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. 2021 Mar 31;16(3):e0249040. doi: 10.1371/journal.pone.0249040

Prognostic and clinicopathological significance of GPRC5A in various cancers: A systematic review and meta-analysis

Lu Dai 1, Xiao Jin 1, Zheng Liu 1,*
Editor: Hiromu Suzuki2
PMCID: PMC8011795  PMID: 33788883

Abstract

Background

GPRC5A is associated with various cancer initiation and progression. Controversial findings have been reported about GPRC5A prognostic characteristics, and no meta-analysis has been conducted to assess the relationship between GPRC5A and cancer prognosis. Therefore, the objective of this meta-analysis is to evaluate the overall prognostic effectiveness of GPRC5A.

Methods

We first conducted a systematic search in the PubMed, Embase, Web of Science, CNKI, Cochrane, and WangFang databases. The hazard ratio (HR) and odds ratios (OR) with 95% CI were then pooled to assess the associations between GPRC5A expression and overall survival (OS), disease-free survival (DFS), event-free survival (EFS), and clinicopathological characteristics. Chi-squared test and I2 statistics were completed to evaluate the heterogeneity in our study. A random‐effects model was used when significant heterogeneity existed (I2>50% and p<0.05); otherwise, we chose the fixed-effect model. Subgroup analysis was stratified by tumor type, region, HR obtained measurements, and sample capacity to explore the source of heterogeneity.

Results

In total, 15 studies with 624 patients met inclusion criteria of this study. Our results showed that higher expression of GPRC5A is associated with worse OS (HR:1.69 95%CI: 1.20–2.38 I2 = 75.6% p = 0.000), as well as worse EFS (HR:1.45 95%CI: 1.02–1.95 I2 = 0.0% p = 0.354). Subgroup analysis indicated that tumor type might be the source of high heterogeneity. Additionally, cancer patients with enhanced GPRC5A expression were more likely to lymph node metastasis (OR:1.95, 95%CI 1.33–2.86, I2 = 43.9%, p = 0.129) and advanced tumor stage (OR: 1.83, 95%CI 1.15–2.92, I2 = 61.3%, p = 0.035), but not associated with age, sex, differentiation, and distant metastasis.

Conclusion

GPRC5A can be a promising candidate for predicting medical outcomes and used for accurate diagnosis, prognosis prediction for patients with cancer; however, the predictive value of GPRC5A varies significantly according to cancer type. Further studies for this mechanism will be necessary to reveal novel insights into application of GPRC5A in cancers.

Introduction

Cancer is an important public health issue worldwide, and most cancer-associated deaths (90%) are caused by metastatic cancer [1]. Due to most patients are already at the advanced stage when diagnosed, which makes them have little chance to be treated with surgery or radiotherapy It is crucial to identify diagnostic or prognostic biomarkers and therapeutic targets to improve clinical outcomes. Cancer molecular targeted therapy has recently experienced remarkable advances. The targeted drugs approved by the FDA for clinical use in the last decades, such as nivolumab [2], olaparib [3], and blinatumomab [4], have made substantial improvements in cancer diagnosis and therapy, thus producing optimism in the fight against cancer. Although many tumor markers have been found playing an essential role in various cancers in recent years, only a few of them have been used in clinical practice.

G-protein-couple receptor, family C, group 5 member A (GPRC5A), which was identified as an all-trans-retinoic acid-inducible protein, is a member of class c orphan GPCRs. GPRC5A, also known as RAI3 or RAIG1, can activate numerous signal transduction cascades, including the NF-κB, cAMP-Gs α, FAK/Scr, and STAT3 signaling pathways [5]. Recently, GPRC5A has been proven to be an essential role in human cancers. However, the biological functions of GPRC5A are controversial. Previous research indicated that GPRC5A is considered an anti-oncogene in lung cancer and the expression level of GPRC5A in lung cancer tissue is much lower than that in normal lung tissue [6]. Tao Q et al. reported that high expression of GPRC5A inhibited NSCLC cell viability and enhanced apoptosis in an in vitro experiment [7]. Later, the same tumor suppressor ability was found in head and neck squamous cell carcinoma (HNSCC) [8] and oral squamous cell carcinoma (OSCC) [9]. Dysregulation of GPRC5A expression has been observed in other human cancers, such as breast cancer [10], colorectal cancer [11], gastric cancer [12], hepatocellular carcinoma [13], pancreatic cancer [14], prostate cancer [15] and ovarian cancer [16]. However, GPRC5A was also found to serve as an oncogene in these cancers, and the high expression of GPRC5A was related to tumorigenesis. This dual behavior makes GPRC5A a fascinating gene to study.

