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Multiparametric functional MRI and 18F-FDG-PET for survival prediction in patients with head and neck squamous cell carcinoma treated with (chemo)radiation. Eur Radiol 2020; 31:616-628. [PMID: 32851444 PMCID: PMC7813703 DOI: 10.1007/s00330-020-07163-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/17/2020] [Accepted: 08/06/2020] [Indexed: 12/02/2022]
Abstract
Objectives To assess (I) correlations between diffusion-weighted (DWI), intravoxel incoherent motion (IVIM), dynamic contrast-enhanced (DCE) MRI, and 18F-FDG-PET/CT imaging parameters capturing tumor characteristics and (II) their predictive value of locoregional recurrence-free survival (LRFS) and overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC) treated with (chemo)radiotherapy. Methods Between 2014 and 2018, patients with histopathologically proven HNSCC, planned for curative (chemo) radiotherapy, were prospectively included. Pretreatment clinical, anatomical, and functional imaging parameters (obtained by DWI/IVIM, DCE-MRI, and 18F-FDG-PET/CT) were extracted for primary tumors (PT) and lymph node metastases. Correlations and differences between parameters were assessed. The predictive value of LRFS and OS was assessed, performing univariable, multivariable Cox and CoxBoost regression analyses. Results In total, 70 patients were included. Significant correlations between 18F-FDG-PET parameters and DWI-/DCE volume parameters were found (r > 0.442, p < 0.002). The combination of HPV (HR = 0.903), intoxications (HR = 1.065), PT ADCGTV (HR = 1.252), Ktrans (HR = 1.223), and Ve (HR = 1.215) was predictive for LRFS (C-index = 0.546; p = 0.023). N-stage (HR = 1.058), HPV positivity (HR = 0.886), hypopharyngeal tumor location (HR = 1.111), ADCGTV (HR = 1.102), ADCmean (HR = 1.137), D* (HR = 0.862), Ktrans (HR = 1.106), Ve (HR = 1.195), SUVmax (HR = 1.094), and TLG (HR = 1.433) were predictive for OS (C-index = 0.664; p = 0.046). Conclusions Functional imaging parameters, performing DWI/IVIM, DCE-MRI, and 18F-FDG-PET/CT, yielded complementary value in capturing tumor characteristics. More specific, intoxications, HPV-negative status, large tumor volume-related parameters, high permeability (Ktrans), and high extravascular extracellular space (Ve) parameters were predictive for adverse locoregional recurrence-free survival and adverse overall survival. Low cellularity (high ADC) and high metabolism (high SUV) were additionally predictive for decreased overall survival. These different predictive factors added to estimated locoregional and overall survival. Key Points • Parameters of DWI/IVIM, DCE-MRI, and 18F-FDG-PET/CT were able to capture complementary tumor characteristics. • Multivariable analysis revealed that intoxications, HPV negativity, large tumor volume and high vascular permeability (Ktrans), and extravascular extracellular space (Ve) were complementary predictive for locoregional recurrence. • In addition to predictive parameters for locoregional recurrence, also high cellularity (low ADC) and high metabolism (high SUV) were complementary predictive for overall survival. Electronic supplementary material The online version of this article (10.1007/s00330-020-07163-3) contains supplementary material, which is available to authorized users.
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Möhlendick B, Schmid KW, Siffert W. The GNAS SNP c.393C>T (rs7121) as a marker for disease progression and survival in cancer. Pharmacogenomics 2019; 20:553-562. [PMID: 31124412 DOI: 10.2217/pgs-2018-0199] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
G-protein receptor signaling plays a key role in multiple signal transduction pathways. Aberrant activity of the stimulatory Gsα subunit has been frequently associated with cancer. GNAS sequence alterations and conformational changes of Gsα can both enhance or diminish its function and change downstream effects of G-protein receptor signaling. In this review and meta-analysis, we focus on the synonymous SNP rs7121 (FokI, c.393C>T), which is associated with either tumor progression or prolonged survival in cancer patients (overall hazard ratio = 2.256; p < 0.001). We finally point out the relevance of GNAS rs7121 as a promising biomarker and a prediction tool for therapy response and the need of further experiments to implement it into routine clinical diagnostics.
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Affiliation(s)
- Birte Möhlendick
- Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany
| | - Kurt W Schmid
- Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany
| | - Winfried Siffert
- Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany
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Song W, Sun Y, Lin J, Bi X. Current research on head and neck cancer-associated long noncoding RNAs. Oncotarget 2018; 9:1403-1425. [PMID: 29416703 PMCID: PMC5787447 DOI: 10.18632/oncotarget.22608] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 09/08/2017] [Indexed: 02/06/2023] Open
Abstract
Head and neck cancers (HNC) are one of the ten leading cancers worldwide, including a range of malignant tumors arising from the upper neck. Due to the complex mechanisms of HNC and lack of effective biomarkers, the 5-year survival rate of HNC has been low and the mortality rate has been high in recent decades. Long noncoding RNAs (lncRNAs), noncoding RNAs longer than 200 bps, are a focus of current cancer research, closely related to tumor biology. LncRNAs have been revealed to be aberrantly expressed in various types of HNC, and the dysregulated lncRNAs participate in HNC progression and induce malignant behavior by modulating gene expression at diverse levels. This review will focus on the functions and molecular mechanisms of dysregulated lncRNAs in HNC tumorigenesis and progression, as well as their diagnostic, therapeutic or prognostic implications in HNC.
