|Year : 2020 | Volume
| Issue : 3 | Page : 93-100
The clinical significance of ARID1A mutations in gastric cancer patients
Chia-Hung Wu1, Chien-Hsun Tseng1, Kuo-Hung Huang1, Wen-Liang Fang1, Ming-Huang Chen2, Anna Fen-Yau Li3, Chew-Wun Wu1
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 Submission||18-Aug-2019|
|Date of Decision||16-Sep-2019|
|Date of Acceptance||26-Mar-2020|
|Date of Web Publication||30-May-2020|
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
Source of Support: None, Conflict of Interest: None
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 Jul 5];53:93-100. Available from: http://www.e-fjs.org/text.asp?2020/53/3/93/285401
| Introduction|| |
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.,,,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.,,, The SWI/SNF complex regulates target genes downstream of TP53; therefore, ARID1A is considered to act as a tumor suppressor gene.
The frequency of ARID1A mutations was reported to be 8%–29% in GC.,, However, the frequencies and patterns of ARID1A mutations are different among various cancers., 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, and common GC-related genes (PI3K/AKT pathway, TP53, BRAF) were also analyzed.
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|| |
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. 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.
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.
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 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.
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.
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, 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. 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, 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, 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|
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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|| |
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 |
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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|
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|Table 3: Clinical profile in diffuse-type gastric cancer patients with/without ARID1A mutation|
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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).
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|
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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|
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|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|
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| Discussion|| |
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%,,,, 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; the loss of ARID1A expression is correlated with mismatch repair deficiency. 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,,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. 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., 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. The loss of ARID1A expression is associated with a poor prognosis in GC. 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. 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.ARID1A-mutant ovarian carcinoma cell lines are sensitive to treatment with the reactive oxygen species-inducing agent elesclomol. 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. 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|| |
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.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]