The prognostic role of GPRC5A in cancer remains unclear. Jin E et al. found that lung cancer patients with high expression of GPRC5A tended to have a better prognosis [17]. Similarly, several studies suggest that overexpression of GPRC5A predicts poor prognosis in gastric [14], pancreatic [16], and colorectal cancer [12] patients. Moreover, some contradictory views exist about the prognostic effect of GPRC5A in various cancers, including breast cancer [10], pancreatic cancer [14], and hepatocellular cancer [13]. Nagahata et al. [10] implied that the upregulation of GPRC5A might be a frequent feature of poor prognosis in breast cancer. However, Cheng et al. reported that there was no significant correlation between GPRC5A expression and clinicopathological characteristic immunohistochemical (IHC) tissue microarray analysis [18]. Therefore, the results of different studies are controversial and no meta‐analysis has been performed to assess the diagnostic utility of GPRC5A among multiple types of cancer. In response, this meta‐analysis was conducted to examine the prognostic value of GPRC5A in different types of human cancers from a collection of published results.

Methods

Search strategy

This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [19], we conducted a systematic search of PubMed, Embase, Web of Science, CNKI, Cochrane Library, and WangFang on July 8, 2020, using the MeSH terms. The studies were identified using the search strategy: (GPRC5A OR RAI3 OR G protein-coupled receptor, family C, group 5, member a protein OR RAIG1) AND (cancer OR carcinoma OR tumor OR neoplasm OR malignancy). All English and Chinese studies were enrolled. Reference lists of the included articles were reviewed to get all the reports about GPRC5A before the deadline.

Inclusion and exclusion criteria

Inclusion criteria include (1) studies of adult human; (2) the cancers in the studies must be certified by the gold standard; (3) GPRC5A was tested by immunohistochemistry(IHC); (4) the content of the article focus on the correction of GPRC5A with the prognosis and clinicopathologic characteristics of multiple cancers; (5) hazard ratio(HR) and 95% confidence interval(CI) were provided in article or enough data was given to calculate the HR with 95% CI; (6) all English and Chinese studies were included.

Exclusion criteria include (1) reviews or meta-analysis; (2) letters, conference reports and basic studies; (2) duplicated records; (3) no sufficient data to calculate the HR with 95%CI.

Data extraction and quality assessment

Two investigators separately gained the information and data from primary publications. The specific information and data were as follows: the first author’s name, publication year, country, cancer type, time of sample collection, sample capacity, outcome measures, method of detection, and cut-off value. For the clinically relevant factors, age, sex, differentiation, tumor invasion depth, lymph node metastasis, and distant metastasis were extracted.

The Newcastle-Ottawa Scale (NOS) was also utilized to assess the quality of studies in the meta-analysis, which ranges from 0–9. A score of 5 or higher indicates strong evidence; a score from 4 to 5 (not included) indicates medium evidence, and a score below 4 indicates weak evidence. Studies with strong evidence (NOS score ≥ 5 points) were included in this study [20].

