IL1RL1

Gene Summary

Gene:IL1RL1; interleukin 1 receptor-like 1
Aliases: T1, ST2, DER4, ST2L, ST2V, FIT-1, IL33R
Location:2q12
Summary:The protein encoded by this gene is a member of the interleukin 1 receptor family. Studies of the similar gene in mouse suggested that this receptor can be induced by proinflammatory stimuli, and may be involved in the function of helper T cells. This gene, interleukin 1 receptor, type I (IL1R1), interleukin 1 receptor, type II (IL1R2) and interleukin 1 receptor-like 2 (IL1RL2) form a cytokine receptor gene cluster in a region mapped to chromosome 2q12. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:interleukin-1 receptor-like 1
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
Show (21)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IL1RL1 (cancer-related)

Zhunussova G, Zhunusbekova B, Djansugurova L
Association between glutathione S-transferase M1 and T1 polymorphisms and colorectal cancer risk in patients from Kazakhstan.
Clin Lab. 2015; 61(1-2):161-8 [PubMed] Related Publications
BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide and the incidence is increasing in developed as well as developing countries including Kazakhstan. Glutathione S-transferases (GSTs) are considered to be cancer susceptibility genes as they play a role in the detoxification of carcinogenic species. In this case-control study the influence of GSTM1 and GSTT1 polymorphisms on CRC risk in Kazakhstan population were evaluated.
METHODS: Blood samples were collected from patients diagnosed with rectal or colon cancer (300 individuals) as well as a control cohort of healthy volunteers (300 individuals), taking into account the age, gender, ethnicity, and smoking habits of the CRC patients. Deletion polymorphisms were genotyped employing a multiplex PCR amplification method. Association between polymorphisms and CRC susceptibility risk was calculated using multivariate analysis and logistic regression for odd ratio (OR).
RESULTS: The homozygous GSTM1 null genotype was associated with significantly increased risk of CRC (OR = 2.01, 95% CI = 1.45-2.79, p = 0.0001) while the homozygous GSST1 null genotype was not associated with the risk of developing CRC (OR = 1.10, 95% CI = 0.78-1.55, p = 0.001), but the heterozygous genotype correlated with CRC susceptibility (OR = 1.98, 95% CI = 1.30-3.00, p = 0.001). Also, separate analyses of each of the main ethnic groups (Kazakh and Russian) showed a strong association of GSTM1 null genotype with CRC risk (for Kazakhs OR = 2.36, 95% CI = 1.35-4.10, p = 0.006 and for Russians OR = 1.84, 95% CI = 1.17-2.89, p = 0.003). The CRC risk of GSTM1 null genotype in smokers was considerably higher (OR = 3.37, 95% CI = 1.78-6.38, p = 0.0007). The combination of the GSTM1 and GSTT1 null genotypes in combined mixed population of Kazakhstan showed a trend to increasing the risk of developing CRC (OR = 1.60, 95% CI = 1.00-2.56), but it was not statistically significant.
CONCLUSIONS: In conclusion, the results of this case-control study for sporadic cases of CRC show that GSTM1 deletion polymorphisms can have predictive value for susceptibility to CRC (OR = 2.01, p = 0.0001) for the mixed population from Kazakhstan and for both main ethnic groups (Kazakhs and Russians (OR = 2.36 and OR = 1.84, respectively)).

