Sato,Aung Kyi Thar Min,Koji Kono,Motonobu Saito,Shotaro Fujita,Katsuharu Saito,Hisahito Endo,Hirokazu Okayama

doi:10.1038/s41598-019-43293-5

Mai Ashizawa, Daisuke Ujiie + Show 13 more

Open Access

https://doi.org/10.1038/s41598-019-43293-5

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Journal: Scientific Reports	Publication Date: May 1, 2019
Citations: 35	License type: open-access

Affiliation: Fukushima Medical University, Akita University

Abstract

AT-rich interactive domain 1A (ARID1A) functions as a tumor suppressor and several therapeutic targets in ARID1A-mutated cancers are under development. Here, we investigated the prognostic value of ARID1A for gastric cancer and its association with expression of PD-L1 and p53. ARID1A expression was examined by immunohistochemistry and negative expression of ARID1A was detected in 39 (19.5%) of 200 cases in a test cohort and in 40 (18.2%) of 220 cases in a validation cohort. Negative expression of ARID1A was associated with worse overall survival in undifferentiated cases, particularly early-stage cases. Negative expression of ARID1A was detected in 11 (50%) of 22 PD-L1-positive cases and in 68 (17.1%) of 398 PD-L1-negative cases in a combined cohort. Negative expression of ARID1A was detected in 45 (22%) of 205 p53-positive cases and in 34 (15.8%) of 215 p53-negative cases in a combined cohort. In addition, expression of EZH2, a potential synthetic lethal target in ARID1A-mutated tumors, was detected in 79 ARID1A-negative cases. An ARID1A-knockdown gastric cancer cell line was subjected to microarray analysis, but no actionable targets or pathways were identified. The present results indicate that ARID1A may serve as an early-stage prognostic biomarker for undifferentiated gastric cancer.

Highlights

AT-rich interactive domain 1A (ARID1A) functions as a tumor suppressor and several therapeutic targets in ARID1A-mutated cancers are under development
Lymphatic invasion and venous invasion were significantly associated with negative ARID1A expression, suggesting that ARID1A plays a role in cancer progression
Because most ARID1A mutations are inactivating mutations leading to decreased ARID1A expression, negative ARID1A expression can be used as a surrogate marker for ARID1A mutations (Supplementary Fig. S5)[5]

Summary

Introduction

AT-rich interactive domain 1A (ARID1A) functions as a tumor suppressor and several therapeutic targets in ARID1A-mutated cancers are under development. We investigated the prognostic value of ARID1A for gastric cancer and its association with expression of PD-L1 and p53. Negative expression of ARID1A was associated with worse overall survival in undifferentiated cases, early-stage cases. Expression of EZH2, a potential synthetic lethal target in ARID1Amutated tumors, was detected in 79 ARID1A-negative cases. A meta-analysis including 15 gastric cancer cohorts revealed that low ARID1A expression is associated significantly with worse patient survival and adverse clinicopathological factors, such as lymphatic invasion and lymph node metastasis[7]. Several therapeutic targets in ARID1A-mutated cancers are currently under development, including enhancer of zeste homolog 2 (EZH2)[8]. We performed microarray analysis to find ARID1A-related genes and pathways

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