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Affiliation(s)
- Wei Song
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yimin Sun
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jie Lin
- Department of Dental Anesthesiology, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiaoqin Bi
- Department of Head and Neck Oncology, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Piedra M, Berja A, Ramos L, García-Unzueta MT, Morán JM, Ruiz D, Amado JA. Analysis of the influence of the T393C polymorphism of the GNAS gene on the clinical expression of primary hyperparathyroidism. ACTA ACUST UNITED AC 2017; 64:524-530. [PMID: 29179855 DOI: 10.1016/j.endinu.2017.08.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 08/06/2017] [Accepted: 08/10/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND The receptor of parathyroid hormone and parathyroid hormone-related-protein (PTH/PTHrp) is located in the cell membrane of target tissues - kidney and osteoblasts. It is a G protein-coupled-receptor whose Gsα subunit is encoded by the GNAS gene. Our aim was to study whether the single nucleotide polymorphism (SNP) T393C of the GNAS gene is associated with renal stones, bone mineral density (BMD), or bone remodelling markers in primary hyperparathyroidism (PHPT). METHODS An analysis was made of clinical and biochemical parameters and densitometric values in three areas and their relationship with the T393C SNP of the GNAS gene in 261 patients with primary hyperparathyroidism and in 328 healthy controls. Genotyping was performed using the Custom Taqman® SNP Genotyping assay. RESULTS The genotype frequencies of GNAS T/C 393 were similar in the control and PHPT groups. No association was found between genotypes and clinical expression of PHPT (renal stones and bone fractures). A nonstatistically significant trend was seen to lower BMD in the lumbar spine, femoral neck, and total hip in both PHPT and control C homozygote subjects. CONCLUSION Genetic susceptibility to PHPT related to the GNAS T393C polymorphism or a major influence in its development and clinical expression were found. A C allele-related susceptibility to lower BMD in trabecular bone in both PHPT and control subjects is not sufficient to suggest a more severe clinical expression of PHPT. This trend may be considered as a basis for further studies with larger sample sizes and complementary functional evaluation.
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Affiliation(s)
- María Piedra
- Servicio de Endocrinología, Hospital Universitario "Marqués de Valdecilla", Instituto de Investigación "Marqués de Valdecilla" (IDIVAL), Universidad de Cantabria, Avda. de Valdecilla s/n, Santander 39008, Cantabria, Spain.
| | - Ana Berja
- Servicio de Endocrinología, Hospital Universitario "Marqués de Valdecilla", Instituto de Investigación "Marqués de Valdecilla" (IDIVAL), Universidad de Cantabria, Avda. de Valdecilla s/n, Santander 39008, Cantabria, Spain
| | - Laura Ramos
- Servicio de Endocrinología, Hospital Universitario "Marqués de Valdecilla", Instituto de Investigación "Marqués de Valdecilla" (IDIVAL), Universidad de Cantabria, Avda. de Valdecilla s/n, Santander 39008, Cantabria, Spain
| | - María Teresa García-Unzueta
- Servicio de Bioquímica, Hospital Universitario "Marqués de Valdecilla", Instituto de Investigación "Marqués de Valdecilla" (IDIVAL), Universidad de Cantabria, Avda. de Valdecilla s/n, Santander 39008, Cantabria, Spain
| | - Jesús Manuel Morán
- Servicio de Endocrinología, Hospital Universitario "Marqués de Valdecilla", Instituto de Investigación "Marqués de Valdecilla" (IDIVAL), Universidad de Cantabria, Avda. de Valdecilla s/n, Santander 39008, Cantabria, Spain
| | - David Ruiz
- Servicio de Endocrinología, Hospital Universitario "Marqués de Valdecilla", Instituto de Investigación "Marqués de Valdecilla" (IDIVAL), Universidad de Cantabria, Avda. de Valdecilla s/n, Santander 39008, Cantabria, Spain
| | - José Antonio Amado
- Servicio de Endocrinología, Hospital Universitario "Marqués de Valdecilla", Instituto de Investigación "Marqués de Valdecilla" (IDIVAL), Universidad de Cantabria, Avda. de Valdecilla s/n, Santander 39008, Cantabria, Spain
