Clinical significance of glutamate metabotropic receptors in renal cell carcinoma risk and survival

doi:10.1002/cam4.1901

. 2018 Dec;7(12):6104-6111.

doi: 10.1002/cam4.1901. Epub 2018 Nov 28.

Clinical significance of glutamate metabotropic receptors in renal cell carcinoma risk and survival

Chao-Yuan Huang^{1

2}, Yu-Mei Hsueh^{3

4}, Lih-Chyang Chen⁵, Wei-Chung Cheng^{6

7

8}, Chia-Cheng Yu^{9

10

11}, Wei-Jen Chen¹², Te-Ling Lu¹³, Kuo-Jin Lan¹³, Cheng-Hsueh Lee¹⁴, Shu-Pin Huang^{14

15

16

17}, Bo-Ying Bao^{13

18

19}

Affiliations

¹ Department of Urology, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
² Department of Urology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan.
³ Department of Family Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
⁴ Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁵ Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
⁶ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
⁷ Research Center for Tumor Medical Science, China Medical University, Taichung, Taiwan.
⁸ Drug Development Center, China Medical University, Taichung, Taiwa.
⁹ Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
¹⁰ Department of Urology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
¹¹ Department of Pharmacy, Tajen University, Pingtung, Taiwan.
¹² School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan.
¹³ Department of Pharmacy, China Medical University, Taichung, Taiwan.
¹⁴ Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
¹⁵ Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁶ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁷ Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
¹⁸ Sex Hormone Research Center, China Medical University Hospital, Taichung, Taiwan.
¹⁹ Department of Nursing, Asia University, Taichung, Taiwan.

PMID: 30488581
PMCID: PMC6308098
DOI: 10.1002/cam4.1901

Clinical significance of glutamate metabotropic receptors in renal cell carcinoma risk and survival

Chao-Yuan Huang et al. Cancer Med. 2018 Dec.

. 2018 Dec;7(12):6104-6111.

doi: 10.1002/cam4.1901. Epub 2018 Nov 28.

Authors

Affiliations

¹ Department of Urology, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
² Department of Urology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan.
³ Department of Family Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
⁴ Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁵ Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
⁶ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
⁷ Research Center for Tumor Medical Science, China Medical University, Taichung, Taiwan.
⁸ Drug Development Center, China Medical University, Taichung, Taiwa.
⁹ Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
¹⁰ Department of Urology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
¹¹ Department of Pharmacy, Tajen University, Pingtung, Taiwan.
¹² School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan.
¹³ Department of Pharmacy, China Medical University, Taichung, Taiwan.
¹⁴ Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
¹⁵ Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁶ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁷ Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
¹⁸ Sex Hormone Research Center, China Medical University Hospital, Taichung, Taiwan.
¹⁹ Department of Nursing, Asia University, Taichung, Taiwan.

PMID: 30488581
PMCID: PMC6308098
DOI: 10.1002/cam4.1901

Abstract

Accumulating evidence suggests the roles of glutamate metabotropic receptors (GRMs) in cancer, in addition to synaptic signalling. The present study assessed the associations of genetic variants in eight GRM genes with regard to risk and overall survival (OS) in 780 renal cell carcinoma (RCC) patients and controls. After adjustment for known risk factors, GRM5 rs7102764 T was associated with an increased risk of RCC (P = 0.006). Additional analysis has provided evidence that rs7102764 T was correlated with a higher expression of GRM5, which is consistently found to be upregulated in tumours, compared to normal tissues. Furthermore, the GRM3 rs701332 C, GRM4 rs2499707 T, and GRM4 rs4713742 T alleles were significantly associated with a poorer OS (P ≤ 0.030). The three loci were also observed to have strong cumulative effects on OS. Additional analysis has revealed a significant genotype-expression correlation of rs2499707 T with increased GRM4 expression, which in turn leads to poorer OS in patients with RCC. GRMs might be involved in RCC development and progression, and genetic variants in GRMs might be promising biomarkers.

Keywords: glutamate metabotropic receptors; prognosis; renal cell carcinoma; single-nucleotide polymorphisms; survival.

