The GNAS1 T393C polymorphism and lack of clinical prognostic value in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with no known single predisposing genetic factor shown in all cases. Recently, a single nucleotide polymorphism (SNP) T393C in the GNAS1 gene has been reported to have a clinical impact on CLL progression and overall survival. In order to further investigate the T393C SNP in CLL, we have genotyped 279 CLL cases and correlated the genotypes to clinical outcome and other known prognostic factors such as the immunoglobulin heavy chain variable (IGHV) gene mutation status and CD38 expression. In the present study, no difference in overall survival or time to treatment was observed in the CLL patients with the different genotypes in contrast to the previous report. Furthermore, no correlation was observed with the T393C genotypes and IGHV mutational status, Binet stage or CD38 in this cohort. In summary, our data does not support the use of the T393C GNAS SNP as a clinical prognostic factor in CLL.     

The GNAS1 T393C single nucleotide polymorphism predicts the natural postoperative course of complete resected esophageal cancer

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?P?=?0.01) and higher recurrence rate (P?=?0.01) compared to CC genotype. The disease-free (P?P?P?=?0.01) and survival (hazard ratio 2.5, P?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.     

TT genotype of GNAS1 T393C polymorphism predicts better outcome of advanced non-small cell lung cancer patients

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.     

Overall and relapse-free survival in oropharyngeal and hypopharyngeal squamous cell carcinoma are associated with genotypes of T393C polymorphism of the GNAS1 gene.

PURPOSE: In previous studies, we have shown 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, e.g., carcinoma of the urinary bladder, kidney, and colorectum. EXPERIMENTAL DESIGN: The prognostic value of the T393C SNP was evaluated in an unselected series of patients treated with curative intent for oropharyngeal and hypopharyngeal squamous cell carcinomas, including all tumor stages with different therapeutic regimens. Genotype analysis was done using DNA from paraffin-embedded tissue samples from 202 patients (162 men, 40 women) with a median follow-up of 38 months (1-133 months). The various genotypes were correlated with relapse-free and overall survival. RESULTS: GNAS1 393C homozygous patients displayed a higher risk for disease progression than T393 homozygous patients (hazard ratio CC versus TT, 1.9; 95% confidence interval, 1.1-3.2; P = 0.019). The same genotype effect was observed for overall survival with CC genotypes at higher risk for death compared with TT genotypes (hazard ratio, 1.7; 95% confidence interval, 1.1-2.9; P = 0.015). Multivariate analysis showed that, besides American Joint Committee on Cancer stage, tumor localization, and gender, the T393C polymorphism was an independent prognostic factor for disease progression and death. CONCLUSION: The T393C SNP could be considered as a genetic marker to predict the clinical course of patients suffering from oropharyngeal and hypopharyngeal cancer.     

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

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?P?GNAS1 T393C polymorphism was independently associated with overall survival after adjusting the clinicopathological factors (P?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.     

The T393C polymorphism in the gene <Emphasis Type="Italic">GNAS1</Emphasis> of G protein is associated with survival of patients with invasive breast carcinoma

The GNAS1 locus encodes the G(alpha)s protein which stimulates the formation of cyclic AMP (cAMP). Subsequently the cAMP pathway mediates various pleiotropic effects including regulation of apoptosis and proliferation. We have recently shown that genotypes of the single nucleotide polymorphism (SNP) T393C in the gene GNAS1 are associated with survival of patients suffering from bladder, renal cell and colorectal carcinoma. In the present study, the genotypes of the T393C SNP were determined in 279 patients with invasive breast carcinoma. Comparing the genotypes with the overall survival as well as important clinico-pathological parameters showed that carriers of the T allele had a significantly less favourable course of the disease when compared to carriers of the homozygous CC genotype. In multivariate analysis the homozygous TT genotype was independently associated with a decreased overall survival. Our results suggest that the GNAS1 T393C SNP is a novel genetic host factor for disease progression in patients with invasive breast carcinoma. Friedrich Otterbach and Rainer Callies contributed equally to this paper.     

The prolyl isomerase Pin1 is a novel prognostic marker in human prostate cancer

Prostate cancer (PCa) is the most common male cancer in the United States. A major challenge that remains is to predict the clinical outcome in managing PCa patients. The prolyl isomerase Pin1 has been shown to be overexpressed in some human cancer tissues and thought to be an important player in several oncogenic pathways. However, the relationship between Pin1 expression and clinical outcome of cancer patients has not been explored. In this study, we investigated the role of Pin1 in human PCa progression and its clinicopathological significance. Immunohistochemical assessment with affinity-purified polyclonal Pin1-specific antibodies was performed on formalin-fixed paraffin sections of tissue microarray composed of 580 radical prostatectomy specimens. As determined by visual semiquantitation and confirmed by automated image analysis quantitation, Pin1 expression was positively correlated with clinical stage. Furthermore, Cox survival analysis results indicated that patients with a higher Pin1 expression had a significantly higher probability of recurrence than their counterparts with low Pin1 expression, as defined by a serum prostate-specific antigen level of > or =0.4 ng/ml on two consecutive occasions after radical prostatectomy. In addition, patients with high Pin1 expression had almost 4 times the risk of having earlier recurrence than those with low Pin1 expression; patients with a very high level had 8.1 times the risk of an earlier recurrence than a low Pin1 expresser. Pin1 was also an excellent predictor of recurrence in the subset of patients with Gleason score 6 or 7 when analyzed separately: a patient with high Pin1 expression had 8.6 times the risk of having earlier recurrence than one with low Pin1 expression. Pin1 expression is as good as or better than currently used postoperatively available clinicopathological parameters and potentially could be used in the preoperative setting to assist in choice of treatment. Thus, this study suggests a role for Pin1 expression as a potentially excellent prognostic marker in PCa and suggests that Pin1 may also serve as a novel therapeutic target for PCa.     