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Hong W, Lin B, Zhang B, Mao W, Zhang Y. [Association between GNAS1 T393C polymorphism and therapeutic efficacy of tyrosine kinase inhibitor in pretreated advanced non-small cell lung cancer with unknown EGFR mutation status]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2015; 17:321-6. [PMID: 24758907 PMCID: PMC6000015 DOI: 10.3779/j.issn.1009-3419.2014.04.06] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND OBJECTIVE Epidermal growth factor receptor (EGFR)-activating mutation predicts excellent response to EGFR tyrosine kinase inhibitors (TKIs). However, lung cancer patients are often with unknown EGFR mutation status because there are little tumor specimen to determine. TKIs induce tumor cell apoptosis which associates with several apoptosis-related genes. To explore the association between GNAS1 T393C polymorphism and therapeutic efficacy of TKI in pretreated advanced non-small cell lung cancer (NCSLC) with unknown EGFR mutation status. METHODS A total of 116 patients were recruited for the study from Zhejiang Cancer Hospital, all of whom were treated with gefitinib or erlotinib after failure to prior chemotherapy. We detected the genotype of peripheral blood lymphocytes of patients with GNAS1 T393C polymorphism through polymerase chain reaction (PCR). Statistical analysis was performed by SPSS version 18.0. RESULTS The overall response rate was 29.3%. No significant associations were found among GNAS1 T393C polymorphism and the objective response rate. The disease control rate of patients with GNAS1 T393C CC genotype was lower than that of patients with variant genotype (TT or CT) (46.2% vs 73.8%, P=0.039). Univariate analysis identified gender, smoking history, histology and GNAS1 T393C polymorphism as predictive marker of PFS (P=0.04, P<0.001, P<0.001 and P=0.005). Multivariate analysis of factors, including smoking history, performance status score, histology, GNAS1 T393C polymorphism demonstrated that GNAS1 T393C polymorphism was correlated independently with PFS (P=0.007). CONCLUSIONS Our data suggest the role of GNAS1 T393C CC genotype as a poor predictive marker both of DCR and PFS in advanced NSCLC patients treated with tyrosine kinase inhibitor.
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Affiliation(s)
- Wei Hong
- Zhejiang Cancer Hospital, Zhejiang Key Laboratory of the Diagnosis and Treatment Technology on Thoracic Oncology, Hangzhou 310022, China
| | - Baochai Lin
- Department of Medical Oncology, the First Affiliated Hospital of WenZhou Medical College, Wenzhou 325000, China
| | - Beibei Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Weimin Mao
- Zhejiang Cancer Hospital, Zhejiang Key Laboratory of the Diagnosis and Treatment Technology on Thoracic Oncology, Hangzhou 310022, China
| | - Yiping Zhang
- Zhejiang Cancer Hospital, Zhejiang Key Laboratory of the Diagnosis and Treatment Technology on Thoracic Oncology, Hangzhou 310022, China
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Gong HY, Hu WG, Wang XL, Zhu F, Song QB. TT genotype of GNAS1 T393C polymorphism predicts better outcome of advanced non-small cell lung cancer patients. World J Gastrointest Oncol 2014; 6:444-449. [PMID: 25516778 PMCID: PMC4266817 DOI: 10.4251/wjgo.v6.i12.444] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 05/07/2014] [Accepted: 11/03/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To evaluate the potential prognostic value of GNAS1 T393C polymorphism in advanced non-small cell lung cancer.
METHODS: We extracted genomic DNA from the peripheral blood leucocytes of 94 patients with advanced non-small cell lung cancer. Quantitative real-time polymerase chain reaction was used to determine the allelic discrimination. The correlation between genotype and overall survival was evaluated using the multivariate analysis and Kaplan-Meier approach.
RESULTS: Thirty-eight out of 94 (40%) patients displayed a TT genotype, 29 out of 94 (31%) a CT genotype and 27 out of 94 (29%) a CC genotype. The median survival of TT (25 mo) genotype carriers was longer than CT (12 mo) or CC (8 mo) genotype carriers. The favorable TT genotype predicted better overall survival (OS) (2-year OS: 48%; P =0.01) compared with CT (2-year OS: 18%) or CC (2-year OS: 15%) genotype. However, dichotomization between C-genotypes (CC + CT) and T-genotypes (TT) revealed significantly lower survival rates (2-year OS: 16%; P = 0.01) for C allele carriers.
CONCLUSION: Our data provided strong evidence that the GNAS1 T393C genetic polymorphism influenced the prognosis in advanced non-small lung cancer with a worse outcome for C allele carriers.