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Figures

**Figure 1**
Impact of genetic variants of *GRM3* and *GRM4* on renal cell carcinoma (RCC) survival. Kaplan‐Meier curves of overall survival for RCC patients with 0, 1‐2, or >2 risk alleles (*GRM3* rs701332 C, *GRM4* rs2499707 T, and *GRM4* rs4713742 T). The numbers in parentheses indicate the number of patients

**Figure 2**
The expression quantitative trait loci analysis of *GRM* SNPs and gene expression levels. Correlations of (A) rs7102764 genotypes with *GRM5* expression, (B) rs701332 genotypes with *GRM3* expression, (C) rs2499707 genotypes with *GRM4* expression, and (D) rs4713742 genotypes with *GRM4* expression. The numbers in parentheses indicate the number of patients

**Figure 3**
Roles of *GRM3*, *GRM4*, and *GRM5* expression in renal cell carcinoma (RCC) progression. *GRM3*, *GRM4*, and *GRM5* expression levels in (A) normal and tumour tissues, (B) different stages, and (C) different grades of RCC. (D) Kaplan‐Meier curves of overall survival according to *GRM3*, *GRM4*, and *GRM5* expression levels. Patients were dichotomised at the mean gene expression level into the low and high groups. The numbers in parentheses indicate the number of patients

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References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7‐30. - PubMed
1. Huang CY, Chu JS, Pu YS, et al. Effect of urinary total arsenic level and estimated glomerular filtration rate on the risk of renal cell carcinoma in a low arsenic exposure area. J Urol. 2011;185(6):2040‐2044. - PubMed
1. Zbar B, Brauch H, Talmadge C, Linehan M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature. 1987;327(6124):721‐724. - PubMed
1. Fairman WA, Amara SG. Functional diversity of excitatory amino acid transporters: ion channel and transport modes. Am J Physiol. 1999;277(4 Pt 2):F481‐F486. - PubMed
1. Prickett TD, Samuels Y. Molecular pathways: dysregulated glutamatergic signaling pathways in cancer. Clin Cancer Res. 2012;18(16):4240‐4246. - PMC - PubMed

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[1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7‐30. - PubMed

[2] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7‐30. - PubMed

[3] Huang CY, Chu JS, Pu YS, et al. Effect of urinary total arsenic level and estimated glomerular filtration rate on the risk of renal cell carcinoma in a low arsenic exposure area. J Urol. 2011;185(6):2040‐2044. - PubMed

[4] Huang CY, Chu JS, Pu YS, et al. Effect of urinary total arsenic level and estimated glomerular filtration rate on the risk of renal cell carcinoma in a low arsenic exposure area. J Urol. 2011;185(6):2040‐2044. - PubMed

[5] Zbar B, Brauch H, Talmadge C, Linehan M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature. 1987;327(6124):721‐724. - PubMed

[6] Zbar B, Brauch H, Talmadge C, Linehan M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature. 1987;327(6124):721‐724. - PubMed

[7] Fairman WA, Amara SG. Functional diversity of excitatory amino acid transporters: ion channel and transport modes. Am J Physiol. 1999;277(4 Pt 2):F481‐F486. - PubMed

[8] Fairman WA, Amara SG. Functional diversity of excitatory amino acid transporters: ion channel and transport modes. Am J Physiol. 1999;277(4 Pt 2):F481‐F486. - PubMed

[9] Prickett TD, Samuels Y. Molecular pathways: dysregulated glutamatergic signaling pathways in cancer. Clin Cancer Res. 2012;18(16):4240‐4246. - PMC - PubMed

[10] Prickett TD, Samuels Y. Molecular pathways: dysregulated glutamatergic signaling pathways in cancer. Clin Cancer Res. 2012;18(16):4240‐4246. - PMC - PubMed

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Clinical significance of glutamate metabotropic receptors in renal cell carcinoma risk and survival

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Clinical significance of glutamate metabotropic receptors in renal cell carcinoma risk and survival

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