Statistical analysis

We used Stata 15.1 software to calculate extracted data in the meta-analysis, and Engauge Digitizer 10.0 was used to get survival data when literature only provided a Kaplan-Meier curve. Pooled HRs with 95% CI for OS, DFS, EFS, and odds ratios (ORs) for clinicopathological parameters were calculated. If HR or OR>1, and 95%CI did not contain 1, the study was recognized as statistically significant. Chi-squared test and I2 statistics were completed to evaluate the heterogeneity in our study. A random‐effects model was used when significant heterogeneity existed (I2>50% and p<0.05); otherwise, we choose the fixed-effect model. Subgroup analysis was stratified by tumor type, region, HR obtained measurements, and sample capacity to explore the source of heterogeneity.

Publication bias was assessed by Begg’s and Egger’s tests [21]. Meanwhile, a sensitivity analysis was performed to assess the reliability and stability of our results; p values<0.05 meant statistically significant.

Results

Search results and study characteristics

According to the literature selection procedure (Fig 1), 624 studies related to GPRC5A and cancer prognosis were identified from online database searches using specific search terms. A total of 609 articles were excluded after reviewing the titles, abstracts and data. Finally, 15 studies comprising a total of 3349 patients were included in the meta-analysis. The types of cancer in the studies included: colorectal cancer [22, 23], pancreatic cancer [24–27], gastric cancer [28, 29], esophageal cancer [30], prostate cancer [31], hepatocellular cancer [32], head and neck squamous cell carcinoma [33], lung cancer [34], and ovarian cancer [35]. The characteristics of the enrolled articles are summarized in Table 1. All studies were published from 2013 to 2020, and the sample sizes ranged from 86 to 503 patients. The expression level of GPRC5A was detected by immunohistochemistry (IHC), and patients were divided into two groups according to their GPRC5A expression level. Of the eligible articles, eight studies were from China, three were from Germany, two were from the UK, one was from Japan, and one was from Sweden. Of these 15 studies, 14 were used to evaluate the HR of OS, three were used to evaluate the HR of DFS, and two were used to evaluate the HR of EFS. Moreover, the NOS score varied from five to eight, suggesting that our study was of solid methodological quality.

Fig 1. Flow diagram of the study search and selection process.

Fig 1

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Table 1. The main characteristic of enrolled records in the meta-analysis.

Author Year Country Cancer type Included period Sample Source of HR Endpoint Assay method Cut-off value NOS
Greenhough et al 2018 UK CRC N 320 indirectly EFS N N 7
Jahny et al 2016 Germany PDAC N 376 indirectly OS IHC staining intensist>30% 6
Liu et al 2015 China GC 2005–2009 106 directly OS IHC Score≥6 6
El et al 2019 Germany ESCC N 235 indirectly OS IHC staining intensist>2+ 8
Sawada et al 2019 Japan PCa N 421 directly 0S N N 7
Zheng et al 2013 China HCC 2001–2009 106 directly OS/DFS IHC Score>4 6
Liu et al 2017 China HNSC N 86 indirectly OS/DFS IHC Score>30% 6
Zougman et al 2013 UK CRC N 367 directly OS IHC Score>3 5
Jin et al 2018 China LC 2007–2009 110 indirectly OS IHC Score≥6 7
Galceran et al 2019 Sweden OC 2002–2006 136 indirectly OS/EFS IHC Score>2 6
Er et al 2020 China LC N 503 indirectly OS IHC N 6
Melling et al 2019 Germany GC 1994–2006 98 indirectly OS IHC Score≥2 7
Chang et al 2019 China PDAC N 135 indirectly OS N N 6
Jiang et al 2019 China PC N 176 indirectly OS/DFS N N 8
Wu et al 2019 China PC N 174 indirectly OS N N 6
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Association between GPRC5A level and OS

In this meta-analysis, fourteen studies demonstrated the correction between GPRC5A expression and OS in human cancer pooled HRs with 95%CIs evaluated for OS was (1.69 95%CI 1.20–2.38 p = 0.05), using a random-effects model for high heterogeneity (I2 = 75.6% P< 0.001) (Fig 2). These results indicated that GPRC5A might be a predictive factor for tumor prognosis and high GPRC5A density is associated with a significantly lower OS rate in cancer patients.