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Wang AC, Wu FX, Gao YS, Sheng XG. Toll-like receptor 4 single-nucleotide polymorphisms Asp299Gly and Thr399Ile in ovarian cancers. Oncol Lett 2014; 8:438-440. [PMID: 24959291 PMCID: PMC4063650 DOI: 10.3892/ol.2014.2113] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 04/01/2014] [Indexed: 01/19/2023] Open
Abstract
Toll-like receptor (TLR4) 4 is present in numerous cell types and serves as the first point of defense in the innate immune system. Single-nucleotide polymorphisms (SNPs) are present in a number TLR genes and have been associated with various infection and inflammation disorders. Asp299Gly and Thr399Ile, TLR4 SNPs, are associated with tumor progression. In the present study, cases of ovarian cancer were analyzed with regards to Asp299Gly and Thr399Ile of the TLR4 gene. Genotype analysis was performed using DNA from tissue samples from stage I–IV patients with ovarian cancer. DNA from tissue samples was extracted and analyzed by a pyrosequencing method following multiplex polymerase chain reaction. The genotypes of these SNPs were analyzed in the present study in a population of 105 patients, with different types of ovarian cancer, between 2004 and 2012. The allele frequencies for TLR4 Asp299Gly identified in this population were 1.00 (A) and 0.00 (G); for TLR4 Thr399Ile the allele frequencies were; 1.00 (C) and 0.00 (T). For TLR4 Asp299Gly the observed genotype frequency was 1.00 (AA), 0.00 (AG) and 0.0 (GG). In TLR4 Thr399Ile the observed genotype frequencies were 1.00 (CC), 0.00 (CT) and 0.00 (TT). TLR4 Asp299Gly and Thr399Ile alleles were not detected in the patients. These results indicated that the TLR4 299Gly and 399Ile alleles were exhibited at a lower frequency in the ovarian cancer patients that were examined.
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Affiliation(s)
- An-Cong Wang
- Department of Reproductive Medicine, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China ; Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P.R. China
| | - Feng-Xia Wu
- Department of Anatomy, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Yong-Sheng Gao
- Department of Pathology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P.R. China
| | - Xiu-Gui Sheng
- Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, P.R. China
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Gupta H, Sakharwade SC, Angural A, Kotambail A, Bhat GK, Hande MH, D'Souza SC, Rao P, Kumari V, Saadi AV, Satyamoorthy K. Evidence for genetic linkage between a polymorphism in the GNAS gene and malaria in South Indian population. Acta Trop 2013; 128:571-7. [PMID: 23962387 DOI: 10.1016/j.actatropica.2013.08.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 07/08/2013] [Accepted: 08/12/2013] [Indexed: 12/12/2022]
Abstract
The complex imprinted GNAS locus which encodes G-alpha subunit (Gαs) is involved in a number of G-protein coupled signaling pathways in eukaryotic cells. Erythrocyte invasion by Plasmodium falciparum parasites is significantly regulated by protein of GNAS gene. This study was designed to evaluate the association between single nucleotide polymorphisms (SNPs) present in GNAS locus and susceptibility to malaria. In this case control study, individuals affected by P. falciparum malaria (n=230), Plasmodium vivax malaria (n=230) and normal controls (n=230) were tested for the association of eighteen (18) known SNPs to evaluate their role in the onset of the disease. There was no significant difference in genotype frequencies of all the SNPs tested between P. falciparum and P. vivax affected individuals. However, when Bonferroni correction for multiple comparisons were performed as a control, our results demonstrated alleles and genotypes of rs7121: C>T (NC_000020.10:g.57478807C>T), a silent polymorphism situated in the exon 5, were significantly (p<0.05) associated with susceptibility to malaria in the South Indians participants. Our results demonstrate that population specific polymorphisms that exist in GNAS gene may alter the risk of occurrence of malaria.
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Xie FJ, Zhao P, Kou JY, Hong W, Fu L, Hu L, Hong D, Su D, Gao Y, Zhang YP. The T393C polymorphism of GNAS1 as a predictor for chemotherapy sensitivity and survival in advanced non-small-cell lung cancer patients treated with gemcitabine plus platinum. Cancer Chemother Pharmacol 2012; 69:1443-8. [PMID: 22371153 DOI: 10.1007/s00280-012-1849-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2011] [Accepted: 02/06/2012] [Indexed: 01/30/2023]
Abstract
PURPOSE The GNAS1 gene is linked to proapoptotic signaling and correlates closely with clinical outcomes in many human cancers. The aim of this study was to evaluate whether the T393C polymorphism of the GNAS1 gene could be used as a chemotherapy sensitivity and prognosis predictive marker of advanced non-small-cell lung cancer (NSCLC) treated with gemcitabine plus platinum (GP). METHODS In this study, we performed the PCR-restriction fragment length polymorphism assay to examine the genotypes of the GNAS1 T393C polymorphism in 131 peripheral blood DNA specimens from advanced NSCLC patients with GP treatment. RESULTS The frequencies of the CC, CT, and TT genotypes in 131 advanced NSCLC cases were 25.2, 47.4, and 26.7%, respectively. The favorable TT genotype was significantly correlated with better overall survival (OS; P < 0.05) and longer progress-free survival (PFS; P < 0.05) compared with the CT or CC genotype. In the multivariate Cox proportional hazards model, the GNAS1 T393C polymorphism was independently associated with overall survival after adjusting the clinicopathological factors (P < 0.05). CONCLUSIONS This study suggests that the TT genotype of the GNAS1 T393C polymorphism could be an independent prognostic marker to predict chemotherapy sensitivity, favorable OS and PFS in advanced NSCLC patients with GP treatment.