Jatkoe TA, Karnes RJ, Freedland SJ, et al.
A urine-based methylation signature for risk stratification within low-risk prostate cancer.
Br J Cancer. 2015; 112(5):802-8 [PubMed] Article available free on PMC after 03/03/2016 Related Publications
BACKGROUND: Prostate cancer overdiagnosis and overtreatment represents a major problem. Many men with low-grade disease on biopsy are undergraded and they harbour high-grade disease at prostatectomy with no reliable way to identify these men. We used a novel urine-based 2-gene methylation test to identify prostate cancers with aggressive features.
METHODS: Following a proof of concept study in 100 post-radical prostatectomy tissue samples, urine samples were tested from 665 men at multiple U.S. centers undergoing prostate needle biopsy for elevated prostate-specific antigen (2-10 ng ml(-1)). A prediction model was then developed from a combination of clinical factors and the urine-based markers. It was then prospectively tested for accurate prediction of adverse disease (surgical Gleason score ⩾7 and/or a pathological stage ⩾T3a) using urine from a separate cohort of 96 men before radical prostatectomy.
RESULTS: Among pre-prostatectomy men with a biopsy Gleason score <7, 41% had adverse disease of which 100% were correctly identified by the test with a negative predictive value of 100% (95% confidence interval, 86-100%).
CONCLUSIONS: This urine-based test accurately identifies men with clinical low-risk disease who do not have adverse pathology in their prostates and would be excellent candidates for active surveillance.

Arantes LM, de Carvalho AC, Melendez ME, et al.
Validation of methylation markers for diagnosis of oral cavity cancer.
Eur J Cancer. 2015; 51(5):632-41 [PubMed] Related Publications
PURPOSE: Activation of proto-oncogenes and inactivation of tumour suppressor genes are the major genetic alterations involved in carcinogenesis. The increase in methylation at the promoter region of a tumour suppressor gene can lead to gene inactivation, selecting cells with proliferative advantage. Thus, promoter hypermethylation is considered a marker in a variety of malignant tumours, including oral cavity.
EXPERIMENTAL DESIGN: The methylation pattern of eight genes was evaluated in 40 oral cavity squamous cell carcinomas (OSCCs) and 40 saliva samples from healthy individuals by Q-MSP. Different combinations of genes were also assessed in order to identify gene panels that could better distinguish between OSCC and saliva samples.
RESULTS: CCNA1, DAPK, DCC and TIMP3 methylation were highly specific for being found in the OSCC samples. Moreover, the combination of these genes improved detection when compared with single markers, reaching values of 92.5% for sensitivity and specificity (when using the panel CCNA1, DCC, TIMP3). Moreover, DAPK, DCC and TIMP3 were hypermethylated in nearly 90% of clinically T1 and T2 cases.
CONCLUSION: The pursuing of this panel of hypermethylated genes is an important tool for the detection of individuals with OSCC. Moreover, the identification of these markers in early stages of OSCC shows the feasibility of using the panel on saliva as possible biomarkers for early diagnosis. The lack of association between the methylation status of these genes and clinical characteristics shows that they are able to distinguish OSCC cases irrespective of social and clinical factors (gender, age, human papillomavirus (HPV) status, clinical stage, vascular embolisation and perineural invasion).

Nishio J, Iwasaki H, Aoki M, et al.
FDG PET/CT and MR imaging of CD34-negative soft-tissue solitary fibrous tumor with NAB2-STAT6 fusion gene.
Anticancer Res. 2015; 35(2):967-71 [PubMed] Related Publications
Extrapleural solitary fibrous tumor (SFT) is an uncommon mesenchymal neoplasm of intermediate biological potential. Herein, we describe the radiological, histological, immunohistochemical and molecular genetic features of an SFT arising in the left thigh of a 55-year-old woman. Magnetic resonance imaging exhibited a well-defined mass with intermediate signal intensity on T1-weighted sequences and heterogeneous high signal intensity on T2-weighted sequences. Contrast-enhanced T1-weighted sequences showed strong homogeneous enhancement of the mass. A prominent vascular pedicle was visible. Integrated positron-emission tomography (PET)/computed tomographic (CT) scan demonstrated a moderate 18F-fluorodeoxyglucose (FDG) uptake (maximum standardized uptake value, 4.45) in the mass. Following an open biopsy, wide excision of the tumor was performed. Histologically, the tumor was composed of a proliferation of spindle cells in a fibrous stroma with focal hyalinization. Thin-walled branching hemangiopericytoma-like vessels were observed. Immunohistochemically, the tumor cells were diffusely positive for signal transducer and activator of transcription 6 (STAT6) but negative for CD34. The MIB-1 labeling index was less than 5%. Subsequent reverse transcriptase-polymerase chain reaction analysis identified a nerve growth factor inducible-A binding protein 2-STAT6 gene fusion. Our case supports the utility of STAT6 immunohistochemistry as an adjunct in the diagnosis of soft-tissue SFT with loss of CD34 positivity. To the best of our knowledge, this is the first report showing the FDG PET/CT findings of soft-tissue SFT.

