• Users Online: 143
  • Print this page
  • Email this page

 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 53  |  Issue : 3  |  Page : 93-100

The clinical significance of ARID1A mutations in gastric cancer patients


1 Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital; Department of Surgery, School of Medicine, National Yang-Ming University, Taipei City, Taiwan
2 Department of Surgery, School of Medicine, National Yang-Ming University; Department of Oncology Taipei Veterans General Hospital, Taipei City, Taiwan
3 Department of Surgery, School of Medicine, National Yang-Ming University; Department of Pathology Taipei Veterans General Hospital, Taipei City, Taiwan

Date of Submission18-Aug-2019
Date of Decision16-Sep-2019
Date of Acceptance26-Mar-2020
Date of Web Publication30-May-2020

Correspondence Address:
Dr. Wen-Liang Fang
Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Road, Beitou District, Taipei City 11217
Taiwan
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fjs.fjs_66_19

Rights and Permissions
  Abstract 


Background: ARID1A is a key component of the SWI/SNF chromatin remodeling complex, which has been identified in various cancers. Loss of ARID1A expression is correlated with poor prognosis in gastric cancer (GC); however, the clinical relevance of ARID1A mutations in GC has not yet been reported.
Materials and Methods: A total of 518 GC patients receiving gastrectomy were enrolled. The analysis of 13 mutations of the ARID1A gene using mass spectrometric single-nucleotide polymorphism genotyping technology was conducted. The clinicopathological features of GC with and without ARID1A mutations were compared.
Results: Among the 518 GC patients, 59 (11.4%) had ARID1A mutations. For diffuse-type GC, patients with ARID1A-mutated tumors were older and had fewer poorly differentiated tumors, fewer incidence of Epstein–Barr virus infection, a higher likelihood of ARID1A expression loss, more microsatellite instability-high tumors, a lower prevalence of peritoneal recurrence, and better survival rates than those with ARID1A nonmutant tumors. For intestinal-type GC, patients with ARID1A-mutant tumors had more PI3K/AKT pathway genetic mutations than patients with ARID1A nonmutant tumors. Multivariate analysis showed that ARID1A mutations are an independent prognostic factor in diffuse-type GC.
Conclusion: ARID1A mutations are associated with a better prognosis in diffuse-type GC.

Keywords: ARID1A expression, ARID1A mutation, diffuse-type, gastric cancer, prognostic factor


How to cite this article:
Wu CH, Tseng CH, Huang KH, Fang WL, Chen MH, Li AF, Wu CW. The clinical significance of ARID1A mutations in gastric cancer patients. Formos J Surg 2020;53:93-100

How to cite this URL:
Wu CH, Tseng CH, Huang KH, Fang WL, Chen MH, Li AF, Wu CW. The clinical significance of ARID1A mutations in gastric cancer patients. Formos J Surg [serial online] 2020 [cited 2020 Sep 24];53:93-100. Available from: http://www.e-fjs.org/text.asp?2020/53/3/93/285401




  Introduction Top


Recent studies demonstrated that human gastric cancer (GC) is characterized by 66–212 mutations in coding regions; among these mutations, only a few are driver mutations.[1],[2],[3],[4]ARID1A is a key component of the SWI/SNF chromatin remodeling complex, which is involved in the carcinogenesis of various organs, including the ovaries, endometrium, uterus, and stomach.[5],[6],[7],[8] The SWI/SNF complex regulates target genes downstream of TP53; therefore, ARID1A is considered to act as a tumor suppressor gene.[9]

The frequency of ARID1A mutations was reported to be 8%–29% in GC.[1],[2],[7] However, the frequencies and patterns of ARID1A mutations are different among various cancers.[9],[10] However, the clinical relevance of ARID1A mutations and their relationship with ARID1A expression in GC has not yet been reported.