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Affiliation(s)
- Fa-Jun Xie
- Department of Medical Oncology, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou City, Zhejiang Province, 310022, China
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El Hindy N, Lambertz N, Bachmann HS, Frey UH, Adamzik M, Zhu Y, Sure U, Siffert W, Sandalcioglu IE. Role of the GNAS1 T393C polymorphism in patients with glioblastoma multiforme. J Clin Neurosci 2011; 18:1495-9. [PMID: 21924916 DOI: 10.1016/j.jocn.2011.02.044] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Revised: 02/28/2011] [Accepted: 02/28/2011] [Indexed: 11/29/2022]
Abstract
The T393C polymorphism of the GNAS1 locus, which encodes the Gαs protein, has recently been found to be associated with patient outcome in various malignancies. We investigated the association between GNAS1 genotype and survival among patients suffering from glioblastoma multiforme (GBM). One hundred and sixty-two patients with GBM were retrospectively investigated. Inclusion criteria were availability of DNA and, for surviving patients, a follow-up of at least 24 months. The results were analysed based on clinical data, type of surgical intervention, adjuvant therapy, and 2-year survival. At the 2-year follow up, 79.6% of patients had died. Two-year survival rates were as follows: CC-homozygous patients, 15.8%; CT-heterozygous patients, 23.1%; and TT-homozygous patients, 18.2% (p = 0.461). Subgroup analysis revealed different 2-year survival rates in the group that underwent stereotactic biopsy, with 0% for CC-homozygous, 2.8% for CT-heterozygous, and 15.4% survival for TT-homozygous patients, but the differences were not statistically significant (p = 0.229). Our results indicate that there is no association between the GNAS1 T393C polymorphism and 2-year survival among patients with GBM.
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Affiliation(s)
- N El Hindy
- Department of Neurosurgery, Medical Faculty, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany.
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Liu Z, Turan S, Wehbi VL, Vilardaga JP, Bastepe M. Extra-long Gαs variant XLαs protein escapes activation-induced subcellular redistribution and is able to provide sustained signaling. J Biol Chem 2011; 286:38558-38569. [PMID: 21890629 DOI: 10.1074/jbc.m111.240150] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Murine models indicate that Gαs and its extra-long variant XLαs, both of which are derived from GNAS, markedly differ regarding their cellular actions, but these differences are unknown. Here we investigated activation-induced trafficking of Gαs and XLαs, using immunofluorescence microscopy, cell fractionation, and total internal reflection fluorescence microscopy. In transfected cells, XLαs remained localized to the plasma membrane, whereas Gαs redistributed to the cytosol after activation by GTPase-inhibiting mutations, cholera toxin treatment, or G protein-coupled receptor agonists (isoproterenol or parathyroid hormone (PTH)(1-34)). Cholera toxin treatment or agonist (isoproterenol or pituitary adenylate cyclase activating peptide-27) stimulation of PC12 cells expressing Gαs and XLαs endogenously led to an increased abundance of Gαs, but not XLαs, in the soluble fraction. Mutational analyses revealed two conserved cysteines and the highly charged domain as being critically involved in the plasma membrane anchoring of XLαs. The cAMP response induced by M-PTH(1-14), a parathyroid hormone analog, terminated quickly in HEK293 cells stably expressing the type 1 PTH/PTH-related peptide receptor, whereas the response remained maximal for at least 6 min in cells that co-expressed the PTH receptor and XLαs. Although isoproterenol-induced cAMP response was not prolonged by XLαs expression, a GTPase-deficient XLαs mutant found in certain tumors and patients with fibrous dysplasia of bone and McCune-Albright syndrome generated more basal cAMP accumulation in HEK293 cells and caused more severe impairment of osteoblastic differentiation of MC3T3-E1 cells than the cognate Gαs mutant (gsp oncogene). Thus, activated XLαs and Gαs traffic differently, and this may form the basis for the differences in their cellular actions.
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Affiliation(s)
- Zun Liu
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
| | - Serap Turan
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Pediatric Endocrinology, Marmara University School of Medicine Hospital, 34662 Istanbul, Turkey
| | - Vanessa L Wehbi
- Laboratory for G Protein-coupled Receptor Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Jean-Pierre Vilardaga
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Laboratory for G Protein-coupled Receptor Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213
| | - Murat Bastepe
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
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Bergmann C, Bachmann HS, Bankfalvi A, Lotfi R, Pütter C, Wild CA, Schuler PJ, Greve J, Hoffmann TK, Lang S, Scherag A, Lehnerdt GF. Toll-like receptor 4 single-nucleotide polymorphisms Asp299Gly and Thr399Ile in head and neck squamous cell carcinomas. J Transl Med 2011; 9:139. [PMID: 21854645 PMCID: PMC3170603 DOI: 10.1186/1479-5876-9-139] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2011] [Accepted: 08/21/2011] [Indexed: 11/13/2022] Open
Abstract
Background Chronic inflammation plays an important role in head and neck squamous cell carcinomas (HNSCC). This study addresses the impact of two single nucleotide polymorphisms (SNP) Asp299Gly and Thr399Ile of the toll-like receptor (TLR) 4 gene on the clinical outcome while accounting for the influence of adjuvant systemic therapy in a large cohort of HNSCC patients. Methods Genotype analysis was done using DNA from tissue samples from 188 patients with HNSCC; TLR4 protein expression was assessed immunohistochemically in tissue microarrays. Classical survival models were used for statistical analyses. Results Ten percent of patients with HNSCC presented with the TLR4 299Gly and 17% with the TLR4 399Ile allele. Patients with the heterozygous genotype TLR4 Asp299Gly had a significantly reduced disease-free and overall survival. Also, patients with the heterozygous genotype TLR4 Thr399Ile had a reduced disease-free survival. Notably, these associations seem to be attributable to relatively poor therapy response as e.g. reflected in a significantly shorter DFS among HNSCC patients carrying the Asp299Gly variant and receiving adjuvant systemic therapy. Conclusion According to this study, TLR4 299Gly und 399Ile alleles may serve as markers for prognosis of head and neck cancer in patients with adjuvant systemic therapy, particularly chemotherapy, and might indicate therapy resistance.