Metadherin is a novel prognostic marker for bladder cancer progression and overall patient survival

Aim: Metadherin (MTDH) is a potential oncogene in tumor development and is highly expressed in various types of human cancers. However, there has been no report on the role of MTDH in bladder cancer. Our aim was to investigate the expression pattern of MTDH in bladder tissue at different clinic pathological stages and evaluate the potential of MTDH as a biomarker of bladder cancer. Methods: The expression of MTDH in bladder tumors at different stages and normal bladder tissue was examined using immunohistochemical staining and quantitative real‐time polymerase chain reaction. A statistical analysis was used to test for the association of MTDH and bladder cancer classification, staging and prognosis. The expression of proliferation marker Ki67 was examined and the relation between MTDH and Ki67 was studied. Results: The expression of MTDH was not detected in normal bladder tissue; however, up to 65% (39/60) of bladder tumors were found to have positive MTDH expression. A significant correlation was found between MTDH expression and the Union for International Cancer Control stage (P < 0.001), World Health Organization classification (P = 0.001), tumor recurrence (P = 0.015) and tumor multiplicity (P = 0.026). Patients with higher MTDH expression had shorter overall survival time, suggesting the potential of MTDH to be an independent prognostic indicator of bladder cancer. The positive correlation between MTDH and of Ki67 suggests the ability to promote tumor growth of MTDH. Conclusions: Our results suggest that MTDH protein may be a valuable marker of bladder cancer progression. MTDH expression is associated with poor overall survival in patients with bladder cancer.     

GNAS1 T393C基因多态性与实体瘤遗传易感性的Meta分析

目的:系统评价GNAS1 T393C基因多态性与实体瘤遗传易感性的关系。方法:检索《PubMed》、《Web of Science》、《Cochrane Library》、《Embase》、《中国期刊全文数据库》、《中国生物医学文献数据库》、《维普数据库》、《万方数据库》,收集研究GNAS1 T393C基因多态性与实体瘤遗传易感性文献,文献发表时间为自数据库建库以来至2018年8月。由两位评价员独立筛选文献、提取资料,采用stata 12.0统计软件进行Meta分析。结果:共纳入7项研究,包括1 313例实体瘤患者。Meta分析结果显示,携带GNAS1 T393C TT基因型和TC+CC基因型人群实体瘤的遗传易感性差异无统计学意义（P=0.292）,携带GNAS1 T393C T等位和C等位基因人群实体瘤的遗传易感性差异无统计学意义（P=0.355）。亚组分析显示,携带GNAS1 T393C TT基因型和TC+CC基因型亚洲人和高加索人实体瘤的遗传易感性差异无统计学意义（P=0.245、P=0.521）,携带GNAS1 T393C T等位和C等位基因亚洲人和高加索人实体瘤的遗传易感性差异无统计学意义（P=0.208、P=0.206）;携带GNAS1 T393C TT基因型和TC+CC基因型人群泌尿生殖系统肿瘤的遗传易感性差异无统计学意义（P=0.300）,携带GNAS1 T393C T等位和C等位基因人群泌尿生殖系统肿瘤的遗传易感性差异无统计学意义（P=0.266）。结论:GNAS1 T393C基因多态性与实体瘤遗传易感性无明显相关性。     

Restriction fragment length polymorphism of the L-myc gene is not a prognostic factor in bladder cancer patients

The L-myc restriction fragment length polymorphism has been suggested to be of prognostic significance in some types of primary tumours. We examined the prognostic and susceptibility significance of the L-myc genotype in a group of 98 bladder cancer patients. The L-myc genotype did not correlate with any pathologic parameter and does not offer any clinical utility in patients with bladder cancer.     

Neovascularisation is a prognostic factor of early recurrence in T1/G2 urothelial bladder tumours.