Mass spectrometric single-nucleotide polymorphism genotyping technology can serve as a cheaper and time-saving alternative for genetic analysis with whole-genome sequencing and offer high precision. In this study, we used this method to analyze thirteen validated mutations of the ARID1A gene that were specific to GC,[7] and common GC-related genes (PI3K/AKT pathway, TP53, BRAF) were also analyzed.[11]

In the present study, the aim was to investigate the correlation between ARID1A mutations, the expression of ARID1A, the clinicopathological features, mutations of common GC-related genes, and the prognosis of GC patients.


  Materials and Methods Top


Ethics statement

All samples were anonymized and collected from the biobank of our hospital, which were in accordance with the committee on human experimentation and the Declaration of Helsinki of 1964 and its later versions. The Ethics Committees of our hospital reviewed and approved this study (2015-03-002A).

Patients and sample collection

Between January 2005 and December 2013, 518 patients receiving surgery for gastric adenocarcinoma were enrolled.

Written informed consent for tissue collection was obtained from all enrolled patients. Tumor and normal tissues were frozen in liquid nitrogen and were stored in the biobank at our institution. The pathological staging of GC was defined according to the eighth American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis (TNM) classification.[12] The data were prospectively collected and were updated regularly throughout the follow-up period.

All patients received chest films, sonography or a computerized tomography (CT) scan of the abdomen before surgery. We performed a total or distal subtotal gastrectomy according to the location of tumor.

Follow-up

No patients received preoperative chemotherapy. Adjuvant chemotherapy after curative surgery was not routinely performed before 2008 and was performed when tumor recurrence was diagnosed. Adjuvant therapy, such as S-1, has been arranged for Stage II or Stage III disease in our hospital since 2008 due to the proven survival benefit.[13]

Postoperative follow-up examinations were performed every 3 months for the first 5 years, followed by every 6 months until the patient's death. The follow-up studies included physical examinations, blood tests with hemoglobin, and tumor marker measurement (including carcinoembryonic antigen and carbohydrate antigen 19–9), chest films, sonography, and CT scans of the abdomen.

DNA extraction

DNA was extracted from tissue specimens using the QIAamp DNA Tissue Kit and MinElute Virus Kit (Qiagen, Valencia, CA) according to the manufacturer's recommendations. The collected material was centrifuged in 2-ml low-bind tubes at 14,500 rpm for 10 min to remove residual cells. All samples were stored at −20°C until cfDNA isolation. DNA quality and quantity were confirmed using a NanoDrop 1000 Spectrophotometer (Thermo Scientific) and Qubit Fluorometer (Thermo Scientific), respectively.

PIK3CA amplification

The copy number of the PIK3CA gene was investigated using quantitative real-time polymerase chain reaction (PCR). The primer sequences of the LINE1 element were used as an internal reference target. The method of identifying PIK3CA amplification was the same as that in a previous study.[14]

MassARRAY-based mutation analysis and Epstein-Barr virus DNA detection

A MassARRAY system (Agena, San Diego, CA) was used to analyze 13 mutation hotspots in the ARID1A gene and their frequencies in the 518 GC patients [Supplementary Table S1]. These 13 mutation hotspots were specific in GC,[7] which was the reason we chose them for the mutation analysis of ARID1A in the present study. Other common GC-related genes (including PIK3CA, PTEN, AKT1, AKT2, AKT3, TP53, and BRAF) were also analyzed as previously described.[11] The PI3K/AKT pathway genetic mutations included five genes: PIK3CA, PTEN, AKT1, AKT2, and AKT3. Both normal and tumor tissues were examined and only somatic mutations were enrolled in the mutation analysis in the present study.



As reported in a previous study,[8] Epstein–Barr virus (EBV) DNA assays were carried out using the MassARRAY system (Agenda, San Diego, CA, USA). The PCR and single-base extension primers were designed using the MassARRAY Assay Design 3.1 software, and one multiplex reaction was designed to detect the EBV virus DNA segment.