Fig 2. Forest plot for the association between GPRC5A expression and OS.

Fig 2

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Association between GPRC5A level and DFS and EFS

Three records, including 368 patients, evaluated HRs for DFS. There was statistically significant heterogeneity (I2 = 73.6% p = 0.023); thus, a random-effect model was conducted to calculate the pooled HR for DFS: (1.86 95%CI 0.70–4.91, p = 0.05) (Fig 3). We found that there was no significant association of high GPRC5A expression with lower DFS. When we come to EFS, only two studies provided data to calculate the HRs. As shown in Fig 4, results showed that high GPRC5A expression was significantly related to pooler EFS in this meta-analysis (HR:1.41 95%CI 1.02–1.95 I2 = 0.0% p = 0.354).

Fig 3. Forest plot for the association between GPRC5A expression and DFS.

Fig 3

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Fig 4. Forest plot for the association between GPRC5A expression and EFS.

Fig 4

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Subgroup analysis of the prognostic effect of GPRC5A among multiple cancer

To explore the sources of high heterogeneity in this meta-analysis, subgroup analyses for OS data were performed by tumor type, region, HR obtained measurements, sample capacity (Table 2). Among 14 enrolled studies in the subgroup analysis, nine different cancers have been discussed, including pancreatic cancer (n = 4), gastric cancer (n = 2), lung cancer (n = 2), prostate cancer (n = 1), hepatocellular cancer (n = 1), head and neck squamous cell carcinoma (n = 1), colorectal cancer (n = 1), ovarian cancer (n = 1), and esophageal cancer (n = 1). As been shown in Fig 5, the mixed effects of individual cancers have been calculated. High expression level of GPRC5A predicted a worse OS in pancreatic cancer (HR: 1.71 95%CI: 1.29–2.26 I2 = 23.8% p = 0.268), Gastric cancer (HR: 1.97 95%CI: 1.33–2.91 I2 = 0.0% p = 0.381), prostate cancer (HR: 6.13 95%CI:1.02–36.80), hepatocellular cancer (HR: 9.10 95%CI: 2.10–39.46), and esophageal cancer (HR:2.58 95%CI:1.26–5.29). However, there was no association in colorectal cancer (HR:1.40 95%CI:0.73–2.66), ovarian cancer (HR:1.45 95%CI:0.52–4.07), and head and neck squamous cell carcinoma (HR: 0.87 95%CI:0.45–1.70). Controversial results observed in lung cancer with pooled HR = 0.73 (95%CI: 0.49–1.11 I2 = 0.0% p = 0.872) and subgroup analysis also showed GPRC5A expression predicted unfavorable prognosis in digestive system (HR: 2.32 95%CI: 1.73–3.11 I2 = 0.0% p = 0.479) (Fig 6), and other systems (HR: 1.29 95%CI:1.09–1.54 I2 = 77.2% p<0.000). To further explore the sources of high heterogeneity, a sensitivity analysis was performed. As shown in Fig 7, the observed heterogeneity disappeared while omitting the two lung cancer studies as a source of heterogeneity.

Table 2. Subgroup analysis for the correction between GPRC5A and OS.

Heterogeneity
Variables Studies(n) HR 95%CI I2 P Model
Cancer type
    Digestive cancer 4 2.32(1.73–3.11) 0.0% 0.479 Random effects
    Non-digestive cancer 10 1.29(1.09–1.54) 77.2% 0.000 Random effects
    Lung cancer 2 0.52(0.34–0.78) 61.6% 0.107 Random effects
    Other cancers except lung cancer 12 1.77(1.50–2.07) 47.9% 0.032 Random effects
Region
    Asian 9 1.31(1.05–1.63) 81.2% 0.000 Random effects
    Non-Asian 5 1.69(1.38–2.07) 49.6% 0.094 Random effects
HR obtained method
    Direct method 4 3.36(2.19–5.14) 0.0% 0.450 Random effects
    Indirect method 10 1.34(1.14–1.57) 74.3% 0.000 Random effects
Sample size
    n>150 7 1.50(1.23–1.83) 83.8% 0.000 Random effects
    n<150 7 1.50(1.20–1.89) 63.2% 0.012 Random effects
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Fig 5. Forest plot of Overall analysis of GPRC5A expression in multiple carcinoma.

