The impact of GGH -401C&gt;T polymorphism on cisplatin-based chemoradiotherapy response and survival in cervical cancer

Silva, Inês Hilário; Nogueira‐Silva, Cristina; Figueiredo, Tiago; Lombo, Liliana; Faustino, I.; Catarino, Raquel; Nogueira, Augusto; Pereira, Deolinda; Medeiros, Rui

doi:10.1016/j.gene.2012.10.038

Cited by 6 publications

(5 citation statements)

References 17 publications

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“…Previous studies have reported higher GGH expression levels in urothelial, invasive breast, ERG-negative prostate, gallbladder, and gastric cancers compared to corresponding control tissues ( Pollard et al, 2009 ; Silva et al, 2013 ; Wang et al, 2014 ; Zali et al, 2019 ; Muralidharan et al, 2020 ), which is consistent with our pancancer analysis of TCGA data showing higher GGH expression in numerous cancers including other gynecologic cancers. This elevated expression was observed at both protein and mRNA levels in UCEC patients.…”

Section: Discussionsupporting

confidence: 92%

Elevated Expression of Gamma-Glutamyl Hydrolase Is Associated With Poor Prognosis and Altered Immune Signature in Uterine Corpus Endometrial Carcinoma

et al. 2022

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Uterine corpus endometrial carcinoma (UCEC) is a common malignant tumor of the female reproductive system with poor prognosis in advanced, recurrent, and metastatic cases. Identification of reliable molecular markers will help in the development of clinical strategies for early detection, diagnosis, and intervention. Gamma-glutamyl hydrolase (GGH) is a key enzyme in folate metabolism pathway. High expression of GGH is associated with severe clinicopathological features and poor prognosis of several cancers. High GGH expression is also related to cell resistance to antifolate drugs such as methotrexate. In this study we focused on the prognostic value of immunohistochemical GGH expression level in UCEC tissue and RNA-seq data from The Cancer Genome Atlas to establish associations with clinical features and outcomes. Further, we conducted comprehensive bioinformatics analyses to identify and functionally annotate differentially expressed genes (DEGs) associated with UCEC upregulation and assessed the effects of upregulation on immune infiltration. Both GGH mRNA and protein expression levels were elevated in tumor tissues, and higher expression was significantly associated with advanced clinicopathological features and poor prognosis by univariate analysis. Further multivariate analysis identified elevated GGH expression as an independent risk factor for poor outcome. Nomograms including GGH expression yielded a c-index for disease-specific survival prediction of 0.884 (95% confidence interval: 0.861–0.907). A total of 520 DEGs (111 upregulated and 409 downregulated) were identified between high and low GGH expression groups. Analysis using Gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway, Gene set enrichment analysis, and protein‒protein interaction indicated significant associations of altered GGH expression with cell proliferation, immune response, and the occurrence and development of UCEC tumors. Finally, GGH expression level was associated with high Th2 cell and low natural killer CD56bright cell infiltration. Collectively, these findings indicate that GGH drives UCEC progression and could be a useful biomarker for survival prediction as well as a therapeutic target.

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Section: Discussionsupporting

confidence: 92%

Elevated Expression of Gamma-Glutamyl Hydrolase Is Associated With Poor Prognosis and Altered Immune Signature in Uterine Corpus Endometrial Carcinoma

et al. 2022

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“…During past decades, a panel of SNPs have been demonstrated to be associated with the susceptibility of cervical cancer. As demonstrated, these SNPs might serve as potential markers for risk evaluation, early diagnosis, sensitivity to clinical treatments, and prognosis prediction . In the present study, we reported that TT genotype of rs920778 strongly indicated a much higher risk of cervical cancer in Chinese women.…”

Section: Discussionsupporting

confidence: 56%

Analysis of the association of HOTAIR single nucleotide polymorphism (rs920778) and risk of cervical cancer