Microsatellite instability analysis

As mentioned in a previous study,[15] the DNA of normal and tumor tissues was extracted, purified, and then amplified using a fluorescent PCR. Five reference microsatellite markers (D5S345, D2S123, D17S250, BAT25, and BAT26) were used for the analysis of microsatellite instability (MSI). MSI-high (MSI-H) was defined as samples with ≥2 loci of instability with 5 markers. MSI-low/stable (MSI-L/S) was defined as samples with one MSI or without MSI.

Immunohistochemical stains for ARID1A

For ARID1A, immunohistochemical (IHC) stains for formalin-fixed paraffin embedded tissue sections were performed on a Leica Bond-MAX system (automated IHC staining systems). The sections were pretreated using heat mediated antigen retrieval with sodium ethylenediaminetetraacetic acid buffer (pH = 9) for 40 min. The sections were then incubated with ARID1A (diluted 1:500, polyclonal, HPA005456; Sigma-Aldrich, St Louis, MO, United States) for 60 min at room temperature and detected using an HRP-conjugated compact polymer system (anti-rabbit IgG–poly-HRP) for 20 min at room temperature. The sections were blocked with peroxide block for 5 min. 3,3'-Diaminobenzidine was used as the chromogen. The sections were then counterstained with hematoxylin and mounted with DPX. Tumors were regarded as positive for ARID1A if tumor cells showed nuclear immunoreactivity. Nonneoplastic cells, such as fibroblasts, endothelial cells, and lymphocytes, served as internal positive controls for ARID1A. The results of IHC staining were demonstrated in [Figure 1].
Figure 1: The immunohistochemical staining of ARID1A in gastric cancer specimen are shown as follows: (a) negative expression of ARID1A (b) positive expression of ARID1A

Click here to view


Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics 25.0 (IBM Corp, Armonk, New York, USA). A Chi-square test with Yates correction or Fisher's exact test was used to compare the categorical data between groups. The overall survival (OS) was calculated from the operation date to the date of death or final follow-up visit. The disease-free survival (DFS) was measured from the operation date to the final follow-up date and indicated patient survival without tumor recurrence. The Kaplan–Meier method was used for univariate analysis of the risk factors of OS and DFS. Cox proportional hazards models were used for multivariate analysis of the risk factors for OS and DFS. A P < 0.05 was defined as statistically significant.


  Results Top


Clinicopathological features

Among the 518 patients, 59 (11.4%) had ARID1A mutations. The clinicopathological features were compared between patients with and without ARID1A mutations. We found that patients with ARID1A mutations were older, more predominantly male, and had more MSI-H tumors and more PI3K/AKT pathway mutations than those without ARID1A mutations [Table 1]. As there are different biological behaviors between intestinal-type and diffuse-type GC, patients with intestinal-type (n = 266) and diffuse-type (n = 252) GC were separated for analysis of the differences between those with and without ARID1A mutations.
Table 1: Clinical profile in gastric cancer patients with/ without ARID1A mutation


Click here to view


For intestinal-type GC, no significant difference was observed in the clinicopathological features between patients with and without ARID1A mutations. Patients with ARID1A mutations had more PI3K/AKT pathway mutations than those without ARID1A mutations [Table 2]. For diffuse-type GC, patients with ARID1A mutations were older and had fewer poorly differentiated tumors, more MSI-H tumors, fewer EBV infections, and a higher propensity for ARID1A expression loss than those without ARID1A mutations [Table 3].
Table 2: Clinical profile in intestinal-type gastric cancer patients with/without ARID1A mutation

Click here to view
Table 3: Clinical profile in diffuse-type gastric cancer patients with/without ARID1A mutation