Fig 5

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Fig 6. Forest plot for the subgroup analysis.

Fig 6

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Digestive cancer.

Fig 7. Forest plot for the subgroup analysis.

Fig 7

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Non-Lung cancer.

In addition, to further demonstrate the predictive role of GPRC5A in multiple tumors, more subgroup analysis was conducted based on region, HR obtained measurements, sample capacity. When it came to the region, pooled HR was (1.31 95%CI 1.05–1.63) for the Asian records with high heterogeneity (I2 = 81.2%, p<0.001). as for the non-Asian subgroup, pooled HR was (HR:1.69, 95%CI 1.38–2.07) with no heterogeneity (I2 = 49.6% p = 0.094) (Fig 8). The combined HR for large and small sample capacity were 1.50 (95%CI 1.23–1.83 I2 = 83.8% p<0.001) and 1.50 (95%CI 1.20–1.89 I2 = 63.2% p = 0.012) (Fig 9). In our meta-analysis, only a few studies provided specific HR data evaluated for OS. Indirectly data based on the Engauge Digitizer could contribute to the high heterogeneity. The pooled HR for directly and indirectly HR obtained measurement were 3.36 (95%CI 2.19–5.14 I2 = 0.0% P = 0.450) and 1.34 (95%CI 1.14–1.57 I2 = 74.3% P = 0.000) (Fig 10). Therefore, these results of subgroup analysis suggested that tumor type might be a major source of high heterogeneity.

Fig 8. Forest plot for the subgroup analysis.

Fig 8

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Region.

Fig 9. Forest plot for the subgroup analysis.

Fig 9

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Sample capacity.

Fig 10. Forest plot for the subgroup analysis.

Fig 10

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HR obtained measurement.

Association between GPRC5A level and clinicopathological parameters

Due to the limitation of the data, we only analyzed clinicopathologic features including age, sex, differentiation, tumor invasion depth, lymph node metastasis, and distant metastasis. All the detailed data are summarized in Table 3. High expression of GPRC5A was associated with Lymph node metastasis (OR:1.95, 95%CI 1.33–2.86, I2 = 43.9%, p = 0.129), advanced Tumor stage (OR: 1.83, 95%CI 1.15–2.92, I2 = 61.3%, p = 0.035), but not related to age (OR:1.14, 95%CI 0.86–1.52, I2 = 0.0%, p = 0.578), sex (OR 1.17, 95%CI 0.91–1.50, I2 = 0.0%, p = 0.863), differentiation (OR: 1.58, 95%CI 0.71–3.50, I2 = 88.5%, p<0.001), and distant metastasis (OR 1.40,95%CI0.59-3-32, I2 = 65.0%, p = 0.036).

Table 3. Meta‐analysis of the relationship between overexpressed GPRC5A and clinicopathological parameters.

Heterogeneity
Studies(n) Number of patients(n) OR LCI UCI I2 P Model
Sex 7 1118 1.17 0.91 1.50 0.0% 0.863 Fixed effects
Age 5 785 1.14 0.86 1.52 0.0% 0.578 Fixed effects
Tumor grade 7 955 1.58 0.71 3.50 88.5% 0.000 Random effects
T stage 5 957 1.83 1.15 2.92 61.3% 0.035 Random effects
Lymph node metastasis 5 783 1.95 1.33 2.86 43.9% 0.129 Fixed effects
Metastasis 4 602 1.40 0.59 3.32 65.0% 0.036 Random effects
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Note. LCI: lower confidence interval; OR: odds ratio; UCI: upper confidence interval.