BACKGROUND: Of patients with superficial bladder cancer, a group are still at risk of disease recurrence, progression and death from their cancer after curative treatment. Angiogenesis is a crucial pathogenic mechanism for this type of urothelial cell carcinoma (UCC), and is a potential therapeutic target. However, the selection of the appropriate patients remains a dilemma. PATIENTS AND METHODS: Vascular endothelial growth factor (VEGF) expression and the presence of angiogenesis and occurrence of CD31, CD34, endoglin and factor VIII immunoexpression, were evaluated in 66 superficial papillary UCCs of the bladder and were correlated with classical histopathological factors and disease outcome. RESULTS: VEGF immunoreactivity was observed in 100% of cases, and more intensely in the luminal surface. The presence of microvessel clusters independently of a fibrovascular core was observed in 22.7% of cases. Of these, the T1/G2 subgroup had an independent and significantly lower recurrence-free survival (P = 0.0002). CONCLUSIONS: These results indicate that the presence of angiogenesis in tumour urothelium is a potential prognostic factor in superficial UCC, particularly in T1/G2 tumours, and may be used to select patients for anti-angiogenic treatments.     

The C1772T genetic polymorphism in human HIF-1alpha gene associates with expression of HIF-1alpha protein in breast cancer

Hypoxia-inducible factor 1 (HIF-1) is an important genetic component involved in the cellular response to hypoxia. HIF-1 is also linked to the regulation of tumor development and growth. In previous studies, the C1772T (P582S) or the G1790A (A588T) polymorphisms of the HIF-1alpha gene have been identified in renal cell carcinoma, head and neck and esophageal squamous cell carcinomas as well as colorectal and prostate cancers. In our study, we investigated whether polymorphisms of the HIF-1alpha gene may account for the expression patterns of HIF-1alpha protein and impact of clinical progression in breast cancer. We also examined the impact of prognosis of HIF-1alpha gene polymorphism and protein expression in the prediction of biological behavior. We performed polymerase chain reaction and direct sequencing to detect polymorphisms in exon 12 of HIF-1alpha from 90 breast cancer patients and 102 healthy controls. The expression of HIF-1alpha was measured in paraffin-embedded specimens from patients by immunohistochemistry. We associated its expression with known prognostic factors. The frequency of the T allele for C1772T in breast cancer patients and healthy controls was 5.6 vs. 4.4%, whereas, the frequency of the A allele for G1790A was 1.7 vs. 4.4%. HIF-1alpha was overexpressed in 56.7% (51 of 90) of the patients. Its overexpression associated with the T1772 polymorphic allele (p=0.04). Elevated levels of HIF-1alpha protein were found in cases of breast cancer with lymph node metastasis (p=0.041), high histological grade (p=0.001) and increased Ki-67 index (p=0.031). These results suggest the potential use of C1772T (P582S) polymorphism and expression analysis in providing a new prognostic factor for unfavorable disease outcomes and may help for clinical decision-making in the treatment of breast cancer patients.     

Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy.

BACKGROUND: Customizing chemotherapy on the basis of chemosentitivity prediction may improve outcome in advanced bladder cancer patients. Since DNA damaging agents are the cornerstones of therapy, we hypothesized that levels of DNA repair genes could predict survival. PATIENTS AND METHODS: Messenger RNA expression levels of excision repair cross complementing 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and caveolin-1 were determined by RT-PCR in tumor DNA from 57 advanced and metastatic bladder cancer patients treated with either gemcitabine/cisplatin or gemcitabine/cisplatin/paclitaxel (Taxol). Levels were correlated with survival, time to disease progression and chemotherapy response. RESULTS: Median survival was significantly higher in patients with low ERCC1 levels (25.4 versus 15.4 months; P = 0.03) (median follow-up 19 months). A trend towards longer time to progression was observed in patients with tumors expressing low levels of all markers. Levels of RRM1, BRCA1 and caveolin-1, however, failed to predict the survival and a clear link with chemotherapy response could not be established. On multivariate analysis with pretreatment prognostic factors, ERCC1 emerged as an independent predictive factor for survival. CONCLUSION: The results of the study indicate that ERCC1 may predict survival in bladder cancer treated by platinum-based therapy.     

The ubiquitin-like molecule interferon-stimulated gene 15 (ISG15) is a potential prognostic marker in human breast cancer

Introduction

ISG15 is an ubiquitin-like molecule that is strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. However, alterations in the ISG15 signalling pathway have also been found in several human tumour entities. To the best of our knowledge, in the current study we present for the first time a systematic characterisation of ISG15 expression in human breast cancer and normal breast tissue both at the mRNA and protein level.

Method

Using semiquantitative real-time PCR, cDNA dot-blot hybridisation and immunohistochemistry, we systematically analysed ISG15 expression in invasive breast carcinomas (n = 910) and normal breast tissues (n = 135). ISG15 protein expression was analysed in two independent cohorts on tissue microarrays; in an initial evaluation set of 179 breast carcinomas and 51 normal breast tissues; and in a second large validation set of 646 breast carcinomas and 10 normal breast tissues. In addition, a collection of benign and malignant mammary cell lines (n = 9) were investigated for ISG15 expression.

Results

ISG15 was overexpressed in breast carcinoma cells compared with normal breast tissue, both at the RNA and protein level. Recurrence-free (p = 0.030), event-free (p = 0.001) and overall (p = 0.001) survival analyses showed a significant correlation between ISG15 overexpression and unfavourable prognosis.

Conclusion

Therefore, ISG15 may represent a novel breast tumour marker with prognostic significance and may be helpful in selecting patients for and predicting response to the treatment of human breast cancer.