Click here to view


Initial recurrence patterns

Among the 518 patients, 439 (84.7%) patients receiving curative resection were enrolled in the analysis of initial recurrence patterns and patient survival. The median follow-up period was 52.2 months. The postoperative adjuvant chemotherapy rate was similar between patients with and without ARID1A mutations and a similar postoperative adjuvant chemotherapy rate was also observed in intestinal-type and diffuse-type GC patients. As shown in [Supplementary Table S2], regarding the initial recurrence patterns, patients with ARID1A mutations had a significantly lower peritoneal recurrence rate than those without ARID1A mutations (1.9% vs. 14.2%, P = 0.013). For intestinal-type GC, no significant difference was observed in the initial recurrence pattern between patients with and without ARID1A mutations. For diffuse-type GC [Supplementary Table S3], there was no peritoneal recurrence for patients with ARID1A mutations, which was significantly lower than the peritoneal recurrence rate for patients without ARID1A mutations (0% vs. 18.5%, P = 0.046).



Survival analysis

Among the 518 patients, 439 (84.7%) patients receiving curative resection were enrolled in the survival analysis. In the 439 patients, the 5-year OS rates (57.2% vs. 53.1%, P = 0.279) and DFS rates (49.6% vs. 50.1%, P = 0.504) were not significantly different between patients with and without ARID1A mutations.

As shown in [Figure 2]a and [Figure 2]b, for intestinal-type GC, the 5-year OS rates (50.0% vs. 56.8%, P = 0.701) and DFS rates (41.2% vs. 54.4%, P = 0.321) were not significantly different between patients with and without ARID1A mutations. For diffuse-type GC [Figure 2]c and d], the 5-year OS rates (71.8% vs. 48.9%, P = 0.037) and DFS rates (65.8% vs. 45.1%, P = 0.037) were significantly better in patients with ARID1A-mutant tumors than in patients with ARID1A nonmutant tumors.
Figure 2: For intestinal-type gastric cancer, the 5-year overall survival rates (52.8% vs. 56.8%, P = 0.855) and disease-free survival rates (47.1% vs. 54.4%, P = 0.454) were not significantly different between patients with and without ARID1A mutations. For diffuse-type gastric cancer, the 5-year overall survival rates (71.8% vs. 48.9%, P = 0.037) and disease-free survival rates (65.8% vs. 45.1%, P = 0.034) were significantly better in patients with ARID1A mutations than in those without. The survival curves are as follows: (a) Overall survival curves of intestinal-type gastric cancer. (b) Disease-free survival curves of intestinal-type gastric cancer. (c) Gastric cancercurves of diffuse-type gastric cancer. (d) Disease-free survival curves of diffuse-type gastric cancer

Click here to view


As shown in [Table 4], the multivariate analysis of factors affecting OS and DFS demonstrated that age, size, and pathological TNM stage were independent prognostic factors. For intestinal-type GC [Supplementary Table S4], the multivariate analysis demonstrated that age, tumor size, and pathological TNM stage were independent prognostic factors for OS; while age and pathological TNM stage were independent prognostic factors for DFS. For diffuse-type GC [Table 5], the multivariate analysis demonstrated that age, gross appearance, pathological TNM stage, and ARID1A mutation status were independent prognostic factors of OS and DFS.
Table 4: Multivariate analysis of factors affecting overall survival and disease-free survival of gastric cancer patients after curative surgery by the Kaplan-Meier method

Click here to view

Table 5: Multivariate analysis of factors affecting overall survival and disease-free survival of diffuse-type gastric cancer patients after curative surgery by the Kaplan-Meier method

Click here to view



  Discussion Top


In this study, diffuse-type GC patients with ARID1A mutations were older and had fewer poorly differentiated tumors, more MSI-H tumors, fewer EBV infections, a higher propensity for ARID1A expression loss, a lower prevalence of peritoneal recurrence, and better 5-year OS and DFS rates than those without ARID1A mutations, which was not observed in intestinal-type GC. Furthermore, ARID1A mutations were associated with more PI3K/AKT pathway mutations, especially in intestinal-type GC. The multivariate analysis confirmed that ARID1A mutation status was an independent prognostic factor of OS and DFS rates in diffuse-type GC only.