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Affiliation(s)
- Christoph Bergmann
- Department of Otorhinolaryngology, University of Duisburg-Essen, Hufelandstrasse 55, 45127 Essen, Germany.
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Klenke S, Siffert W. SNPs in genes encoding G proteins in pharmacogenetics. Pharmacogenomics 2011; 12:633-54. [DOI: 10.2217/pgs.10.203] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Heterotrimeric guanine-binding proteins (G proteins) transmit signals from the cell surface to intracellular signal cascades and are involved in various physiological and pathophysiological processes. Polymorphisms in the genes GNB3 (encoding the Gβ3 subunit), GNAS (encoding the Gαs subunit) and GNAQ (encoding the Gαq subunit) have been the primary focus of investigation. Polymorphisms in these genes could be associated with different complex phenotypes underlining that alterations in G-protein signaling can cause multiple disorders. G proteins present a point of convergence or ‘bottleneck’ between various receptors and effectors, thus making them a sensible tool for pharmacogenetic studies. The pharmacogenetic studies performed to date mostly demonstrate an association between G-protein polymorphisms and response to therapy or occurrence of adverse drug effects. Therefore, polymorphisms in genes encoding G-protein subunits may help to individualize drug treatment in various diseases with regard to both efficacy and safety.
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Affiliation(s)
| | - Winfried Siffert
- Institut für Pharmakogenetik, Universität Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany
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Vashist YK, Kutup A, Musici S, Yekebas EF, Mina S, Uzunoglu G, Zehler O, Koenig A, Cataldegirmen G, Bockhorn M, Effenberger K, Kalinin V, Pantel K, Izbicki JR. The GNAS1 T393C single nucleotide polymorphism predicts the natural postoperative course of complete resected esophageal cancer. Cell Oncol (Dordr) 2011; 34:281-8. [PMID: 21340746 DOI: 10.1007/s13402-011-0016-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2011] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Genetic variations in cancer patients may serve as important prognostic indicators of clinical outcome. The GNAS1 T393C single nucleotide polymorphism (SNP) diversely correlates with the clinical outcome in cancer. The aim of this study was to evaluate the potential prognostic value of T393C-SNP in complete resected only surgically treated esophageal cancer (EC). METHODS Genomic DNA was extracted from peripheral blood leucocytes of 190 patients who underwent only complete surgical resection for EC. T393C-SNP was correlated with clinic-pathological parameters, tumor cell dissemination in bone marrow (DTC) and clinical outcome. RESULTS T-allele carriers had more advanced disease due to presence of lymph node metastasis (P < 0.0001) and DTC (P = 0.01) and higher recurrence rate (P = 0.01) compared to CC genotype. The disease-free (P < 0.001) and overall survival (P < 0.001) was better in CC compared to TT and TC patients. In the multivariate Cox regression disease-stage adjusted analysis the T393C-SNP was identified as a strong independent prognostic factor for recurrence (hazard ratio 1.8, P = 0.01) and survival (hazard ratio 2.5, P < 0.001) in EC patients. CONCLUSION Determination of T393C-SNP preoperatively will allow allocation of EC patients into different risk profiles which may help to stratify patients eligible for neoadjuvant and or adjuvant therapy.
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Affiliation(s)
- Yogesh Kumar Vashist
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Germany.