Noorlag R, van Kempen PM, Stegeman I, et al.
The diagnostic value of 11q13 amplification and protein expression in the detection of nodal metastasis from oral squamous cell carcinoma: a systematic review and meta-analysis.
Virchows Arch. 2015; 466(4):363-73 [PubMed] Article available free on PMC after 03/03/2016 Related Publications
Despite improvements in both diagnostic and therapeutic strategies, the prognosis of oral squamous cell carcinoma (OSCC) has not changed significantly over the last decades. Prognosis of OSCC particularly depends on the presence of nodal metastasis in the neck. Therefore, proper determination of the nodal status is pivotal for appropriate treatment. Unfortunately, current available imaging techniques (magnetic resonance imaging or ultrasound even with fine needle aspiration of suspected lymph nodes (LNs)) fail to detect occult nodal disease accurately. Clinicians in head and neck oncology urgently need new diagnostic tools to reliably determine the presence of nodal metastasis of the neck. Gain of the chromosomal region 11q13 is one of the most prominent genetic alterations in head and neck cancer and is associated with poor prognosis and metastasis. The aim of this systematic review and meta-analysis was to determine the diagnostic value of either 11q13 amplification or amplification/protein overexpression of individual genes located on 11q13 to detect nodal metastasis in OSCC. A search was conducted in Pubmed, EMBASE, and Cochrane, and 947 unique citations were retrieved. Two researchers independently screened all articles and only 18 were found to meet our inclusion criteria and were considered of sufficient quality for meta-analysis. Pooled results of those show that both amplification of CCND1 and protein overexpression of cyclin D1 significantly correlate with lymph node metastasis (LNM) in OSCC. In addition, amplification of CCND1 shows a negative predictive value of 80 % in the detection of LNM in early stage OSCCs which are clinically lymph node negative although this evidence is sparse and should be validated in a larger homogeneous cohort of T1-2 OSCC.

Hammam O, Wishahiz M, Khalil H, et al.
Expression of cytokeratin 7, 20, 14 in urothelial carcinoma and squamous cell carcinoma of the Egyprian urinary bladder cancer.
J Egypt Soc Parasitol. 2014; 44(3):733-40 [PubMed] Related Publications
This study estimated the expression of CK-7, CK14, and CK-20 protein in human bladder carcinoma, urothelial carcinoma (UC) in comparison to squamous cell carcinoma (SCC) and to show its possible correlation to clinicopathologic parameters (grade and stage and bilharziasis), and investigate whether cytokeratin 14 immunostaining may be useful to detect early squamous metaplasia in bladder biopsies and in association with UC. We evaluated the bladder tissues of 200 patients with bladder carcinoma, 150 patients had UC, and 50 patients had SCC. Imunohistochemical technique was used for detection of CK7, CK14 and CK20 monoclonal antibodies. The mean age of the patients was 55 years (range 51-70 years). The UC were classified according to grades into grade I, II and III in 20, 40 and 90 cases, respectively. Stages of UC were: Ta in 10, T1 in 60 and 90 patients with muscle-invasive T2-3. In UC cases 105 /150 (70%) were positive for over expression of CK20. In the same group of UC 120/150 (80) were positive for over expression of CK7. Negative expression was found in SCC cases. A High grades of the UC were associated with decrease expression of CK 20, there were 20 (100%) in GI, 35 (87.5%) in GII, 50 (68.6%) in GIII (P <0.01), and an increase expression of CK7 4 (20%) in GI, 26 (65%) in GII, 90(100%) in GIII (P <0.01). CK20 expression decreased as the tumor stages increased, it was 15 (100%) in Ta, 50 (83.3%) in T1, 40 (50%) in T2-3 (P <0.01), while CK7 showed increase expression in 2 cases with Ta tumor (20%), 38 (47.5%) in T1, 80 (100%) in T2-T3 (P <0.01). The present study confirmed that CK14 is expressed in SCC and in UC with squamous differentiation.