Sensitivity analyses and publication bias

A sensitivity analysis was conducted to evaluate the reliability and stability of our results by omitting any individual studies (Fig 11). Fortunately, the pooled HR for OS was not influenced; this suggested that the result of our meta-analysis was believable. Additionally, Begg’s funnel plots and Egger’s test showed no significant publication bias was found for OS (Fig 12 Begg’sP ¼ 0.155 and Egger’s P ¼ 0.908).

Fig 11. Sensitivity analysis of the relationship between GPRC5A expression and OS.

Fig 11

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Fig 12. Begg’s funnel plot analysis of potential publication bias for OS.

Fig 12

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Discussion

The lack of effective biomarkers for early diagnosis of aggressive cancers is one of the most intractable issues in clinical cancer management. Recently, GPRC5A has received attention for its intriguing dual behavior in cancer. GPRC5A is dysregulated in several human cancers and may be a candidate target for cancer treatment. The effect of GPRC5A in various cancers has been reported to be different. GPRC5A has been reported as a tumor-suppressor gene in lung cancer. Loss of the GPRC5A gene may lead to the development of spontaneous lung cancers in mice [36]. Fujimoto J et al. found that deletion of GPRC5A can promote tumorigenesis by activating the NF-κB signaling pathway, which may lead to the development of acidophilic macrophage pneumonia (AMP) in GPRC5A knockout mice [37]. However, GPRC5A frequently expresses oncogenic characteristics in other cancers such as colon, gastric, liver, breast and pancreatic cancers. Knockdown of GPRC5A with siRNA can promote tumor cell apoptosis and reduce cell proliferation in colorectal cancer [38]. A vivo mouse model found that a lack of GPRC5A inhibited colitis-associated tumorigenesis [39]. In gastric cancer, GPRC5A expression levels are elevated in GC tissues compared with normal tissues and high expression of GPRC5A is significantly related to aggressive clinicopathological parameters and poor OS [40]. The same oncogenic characteristics of GPRC5A were observed in HCC [41].

In this study, we conducted a systematic review and meta-analysis to examine the prognostic value of GPRC5A in different types of human cancers from a collection of published results. Consistent with our hypothesis, we observed that high GPRC5A expression predicted poor OS, DFS, and EFS, in multiple cancer patients. To assess the specific relationship between the GPRC5A and the OS of each cancer type, subgroup analysis showed high expression of GPRC5A was significantly associated with poor prognosis in the majority of solid cancers studied such as pancreatic, gastric, prostate, hepatocellular and esophageal cancer, but no significant effect was observed in colorectal and ovarian cancer. In lung, as well as head and neck squamous cancer, high GPRC5A expression was associated with favorable prognosis. These findings suggest that GPRC5A expression may have clinical potential as an independent prognostic indicator for some types of cancer patients; however, the application CPRC5A may be different based on the types of cancer.

The results of this study should be taken into consideration in the context of certain limitations. First, as only 15 studies were enrolled, the data were relatively insufficient to pool results by tumor type, which prevented us from obtaining more comprehensive results. Well-designed and large-scale cohort studies are needed to certify the clinical value of GPRC5A in multiple cancers. Second, all the studies enrolled in our meta-analysis were retrospective articles. Most of these reports were not meant to explore the prognostic influence of GPRC5A. The accuracy of the collected data related to OS is unknown. HR and 95% CI values were not available for many of the studies, and extraction of the data from survival curves may have led to minor statistical errors. Third, heterogeneity existed in our study and may have been a result of the different cutoff values, tumor types, sample sources and follow-up periods across the studies. Additionally, we only included studies in English and Chinese, and records reported in other languages were omitted. Finally, although our results showed that the predictive value of GPRC5A varies significantly according to cancer type, we did not further study the mechanisms of this. Further studies will be needed to reveal novel insights into application of GPRC5A in cancer.