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Ge N, Lin HX, Xiao XS, Guo L, Xu HM, Wang X, Jin T, Cai XY, Liang Y, Hu WH, Kang T. Prognostic significance of Oct4 and Sox2 expression in hypopharyngeal squamous cell carcinoma. J Transl Med 2010; 8:94. [PMID: 20937145 PMCID: PMC2958910 DOI: 10.1186/1479-5876-8-94] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Accepted: 10/12/2010] [Indexed: 12/12/2022] Open
Abstract
Background Oct4 and Sox2 are two major transcription factors related to the stem cell self-renewal and differentiation. The aim of this study was to examine the association between Oct4 and Sox2 expression levels with both the clinicopathological characteristics and prognoses of patients with hypopharyngeal squamous cell carcinoma. Method Tumor tissue samples from 85 patients with hypopharyngeal squamous cell carcinoma were collected, and the clinical follow-up data of these patients were recorded, and expression status of Oct4 and Sox2 were examined in these tissue samples by immunohistochemistry (IHC). Results Oct4 expression was found to be an independent predictive factor for overall survival (p = 0.004) in patients with hypopharyngeal squamous cell carcinoma and was independently related to loco-regional control (p = 0.001). Although Sox2 expression status showed no significant association with overall survival (p = 0.166), disease-free survival (p = 0.680) or loco-regional control (p = 0.383), when using a subgroup analysis, the subgroup with both high Oct4 and Sox2 expression had the best prognosis (p = 0.000). Sox2 expression could be a potential prognostic predictor for patients with hypopharyngeal squamous cell carcinoma. Simultaneous analyses of Oct4 and Sox2 expression could be more effective in evaluating the prognoses of patients with hypopharyngeal squamous cell carcinoma. Conclusion Oct4 expression is an independent predictive factor for patients with hypopharyngeal squamous cell carcinoma, suggesting that Oct4 expression may be a useful indicator for predicting the prognosis of hypopharyngeal squamous cell carcinoma.
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Affiliation(s)
- Nan Ge
- State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou 510060, China
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Yamamoto S, Midorikawa Y, Morikawa T, Nishimura Y, Sakamoto H, Ishikawa S, Akagi K, Aburatani H. Identification of chromosomal aberrations of metastatic potential in colorectal carcinoma. Genes Chromosomes Cancer 2010; 49:487-96. [PMID: 20175194 DOI: 10.1002/gcc.20759] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
In colorectal cancer (CRC) care, treatment decisions depend on the efforts to estimate the metastatic potential of tumors. The liver is one of the most common metastatic sites of CRC and the prognosis of CRC patients often reflects metastases to distant sites. To identify chromosomal aberrations associated with liver metastasis, we performed allelic copy number analysis for CRC with or without synchronous liver metastasis using genotyping arrays. By allelic copy number analysis of CRC samples, we observed common aberrations in 14 chromosomal arms in two groups, that is, gains on 7p22.3-p11.2, 8q22.3-q24.3, 13q12.12-q34, and 20q11.22-q13.33 and loss of heterozygosity (LOH) on 4q12-q35.1, 5q11.2-q35.3, 8p23.3-p12, 15q11.2-q26.3, 17p13.3-p11.2, 17q11.2-q25.1, 18p11.32-p11.21, 18q11.2-q23, 20p13-p12.1, and 22q11.1-q13.32. We found that gains on 20p13-p12.1 and 20q11.21-q13.33 and LOH on 6q14.1-q25.1 were more frequent in CRC with liver metastasis. We also compared chromosomal aberrations in primary CRC lesions with those of the corresponding liver metastasis and found that the allelic genome imbalance status of a metastatic lesion is similar to that of the primary cancer, which suggests that chromosomal aberrations are largely maintained on hematogenous spread. Intriguingly, several chromosomal aberrations in CRC were found in the primary cancer but not in the corresponding liver metastasis, thus suggesting heterogeneity of cancer cells within solid tumors or the presence of events uniquely developed in primary tumors. Consequently, CRC with and without liver metastasis harbor similar chromosomal aberrations, and chromosomal aberration at 6q, 20p, and 20q may be involved in the process of liver metastasis of CRC.
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Affiliation(s)
- Shogo Yamamoto
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Tokyo, Japan
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Tumormarker und Prognosefaktoren bei Plattenepithelkarzinomen der Kopf-Hals-Region. HNO 2010; 58:713-23; quiz 724-5. [DOI: 10.1007/s00106-010-2108-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Fingas CD, Katsounas A, Kahraman A, Siffert W, Jochum C, Gerken G, Nückel H, Canbay A. Prognostic assessment of three single-nucleotide polymorphisms (GNB3 825C>T, BCL2-938C>A, MCL1-386C>G) in extrahepatic cholangiocarcinoma. Cancer Invest 2010; 28:472-8. [PMID: 19968497 DOI: 10.3109/07357900903095714] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS Cholangiocellular carcinoma (CCA) has a devastating prognosis and markers enabling a precise prediction of the clinical outcome have long remained scarce. Recently, it has been demonstrated that genotype distribution of several single-nucleotide polymorphisms (SNPs) in genes that modulate G protein-signal transduction and apoptosis can serve as helpful predictive parameters in various carcinomas. We here aimed at extending the panel of SNPs suitable for predicting the outcome of CCA. METHODOLOGY Forty Caucasian patients with extrahepatic CCA and 40 age- and sex-matched healthy white Caucasians were genotyped to elucidate putative associations between clinical outcome and genotypes of the three following SNPs: G protein beta 3 (GNB3) 825C>T, B-cell-lymphoma-2 (Bcl-2) -938C>A, and myeloid cell leukemia-1 (Mcl-1) -386C>G. RESULTS Patients homozygous for the C allele of the GNB3 825C>T polymorphism exhibited a significant prolonged overall survival compared with patients displaying the CT or TT genotype (median survival [months]: 31 vs. 13 vs. 7; p < .05) and also showed lower bilirubin serum levels. Additionally, the CC genotype of the BCL2-938C>A polymorphism was associated with higher GLDH serum activities (U/l; 29.8 +/- 7.1 vs. 11.4 +/- 4.3 vs. 5.6 +/- 1.7 comparing CC vs. CA vs. AA; p < .05). Genotype distributions for all SNPs were not significantly different in patients vs. controls. CONCLUSIONS GNB3 825C>T SNP may be a novel independent prognostic marker for patients suffering from extrahepatic CCA with the CC genotype to be associated with a favorable clinical outcome. Further prospective studies are needed to confirm these results and reveal additional functional SNP effects.