Hammam O, Wishahi M, Hindawi A, et al.
Superiority of fluorescent in situ hybridization over immunohistochemistry in detection of HER2 gene in carcinoma of the urinary bladder associated with and without schistosomiasis.
J Egypt Soc Parasitol. 2014; 44(3):719-31 [PubMed] Related Publications
HER2 is an oncogene encoding a type 1 tyrosine kinase growth factor receptor and the role of HER2 in the development of numerous types of human cancer is still understood and correlates with clinical outcome, poor prognosis, it is a predictor factor for poor response to chemotherapy. HER2 overexpression is associated with reduced disease free and overall survival. Patients who have HER2 negative expression have a poor prognosis. The aim of the present study is to explore the accuracy of detection of expression of HER2 protein by two different techniques of immunohistochemistry (IHC) and gene amplification by fluorescent in situ hybridization (FISH). The two techniques were applied to sixty two patients that included different cell types of carcinoma of the bladder, benign bilharzial lesions and control. Characteristics of the 62 patients are: 10 chronic cystitis, 19 squamous cell carcinoma (SCC) with schistosomiasis, 33 urothelial carcinoma (UC) schistosomal and non-schistosomal, ten healthy individuals without schistosomiasis served as controls. Gene amplification of HER2 was done using FISH and protein expression of HER2 by IHC. The study was applied on archival data of formalin-fixed paraffin embedded tissues and patient clinical data and follow up for 5 years. Overexpression of HER2 protein was found in 30/52 (57.7%). Fourteen cases had score of 2+, and sixteen cases had score of 3+. Using FISH technique it showed more accurate detection of HER2 gene as those fourteen cases who had score of 2+ had been found to be 5 out of 14 were positive for gene over expression, the other sixteen who had score of 3+ all were positive for gene amplification. HER2 protein and gene was found to be significantly overexpressed in carcinoma of the bladder in both cell types SCC and UC with or without schistosomiasis compared to the benign lesions and control groups (P <0.01) by both techniques. There is significant increase in expression of HER2 protein and gene in SCC compared to UC (P< 0.01). In UC overexpression of HER2 protein and gene was evident in all stages Ta, T1, T2-4. HER2 protein and gene overexpressed in different grades of UC. In SCC HER2 protein and gene had overexpression in different stages and grades.

Bănescu C, Trifa AP, Voidăzan S, et al.
CAT, GPX1, MnSOD, GSTM1, GSTT1, and GSTP1 genetic polymorphisms in chronic myeloid leukemia: a case-control study.
Oxid Med Cell Longev. 2014; 2014:875861 [PubMed] Article available free on PMC after 03/03/2016 Related Publications
Oxidative damage at the DNA level may be promoted by high levels of reactive oxygen species (ROS), leading to genomic instability and increased neoplastic risk. Superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) enzymes are implicated in the prevention of DNA damage by ROS. The aim of the study was to investigate the relationships between CAT C262T, GPX1 Pro198Leu, MnSOD Ala16Val, GSTM1, GSTT1, and GSTP1 Ile105Val polymorphisms and the risk of CML. No association was observed between CML and variant genotypes of GPX1, MnSOD, GSTM1, and GSTT1 polymorphisms in any of the investigated cases. Our study suggests that the homozygous variant genotype of the GSTP1 Ile105Val gene polymorphisms may be associated with the risk of developing CML (OR = 2.5; 95% CI = 1.08-5.7; P value = 0.02), while the heterozygous genotype of the CAT C262T polymorphism seems to have a protective effect against CML (OR = 0.59, 95% CI = 0.39-0.89, P value = 0.01). In most cases, no association was found between laboratory parameters and prognostic factors and the variant genotype of investigated gene polymorphisms. We concluded that CAT, GPX, MnSOD, GSTM1, and GSTT1 gene polymorphisms are not associated with the risk of CML. Variant genotype of the GSTP1 Ile105Val gene polymorphisms may contribute to the risk of developing CML.