Conclusion

Although limitations were noted above, this was the first meta‐analysis to systematically assess the prognostic value of GPRC5A in human cancer. We enrolled 15 recent studies covering nine different types of cancers reported between 2010 and 2018 for our meta-analysis. In summary, our results suggest that GPRC5A can be a promising candidate for predicting medical outcomes and used for accurate diagnosis, prognosis prediction for patients with cancer; however, the predictive value of GPRC5A varies significantly according to cancer type. Current knowledge of the exact mechanism of these processes is limited. Further studies focused on the cellular and molecular mechanisms will be necessary to reveal novel insights into application of GPRC5A in cancers.

Supporting information

S1 Checklist

(DOC)

Click here for additional data file. (62.5KB, doc)

Acknowledgments

We would like to thank the researchers and study participants for their contributions.

Abbreviations

GPRC5A

G-protein-couple receptor, family C, group 5 member A

RAI3

retinoic acid-induced protein 3

RAIG1

retinoic acid-inducible gene 1

GPCRs

G protein-coupled receptors

HRs

hazard ratios

ORs

odds ratios

CIs

confidence intervals

OS

overall survival

DFS

disease-free survival

EFS

event-free survival

NOS

Newcastle-Ottawa Scale

IHC

Immunohistochemical

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Hiromu Suzuki

14 Jan 2021

PONE-D-20-28866

Prognostic and clinicopathological significance of GPRC5A in various cancers: a systematic review and meta-analysis

PLOS ONE

Dear Dr. liu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

This manuscript was carefully reviewed by 2 experts, and both of them found several issues which need to be addressed before this manuscript becomes potentially accepted. For instance, reviewer 1 suggested revision of the main text including introduction and discussion. Reviewer 2 indicted English writing problems. Please respond to each of the reviewer comments.

==============================

Please submit your revised manuscript by Feb 21 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

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Hiromu Suzuki, M.D., Ph.D.

Academic Editor

PLOS ONE

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have worked with detail meta-analysis wiith large subgroup analysis

The following commets are need to be corrected

1. Please update the introduction part wiht recent comments

2. Discussion part should be dicussed based on subgroup analsyis as well

3. strength and limitations of the study should be included

4 I couldnt see PRISMA statement. Kindly include the info regarding PRISMA guidleines

5. details on publication bias should be discussed on methodology and results section in detail

6. results on quality assessment should be discussed in detail

Reviewer #2: English wording need to be improved

Discussion should be improved in terms of structure and concept and comparison with the literature. The current discussion section is not strong enough to support the findings.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Shanthi Sabarimurugan

Reviewer #2: No

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PLoS One. 2021 Mar 31;16(3):e0249040. doi: 10.1371/journal.pone.0249040.r002

Author response to Decision Letter 0

5 Feb 2021

The details of our edits in the manuscript are outlined below.

REVIEWER #1

The authors have worked with detail meta-analysis with large subgroup analysis

The following comments are needed to be corrected

• Our Response: We thank the reviewer for their comments and enthusiasm for our paper.

•

Comment 1: Please update the introduction part with recent comments

• Our Response: We have updated the overall introduction section. Please see the revision in the second submission.

Comment 2: .Discussion part should be discussed based on subgroup analysis as well

• Our Response: We have added the discussion for subgroup analysis.

• From text: “To assess the specific relationship between the GPRC5A and the OS of each cancer type, subgroup analysis showed high expression of GPRC5A was significantly associated with poor prognosis in the majority of solid cancers studied such as pancreatic, gastric, prostate, hepatocellular and esophageal cancer, but no significant effect was observed in colorectal and ovarian cancer. In lung and head and neck squamous cancer, high GPRC5A expression was associated with favorable prognosis. These findings suggest that GPRC5A expression may have clinical potential as an independent prognostic indicator for some types of cancer patients; however, the application CPRC5A may be different based on the type of cancers.”

Comment 3. Strength and limitations of the study should be included

• Our Response: We did include both strength and limitations in the first submission and we also updated them in this revision.

