Polymorphisms of the receptor for advanced glycation end-products and glyoxalase I in patients with renal cancer

Abstract

The receptor for advanced glycation end products (RAGE) and its ligands are involved in the pathogenesis of cancer. Glyoxalase I (GLO1) is an enzyme which detoxifies advanced glycation end product (AGE) precursors. The aim of the study was to find out the relationship between four polymorphisms (single nucleotide polymorphism, SNP) of the RAGE gene (AGER) and one SNP of the GLO1 gene and clear cell renal cancer (ccRCC). All polymorphisms (rs1800625 RAGE -429T/C, rs1800624 -374T/A, rs3134940 2184A/G, rs2070600 557G/A (G82S), and GLO1 rs4746 419A/C(E111A)) were determined by PCR-RFLP in 214 patients with ccRCC. A group of 154 healthy subjects was used as control. We found significant differences in the allelic and genotype frequencies of GLO1 E111A (419A/C) SNP between patients and controls-higher frequency of the C allele in ccRCC-58.6 vs. 44.5% in controls, OR (95% CI) 1.77 (1.32-2.38), p = 0.0002 (corrected p = 0.001); OR (95% CI) CC vs. AA 2.76 (1.5-4.80), p = 0.0004 (corrected p = 0.002); and AC+CC vs. AA 2.03 (1.23-3.30), p = 0.0034 (corrected p = 0.017). High aggressiveness of the tumor (grade 4) was associated with the presence of C allele RAGE -429T/C SNP (original p = 0.001, corrected p = 0.005) and G allele RAGE 2184A/G SNP (p < 0.001 and p < 0.005), and for genotypes RAGE -429CC (original p = 0.008, corrected p = 0.04) and RAGE 2184GG SNP (original p = 0.005, corrected p = 0.025). Our results demonstrate the link of E111A GLO1 SNP to the presence of the tumor and the connection of RAGE -429T/C and 2184A/G SNPs with the aggressiveness of the tumor. Further studies are required, especially with respect to potential therapeutic implications.

HMGB1, S100 proteins and other RAGE ligands in cancer - markers, mediators and putative therapeutic targets

“…No difference in allelic and genotype frequencies of glyoxalase I gene was found in patients with pancreatic cancer 39 . Very recently in a large study, Ala111Glu glyoxalase polymorphism was shown to be associated with clear cell renal cancer and RAGE polymorphisms (-429T/C and 2184A/G) with its aggressiveness 40 . The role of glyoxalase gene polymorphisms in cancer thus remain uncertain, but impaired glyoxalase activity may be associated with clear cell renal cancer and with outcome in breast cancer.…”

“…23,24,39,57,61 ) Kidney cancer EN-RAGE related to obesity status in renal cancer, upregulated in tumor tissue of clear cell renal cancer, especially in pts with poorer overall survival and related to obesity status, Ala111Glu polymorphism linked to clear cell renal cancer (ref. 40,71 )…”

Scavenger Receptors

“…More than 30 gene polymorphisms in RAGE have been identified in multiple cancers, including renal caner, oral cancer, breast cancer, colorectal cancer, lung cancer, ovarian cancer, pancreatic cancer, nasopharyngeal carcinoma, and gastric cancer (Cheng et al, 2005; Chocholaty et al, 2014; Gu et al, 2008; Krechler et al, 2010; Pan et al, 2013; Qian, Sun, Zhang, Ke, & Zhu, 2014; Su, Chien, Lin, Chen, & Yang, 2015; Zhang et al, 2013; Zhou, Deng, Li, Yin, & Ye, 2014). A comprehensive meta-analysis suggested that the 82G/S polymorphism (3374 cancer cases vs. 3757 controls) in the RAGE promoter region is associated with a significantly increased risk of cancer, where −374T/A polymorphism (2936 cancer cases vs. 3,338 control) is associated with a reduced risk of cancer (Xia et al, 2015).…”

Glyoxalases in Urological Malignancies

“…Moreover, it was suggested that Glo1 might represent a useful target for therapy in cancers with Glo1 amplification, as RCa. As to studies on the association of Glo1 A111E polymorphism with the risk of RCa, they have been limited to only one study in a cohort of 214 patients with CCA [71]. This study demonstrated the link of E111A (419A/C) Glo1 SNP to the presence of CCR.…”