Mota P, Silva HC, Soares MJ, et al.
Genetic polymorphisms of phase I and phase II metabolic enzymes as modulators of lung cancer susceptibility.
J Cancer Res Clin Oncol. 2015; 141(5):851-60 [PubMed] Related Publications
OBJECTIVES: Tobacco exposure remains the main etiologic factor for lung cancer (LC). Interactions between environment and individual genetic profile are particularly important for this disease. The aim of this study was to evaluate the contribution of CYP1A1*2A, CYP1A1*2C, CYP2D6*4, GSTP1, GSTM1, GSTT1 and NAT2 polymorphisms for the susceptibility to LC in a Portuguese population considering their demographic and clinical characteristics.
MATERIALS AND METHODS: A total of 200 LC and 247 controls subjects from the Centre of Portugal were studied. Clinical and demographic characteristics were collected from clinical files and by individual questionnaires. Polymorphisms of CYP1A1*2A, CYP1A1*2C, CYP2D6*4, GSTP1, GSTM1, GSTT1 and NAT2 were genotyped using PCR-RFLP, PCR multiplex, ARMS and real time.
RESULTS: Gender, family history of cancer, smoke cessation and alcohol consumption were independent risk factors (p < 0.05). Associations found between phases I and II genes and LC population reveal a sex dependent distribution. Logistic regression analysis demonstrates that enhanced activation by CYPs, associated by reduced or loss of function of phase II enzymes, can lead to a greater risk. GSTP1 and NAT2 polymorphisms studied have a significant contribution for the histological tumour types and the presence of metastases, at time of diagnosis, respectively, when males with smoking habits were considered.
CONCLUSION: Multiple interactions between environment and individual characteristics are clearly associated to this disease. Variants of the detoxification genes may act synergistically contributing to this disease and modifying the risk posed by smoking and sex. The GSTT1*0 and GSTP1 (Ile462Val) might contribute to the malignant phenotype through different mechanisms.

Chirilă DN, Bălăcescu O, Popp R, et al.
GSTM1, GSTT1 and GSTP1 in patients with multiple breast cancers and breast cancer in association with another type of cancer.
Chirurgia (Bucur). 2014 Sep-Oct; 109(5):626-33 [PubMed] Related Publications
INTRODUCTION: breast cancer has the highest incidence in women.Glutathione S-transferases (GSTs) are a large group of enzymes involved in the metabolism of xenobiotics. The members of this gene superfamily are involved in the development of multiple cancers.
OBJECTIVES: the aim of the study was to see whether the GSTM1, GSTT1 and GSTP1 genetic polymorphisms are risk factors for patients diagnosed with multiple malignancies, of which at least one is located in the breast.
MATERIALS AND METHODS: in the period between 2005 and 2012,of the 520 patients diagnosed with breast cancer, 69 had multiple primitive malignant tumors, of which at least one was localized in the breast. The research on GSTM1, GSTT1 and GSTP1 genotypes consisted of 59 patients diagnosed with multiple breast cancers or with breast cancer in association with another type of cancer, compared with a group of healthy controls.
RESULTS: in the subgroup of patients with breast cancer in association with another type of cancer, the GSTM1 null genotype was present in 61.2% of patients, compared to 29% of controls; the subgroup of metachronous breast cancers, the presence of any of the GSTT1 or GSTM1 null genotypes was statistically significantly different from that of controls (65.2%vs. 28.5%); in the subgroup with synchronous cancers, the GSTM1 null genotype was found in 66.6% of patients compared to 9% for the controls, and the presence of any null genotype (GSTM1 and GSTT1) was also statistically significant in the case group.
CONCLUSIONS: the GSTM1 null genotype is a risk factor for synchronous breast cancers and for breast cancer associated with extramammary cancer; the presence of null genotypes(GSTM1 or GSTT1) is a risk factor for multiple breast cancer(bilateral or synchronous); the GSTT1 null genotype and the heterozygous variant allele (Ile105Val) and homozygous variant allele (Val105Val) of GSTP1 are not risk factors for the cases studied.