Few studies have investigated ARID1A mutations in GC, and the frequency was reported to be 8%–29%,[1],[2],[7],[16] which was similar to the 11.4% reported in this study. The patient population in this study is larger than those of the previous studies regarding ARID1A mutations in GC. We believe that our results can provide useful and reliable information for the future study of ARID1A mutations in GC.

It was reported that ARID1A mutations are significantly correlated with MSI-H tumors in GC;[16] the loss of ARID1A expression is correlated with mismatch repair deficiency.[17] To date, there have been no reports regarding the relationship between ARID1A mutations and ARID1A expression in GC. Our findings demonstrated that ARID1A mutations are associated with the loss of ARID1A expression and MSI-H in diffuse-type GC only. According to the present study and the other reports mentioned above,[17],[18]ARID1A mutations might lead to the loss of ARID1A expression and mismatch repair deficiency in diffuse-type GC, which are associated with mismatch repair deficiency and the MSI-H phenotype. In contrast, ARID1A mutations were not associated with the loss of ARID1A expression or MSI status in intestinal-type in our GC patients. For intestinal-type GC, the only difference in the clinicopathological characteristics was more PI3K/AKT pathway mutations in ARID1A-mutant tumors than ARID1A nonmutant tumors. However, PI3K/AKT pathway mutation was reported to be not associated with GC patient prognosis. As a result, we hypothesize that the reason why ARID1A mutation were associated with a better prognosis in diffuse-type GC only was due to more MSI-H tumors and more likely to lose ARID1A expression in ARID1A-mutant tumors than ARID1A nonmutant tumors, which was not observed in intestinal-type GC.

ARID1A can suppress GC proliferation by targeting PIK3CA and PDK1.[18] Our results demonstrate that ARID1A mutations are associated with more PI3K/AKT pathway mutations and a lower prevalence of peritoneal recurrence. Furthermore, our patients with ARID1A mutations had significantly more PTEN mutations than those without ARID1A mutations (13.6% vs. 2.4%, P < 0.001). In a study by Davidson et al.,[19] the loss of ARID1A and PTEN expression was a specific predictor of malignancy in the cytology of body effusion. Consequently, ARID1A and PI3K/AKT pathway mutations played an important role in peritoneal recurrence in GC; however, furtherin vivo andin vitro studies regarding this issue are required.

Our results showed that the 5-year OS and DFS rates were not significantly different between ARID1A-mutant and ARID1A nonmutant GC. However, only in diffuse-type GC, patients with ARID1A mutations are associated with better 5-year OS and DFS rates than those without ARID1A mutations. As shown in [Table 3], diffuse-type GC patients with ARID1A mutations have fewer poorly differentiated tumors, more MSI-H tumors, fewer EBV infections, and are more likely to lose ARID1A expression. MSI-H GCs are reported to have a better survival rate than MSI-L/S GCs.[15] The loss of ARID1A expression is associated with a poor prognosis in GC.[20] More MSI-H tumors and loss expression of ARID1A expression which were reported to be associated with a better prognosis were more frequent in our diffuse-type GC patients with ARID1A mutations than those without ARID1A mutations. As a result, the above reasons might explain why ARID1A-mutant GCs were associated with better survival rates than ARID1A nonmutant GCs in our diffuse-type GC patients.

In the present study, intestinal-type GC patients with ARID1A mutations were associated with more PI3K/AKT pathway mutations than those without ARID1A mutations; however, PI3K/AKT pathway mutations have been reported to not be correlated with patient survival.[14] With the exception of the PI3K/AKT pathway mutations, the other clinicopathological characteristics were similar between patients with and without ARID1A mutations in intestinal-type GC patients. As a result, ARID1A mutations did not affect patient survival in our intestinal-type GC patients.