Qiu

Liu

et al. 2016

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We recently demonstrated that overexpression of HOTAIR (Hox transcript antisense intergenic RNA) was associated with tumor progression and radio-resistance in human cervical cancer. Considering the single nucleotide polymorphism (SNP) rs920778 (C>T) could influence HOTAIR expression and cancer predisposition in other malignancies, we herein investigated the association between rs920778 status and cervical cancer susceptibility in a Chinese population. Using the specific TaqMan PCR assay, we genotyped rs920778 in 215 cervical cancer patients and 430 age-matched healthy controls. As shown in our data, TT genotype of rs920778 was significantly correlated with the upregulation of HOTAIR (p = 0.008). Compared with the healthy control, TT genotype and T allele notably indicated a much higher risk of cervical cancer [TT genotype: odds ratio (OR) = 2.186, 95% confidence interval (CI) = 1.378-3.466, p = 0.003; T allele: OR = 1.556, 95% CI = 1.221-1.981]. In addition, we also found that the TT genotype of rs920778 was correlated with advanced tumor stage (p = 0.039), highly histological grade (p = 0.013), lympho node metastasis (p < 0.001) and positive infection of high risk HPV (p < 0.001). Among the patients who underwent concurrent chemo-radiotherapy, TT genotype carriers present notably resistance to the combination of EBRT + ICBT + cisplatin (p = 0.023). In conclusion, we firstly reported that TT genotype of HOTAIR rs920778 was significantly associated with the cervical cancer susceptibility. Moreover, the TT genotype of rs920778 might be a potent prognostic marker in cervical cancer patients.

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“…High GGH expression was shown to be associated with a higher risk of developing advanced toxicity to pemetrexed, a multi-targeted antifolate, in patients with advanced breast cancer (Llombart-Cussac et al 2007). Furthermore, several recently identified and characterized functionally significant genetic and epigenetic polymorphisms of GGH have been reported to predict response to and toxicity of antifolate-based treatment in patients with several cancers (Cheng et al 2004;Kim et al 2008;Koomdee et al 2012;Silva et al 2013;Smit et al 2012;Wang et al 2014) and inflammatory arthritis (Dervieux et al 2004;Hayashi et al 2009;Jekic et al 2013;Owen et al 2012;van der Straaten et al 2007;Yanagimachi et al 2011). Our data herein provide evidence that GGH modulation significantly influences expression and CpG DNA methylation of genes involved in important biological pathways that might account for the observed effects of GGH modulation on cancer risk, prognosis, and treatment response.…”

Section: Discussionsupporting

confidence: 54%

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

et al. 2014

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c-Glutamyl hydrolase (GGH) plays an important role in folate homeostasis by catalyzing hydrolysis of polyglutamylated folate into monoglutamates. Polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence, GGH modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, and in chromatin modifications, and aberrant or dysregulation of DNA methylation has been mechanistically linked to the development of human diseases including cancer. Using a recently developed in vitro model of GGH modulation in HCT116 colon and MDA-MB-435 breast cancer cells, we investigated whether GGH modulation would affect global and gene-specific DNA methylation and whether these alterations were associated with significant gene expression changes. In both cell lines, GGH overexpression decreased global DNA methylation and DNA methyltransferase (DNMT) activity, while GGH inhibition increased global DNA methylation and DNMT activity. Epigenomic and gene expression analyses revealed that GGH modulation influenced CpG promoter DNA methylation and gene expression involved in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation. Some of the observed altered gene expression appeared to be regulated by changes in CpG promoter DNA methylation. Our data suggest that the GGH modulation-induced changes in total intracellular folate concentrations and content of long-chain Electronic supplementary material The online version of this article

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The impact of GGH -401C>T polymorphism on cisplatin-based chemoradiotherapy response and survival in cervical cancer

Cited by 6 publications

References 17 publications

Elevated Expression of Gamma-Glutamyl Hydrolase Is Associated With Poor Prognosis and Altered Immune Signature in Uterine Corpus Endometrial Carcinoma

Elevated Expression of Gamma-Glutamyl Hydrolase Is Associated With Poor Prognosis and Altered Immune Signature in Uterine Corpus Endometrial Carcinoma

Analysis of the association of HOTAIR single nucleotide polymorphism (rs920778) and risk of cervical cancer

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

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