• From text:

Strength: “Although limitations were noted above, this was the first meta‐analysis to systematically assess the prognostic value of GPRC5A in human cancers. We enrolled 15 recent studies covering nine different types of cancers reported between 2010 and 2018 for our meta-analysis. In summary, our results suggest that GPRC5A can be a promising candidate for predicting medical outcomes and used for accurate diagnosis, prognosis prediction for patients with cancer; however, the predictive value of GPRC5A varies significantly according to cancer type.”

Limitations: “The results of this study should be taken into consideration in the context of certain limitations. First, as only 15 studies were enrolled, the data were relatively insufficient to pool results by tumor type, which prevented us from obtaining more comprehensive results. Well-designed and large-scale cohort studies are needed to certify the clinical value of GPRC5A in multiple cancers. Second, all the studies enrolled in our meta-analysis were retrospective articles. Most of these reports were not meant to explore the prognostic influence of GPRC5A. The accuracy of the collected data related to OS is unknown. HR and 95% CI values were not available for many of the studies, and extraction of the data from survival curves may have led to minor statistical errors. Third, heterogeneity existed in our study and may have been a result of the different cutoff values, tumor types, sample sources and follow-up periods across the studies. Additionally, we only included studies in English and Chinese, and records reported in other languages were omitted. Finally, although our results showed that the predictive value of GPRC5A varies significantly according to cancer type, we did not further study the mechanisms of this. Further studies will be needed to reveal novel insights into application of GPRC5A in cancer..”

Comment 4: I couldn’t see PRISMA statement. Kindly include the info regarding PRISMA

Guidelines

• Our Response: We did included PRISMA statement in the method section and we updated it in this revision.

• From text:

“This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.”

Comment 5: details on publication bias should be discussed on methodology and results section in detail

• Our Response: We did include publication bias in the methods and result section in the first submission and we updated it in this revision.

• From text:

“Publication bias was assessed by Begg’s and Egger’s tests.”

“Additionally, Begg’s funnel plots and Egger’s test showed no significant publication bias was found for OS (Fig. 6 Begg’sP ¼ 0.155 and Egger’s P ¼ 0.908).”

Comment 6: results on quality assessment should be discussed in detail

• Our Response: We did quality assessment in the first submission and we have added more details in this revision.

• From text:

“Two investigators separately gained the information and data from primary publications. The specific information and data were as follows: The first author’s name, publication year, country, cancer type, time of sample collection, sample capacity, outcome measures, method of detection, and Cut-off value. For the clinically relevant factors, Age, Sex, differentiation, tumor invasion depth, lymph node metastasis, and distant metastasis were extracted.

The Newcastle-Ottawa Scale (NOS) was also utilized to assess the quality of studies in the meta-analysis, which ranges from 0-9. A score of 5 or higher indicates strong evidence; a score from 4 to 5 (not included) indicates medium evidence, and a score below 4 indicates weak evidence. Studies with strong evidence (NOS score ≥ 5 points) were included in this study.”

REVIEWER #2

Comment 1: English wording need to be improved

• Our Response: We have improved the overall English wording of this paper. This paper has been reviewed by a native English speaker. Please see the revision in the second submission.

Comment 2: Discussion should be improved in terms of structure and concept and comparison with the literature. The current discussion section is not strong enough to support the findings.

• Our Response: We have updated the overall discussion and added the discussion of subgroup analysis. Please see the revision in the second submission.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (211KB, docx)

Decision Letter 1

Hiromu Suzuki

10 Mar 2021

Prognostic and clinicopathological significance of GPRC5A in various cancers: a systematic review and meta-analysis

PONE-D-20-28866R1

Dear Dr. liu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Hiromu Suzuki, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Shanthi Sabarimurugan

Acceptance letter

Hiromu Suzuki

22 Mar 2021

PONE-D-20-28866R1

Prognostic and Clinicopathological significance of GPRC5A in various cancers: A systematic review and meta-analysis

Dear Dr. Liu:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Hiromu Suzuki

Academic Editor

PLOS ONE

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