Zhang Z, Wang Q, Chen F, Liu J
Elevated expression of HMGA1 correlates with the malignant status and prognosis of non-small cell lung cancer.
Tumour Biol. 2015; 36(2):1213-9 [PubMed] Related Publications
High-mobility group A1 (HMGA1) has been suggested to play a significant role in tumor progression, but little is known about the accurate significance of HMGA1 in non-small cell lung cancer (NSCLC) patients. The aim of this study was to identify the role of HMGA1 in NSCLC. The expression status of HMGA1 was observed initially in NSCLC by Gene Expression Omnibus (GEO). The expression of HMGA1 messenger RNA (mRNA) and protein was examined in NSCLC and adjacent normal lung tissues through real-time PCR and immunohistochemistry. Meanwhile, the relationship of HMGA1 expression levels with clinical features and prognosis of NSCLC patients was analyzed. In our results, HMGA1 was overexpressed in NSCLC tissues compared with adjacent normal lung tissues in microarray data (GSE19804). HMGA1 mRNA and protein expressions were markedly higher in NSCLC tissues than in normal lung tissues (P < 0.001 and P = 0.010, respectively). Using immunohistochemistry, high levels of HMGA1 protein were positively correlated with the status of clinical stage (I-II vs. III-IV, P < 0.001), T classification (T1-T vs. T3-T4, P = 0.003), N classification (N0N1 vs. N2-N3, P < 0.001), M classification (M0 vs. M1, P = 0.002), and differentiated degree (high or middle vs. low or undifferentiated, P = 0.003) in NSCLC. Patients with higher HMGA1 expression had a significantly shorter overall survival time than did patients with low HMGA1 expression. Multivariate analysis indicated that the level of HMGA1 expression was an independent prognostic factor (P < 0.001) for the survival of patients with NSCLC. In conclusion, HMGA1 plays an important role on NSCLC progression and prognosis and may act as a convictive biomarker for prognostic prediction.

Park SJ, Kim SM, Hong YS, et al.
TFAP2E methylation status and prognosis of patients with radically resected colorectal cancer.
Oncology. 2015; 88(2):122-32 [PubMed] Related Publications
OBJECTIVES: This study investigates the clinical significance of the gene encoding AP-2ε (TFAP2E) in colorectal cancer (CRC) patients undergoing curative resection.
METHODS: A single-institution cohort of 248 patients who underwent curative resection of stage I/II/III CRCs between March and December 2004 was enrolled, and 193 patients whose tumors were available for the determination of the TFAP2E methylation status were included in the analysis.
RESULTS: TFAP2E hypermethylation was detected in 112 patients (58%) and was significantly associated with distally located CRCs, low pathologic T stage (T1/T2), and stage I tumors. After a median follow-up of 86.3 months, the patients with TFAP2E hypermethylation tended to show better relapse-free survival (RFS) and overall survival (OS) than the patients with TFAP2E hypomethylation (5-year RFS rate: 90 vs. 80%, p = 0.063; 6-year OS rate: 88 vs. 80%, p = 0.083). Multivariate analysis showed that the pathologic nodal stage and TFAP2E methylation status were independent prognostic factors for RFS and OS, and they remained significant factors in the subgroup analysis that included 154 patients with stage II/III CRCs who had received adjuvant chemotherapy.
CONCLUSIONS: TFAP2E hypermethylation is associated with good clinical outcomes and may be considered as an independent prognostic factor in patients with curatively resected CRCs.