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Alakus H, Mönig SP, Warnecke-Eberz U, Alakus G, Winde G, Drebber U, Schmitz KJ, Schmid KW, Riemann K, Siffert W, Bollschweiler E, Hölscher AH, Metzger R. Association of the GNAS1 T393C polymorphism with tumor stage and survival in gastric cancer. World J Gastroenterol 2009; 15:6061-7. [PMID: 20027678 PMCID: PMC2797662 DOI: 10.3748/wjg.15.6061] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the impact of the GNAS1 T393C polymorphism on prognosis and histopathology of gastric cancer.
METHODS: Genomic DNA was extracted from paraffin-embedded tissues of 122 patients with primary gastric carcinoma and from the blood of 820 healthy white individuals. Allelic discrimination was performed by quantitative real-time polymerase chain reaction. Genotyping was correlated with histopathologic parameters and with overall survival according to the Kaplan-Meier approach and with multivariate analysis by multiple stepwise regression.
RESULTS: Thirty-nine (32%) patients displayed a CC genotype, 57 (46.7%) a CT genotype and 26 (21.3%) a TT genotype. The frequency of the C allele (fC) in the patient group was 0.55, which was not significantly different from that of healthy blood donors. The distribution was compatible with the Hardy-Weinberg equilibrium. Analysis of clinicopathological parameters did not show any significant correlation of the T393C genotype with gender (P = 0.50), differentiation (P = 0.29), pT-category (P = 0.19), pN-category (P = 0.30), pM-category (P = 0.25), R-category (P = 0.95), the classifications according to WHO (P = 0.34), Laurén (P = 0.16), Goseki (P = 1.00) and Ming (P = 0.74). Dichotomization between C+ (CC+CT) and C-genotypes (TT), however, revealed significantly more advanced tumor stages (P = 0.023) and lower survival rates (P = 0.043) for C allele carriers.
CONCLUSION: The present study provides strong evidence to suggest that the GNAS1 T393C allele carrier status influences tumor progression and survival in gastric cancer with higher tumor stages and a worse outcome for C allele carriers.
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Lurje G, Schneider PM. Research Highlights. Pharmacogenomics 2009. [DOI: 10.2217/pgs.09.94] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Georg Lurje
- Department of Visceral & Transplantation Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland
| | - Paul Magnus Schneider
- Department of Visceral & Transplantation Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland
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The GNAS1 T393C polymorphism predicts survival in patients with advanced squamous cell carcinoma of the larynx. Laryngoscope 2008; 118:2172-6. [PMID: 19029852 DOI: 10.1097/mlg.0b013e318185793ds] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVES/HYPOTHESIS In previous studies, we have demonstrated that the T-allele of a specific single nucleotide polymorphism (SNP) in the Galphas gene (T393C) correlates with increased Galphas expression and hence apoptosis. The T-allele was associated with a favorable outcome in a variety of human cancers, for example, carcinoma of the urinary bladder, kidney, colorectal, oro- and hypopharynx. STUDY DESIGN The prognostic value of the T393C SNP was retrospectively evaluated in an unselected series of patients treated with curative intent for laryngeal squamous cell carcinomas including all tumor stages with different therapeutic regimens. METHODS DNA analysis was performed using DNA from paraffin-embedded tissue samples from 157 patients (142 men, 15 women) with a median follow-up of 68 (3-143) months. The various genotypes were correlated with the overall survival. RESULTS Survival was significantly dependent on the T393C genotype in advanced American Joint Committee on Cancer (AJCC) stages (III-IV) with an apparent gene-dose effect (P = .0437). Five-year survival rates were 76% for TT, 49% for TC, and 43.5% for CC. In multivariate analysis including age at diagnosis, AJCC stage, grade, gender, and T393C genotypes, patients with CC genotype displayed a higher risk for death with a hazard ratio of 2.59 (95% confidence interval: 1.01-6.64, P = .047) compared with the reference group consisting of T393 homozygous individuals. CONCLUSIONS The T393C SNP is a prognostic marker that could help to identify high risk patients suffering from head and neck cancer.
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