Targeted therapy for cancers with chromatin defects has been the spindle of research. Forin vitro andin vivo studies, ARID1A mutations could sensitize cancer cells to ATR inhibitors and affect topoisomerase 2A and the cell cycle, thus increasing the reliance on ATR checkpoint activity.[21]ARID1A-mutant ovarian carcinoma cell lines are sensitive to treatment with the reactive oxygen species-inducing agent elesclomol.[22] Furthermore, for advanced nonclear cell renal cell carcinoma patients, ARID1A-mutant tumors show a good response to the combination of the VEGF inhibitor bevacizumab and the mTOR inhibitor everolimus.[23] Consequently, morein vivo andin vitro studies are required to investigate targeted therapies for ARID1A-mutant GC in the future.

There are some limitations of our study. This is a retrospective study and selection bias might exist. Although the present study enrolled the largest population investigating ARID1A mutations and expression in GC, more patients reenrolled from different countries and races are required to further validate our results. As shown in Supplementary Table S1, the frequencies of the mutation hot spots range from 0% to 2.32% in this project. Due to high heterozygosity in cancer samples, it is hard to discriminate somatic homozygous or heterozygous mutations in the data. If we focus on variant percentage of the mutant allele, all mutations in this study exist as heterozygous. Moreover, we did not perform single-nucleotide polymorphism (SNP) of these mutated regions in ARID1A gene. In our future study, we will investigate SNP of these mutated regions and their correlation with GC patient prognosis.


  Conclusion Top


Our results demonstrate that diffuse-type GC patients with ARID1A mutations were correlated with fewer poorly differentiated tumors, more MSI-H tumors, fewer EBV infections, increased likelihood for ARID1A expression loss, a lower prevalence of peritoneal recurrence, and better OS and DFS rates than ARID1A nonmutant GC patients, which was not observed in intestinal-type GC patients. We hope our findings will provide physicians with useful information for GC treatment in the future.

Financial support and sponsorship

This research was supported by the Ministry of Science and Technology, Taiwan (105-2628-B-075-004-MY2). None of the sources of funding played a role in the study design, data collection, the analysis and interpretation of data, the writing of the manuscript, or the decision to submit the manuscript for publication.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Wang K, Kan J, Yuen ST, Shi ST, Chu KM, Law S, et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet 2011;43:1219-23.  Back to cited text no. 1
    
2.
Zang ZJ, Cutcutache I, Poon SL, Zhang SL, McPherson JR, Tao J, et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet 2012;44:570-4.  Back to cited text no. 2
    
3.
Nagarajan N, Bertrand D, Hillmer AM, Zang ZJ, Yao F, Jacques PÉ, et al. Whole-genome reconstruction and mutational signatures in gastric cancer. Genome Biol 2012;13:R115.  Back to cited text no. 3
    
4.
Yoon K, Lee S, Han TS, Moon SY, Yun SM, Kong SH, et al. Comprehensive genome- and transcriptome-wide analyses of mutations associated with microsatellite instability in Korean gastric cancers. Genome Res 2013;23:1109-17.  Back to cited text no. 4
    
5.
Wiegand KC, Lee AF, Agha OM, Chow C, Kalloger SE, Scott DW, et al. Loss of BAF250a (ARID1A) is frequent in high-grade endometrial carcinomas. J Pathol 2011;224:328-33.  Back to cited text no. 5
    
6.
Guan B, Mao TL, Panuganti PK, Kuhn E, Kurman RJ, Maeda D, et al. Mutation and loss of expression of ARID1A in uterine low-grade endometrioid carcinoma. Am J Surg Pathol 2011;35:625-32.  Back to cited text no. 6
    
7.
Jones S, Li M, Parsons DW, Zhang X, Wesseling J, Kristel P, et al. Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. Hum Mutat 2012;33:100-3.  Back to cited text no. 7
    
8.
Wiegand KC, Shah SP, Agha OM, Zhao Y, Tse K, Zeng T, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 2010;363:1532-43.  Back to cited text no. 8
    
9.
Wu RC, Wang TL, Shih IeM. The emerging roles of ARID1A in tumor suppression. Cancer Biol Ther 2014;15:655-64.  Back to cited text no. 9
    
10.
Wu JN, Roberts CW. ARID1A mutations in cancer: Another epigenetic tumor suppressor? Cancer Discov 2013;3:35-43.  Back to cited text no. 10
    
11.
Fang WL, Lan YT, Huang KH, Liu CA, Hung YP, Lin CH, et al. Clinical significance of circulating plasma DNA in gastric cancer. Int J Cancer 2016;138:2974-83.  Back to cited text no. 11
    
12.
Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al., edtiors. AJCC cancer staging manual. 8th ed. Chicago: Springer; 2017.  Back to cited text no. 12
    
13.
Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810-20.  Back to cited text no. 13
    
14.
Fang WL, Huang KH, Lan YT, Lin CH, Chang SC, Chen MH, et al. Mutations in PI3K/AKT pathway genes and amplifications of PIK3CA are associated with patterns of recurrence in gastric cancers. Oncotarget 2016;7:6201-20.  Back to cited text no. 14
    
15.
Fang WL, Chang SC, Lan YT, Huang KH, Chen JH, Lo SS, et al. Microsatellite instability is associated with a better prognosis for gastric cancer patients after curative surgery. World J Surg 2012;36:2131-8.  Back to cited text no. 15
    
16.
Kim YS, Jeong H, Choi JW, Oh HE, Lee JH. Unique characteristics of ARID1A mutation and protein level in gastric and colorectal cancer: A meta-analysis. Saudi J Gastroenterol 2017;23:268-74.  Back to cited text no. 16
[PUBMED]  [Full text]  
17.
Kim KJ, Jung HY, Oh MH, Cho H, Lee JH, Lee HJ, et al. Loss of ARID1A expression in gastric cancer: Correlation with mismatch repair deficiency and clinicopathologic features. J Gastric Cancer 2015;15:201-8.  Back to cited text no. 17
    
18.
Zhang Q, Yan HB, Wang J, Cui SJ, Wang XQ, Jiang YH, et al. Chromatin remodeling gene AT-rich interactive domain-containing protein 1A suppresses gastric cancer cell proliferation by targeting PIK3CA and PDK1. Oncotarget 2016;7:46127-41.  Back to cited text no. 18
    
19.
Davidson B, Pinamonti M, Cuevas D, Holth A, Zeppa P, Hager T, et al. The diagnostic role of PTEN and ARID1A in serous effusions. Virchows Arch 2018;472:425-32.  Back to cited text no. 19
    
20.
Inada R, Sekine S, Taniguchi H, Tsuda H, Katai H, Fujiwara T, et al. ARID1A expression in gastric adenocarcinoma: Clinicopathological significance and correlation with DNA mismatch repair status. World J Gastroenterol 2015;21:2159-68.  Back to cited text no. 20
    
21.
Williamson CT, Miller R, Pemberton HN, Jones SE, Campbell J, Konde A, et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat Commun 2016;7:13837.  Back to cited text no. 21
    
22.
Kwan SY, Cheng X, Tsang YT, Choi JS, Kwan SY, Izaguirre DI, et al. Loss of ARID1A expression leads to sensitivity to ROS-inducing agent elesclomol in gynecologic cancer cells. Oncotarget 2016;7:56933-43.  Back to cited text no. 22
    
23.
Voss MH, Molina AM, Chen YB, Woo KM, Chaim JL, Coskey DT, et al. Phase II trial and correlative genomic analysis of everolimus plus bevacizumab in advanced non-clear cell renal cell carcinoma. J Clin Oncol 2016;34:3846-53.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed662    
    Printed51    
    Emailed0    
    PDF Downloaded133    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]