Cui G, Qi H, Gundersen MD, et al.
Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer.
Cancer Immunol Immunother. 2015; 64(2):181-90 [PubMed] Related Publications
Most sporadic colorectal cancers (CRCs) develop from preformed adenomas. Cytokines are involved in the transition from adenoma to CRC. Interleukin-33 (IL-33) is a newly discovered proinflammatory cytokine belonging to the IL-1 cytokine family and involved in the development of chronic inflammation and cancer. The aim of this study was to evaluate the dynamics of the IL-33/ST2 axis during the sequence of progression from normal colorectum to adenoma to carcinoma and to investigate the association of IL-33 and ST2 expression with clinicopathological parameters and prognosis. The results demonstrated that the levels of IL-33 and ST2 in adenomas (n = 50), determined by real-time PCR, were significantly higher than those of normal controls (n = 30); the levels of both IL-33/ST mRNA in CRCs (n = 50) were higher than in normal controls but lower than in adenomas. Further analysis revealed that the expression level of ST2 in CRCs was associated with tumor/node/metastasis (TNM) stage. The log-rank test showed that neither the IL-33 nor the ST2 expression level was correlated with overall survival in patients with CRC. The increased expression of IL-33/ST2 in adenomas and CRC tissues was confirmed by immunohistochemistry and was observed in both the tumor stromal cells and adenomatous/cancerous cells. Notably, increased densities of IL-33-positive and ST2-positive microvessels were found in the stroma of adenomas and CRCs. In conclusion, increased expression of the IL-33/ST2 axis along the colorectal adenoma-carcinoma sequence might be involved in the neoplastic transformation via the participation of this axis in the regulation of angiogenesis.

Yepes MM, Romilly AP, Collado-Mesa F, et al.
Can mammographic and sonographic imaging features predict the Oncotype DX™ recurrence score in T1 and T2, hormone receptor positive, HER2 negative and axillary lymph node negative breast cancers?
Breast Cancer Res Treat. 2014; 148(1):117-23 [PubMed] Related Publications
To determine whether mammographic or sonographic features can predict the Oncotype DX™ recurrence scores (RS) in patients with TI-II, hormone receptor (HR) positive, HER2/neu negative and node negative breast cancers. Institutional board review was obtained and informed consent was waived for this retrospective study. Seventy-eight patients with stage I-II invasive breast cancer that was HR positive, HER2 negative, and lymph node negative for whom mammographic and or sonographic imaging and Oncotype DX™ assay scores were available were included in the study Four breast dedicated radiologists blinded to the RS retrospectively described the lesions according to BI-RADS lexicon descriptors. Multivariable logistic regression was used to test for significant independent predictors of low (<18) versus intermediate to high range (≥18). Two imaging features reached statistical significance in predicting low from intermediate or high risk RS: pleomorphic microcalcifications within a mass (P = 0.017); OR 8.37, 95 % CI (1.47-47.79) on mammography and posterior acoustic enhancement in a mass on ultrasound (P = 0.048); OR 4.35, 95 % CI (1.01-18.73) on multivariable logistic regression. A mass with pleomorphic microcalcifications on mammography or the presence of posterior acoustic enhancement on ultrasound may predict an intermediate to high RS as determined by the Oncotype DX(TM) assay in patients with stage I-II HR positive, HER2 negative, and lymph node negative invasive breast cancer.

Så RA, Moreira Ados S, Cabello PH, et al.
Human glutathione S-transferase polymorphisms associated with prostate cancer in the Brazilian population.
Int Braz J Urol. 2014 Jul-Aug; 40(4):463-73 [PubMed] Related Publications
OBJECTIVE: To evaluate the influence of polymorphisms in GSTA1, GSTM1, GSTT1, and GSTP1 in the risk of developing Prostate Cancer (PCa) in a population of Rio de Janeiro and compare the distribution of allele and genotype frequencies of the polymorphisms analyzed in the present study population with other regions in the country and different ethnic groups.
MATERIALS AND METHODS: We analyzed a sample of the Brazilian population, comprising 196 patients with PCa treated by the urology services of the Brazilian National Cancer Institute (INCA) and Mario Kroeff Hospital (HMK), and 208 male blood donors from the Clementino Fraga Filho Hospital, Federal University of Rio de Janeiro (UFRJ). The polymorphisms were determined in DNA, extracted from peripheral blood leucocytes using the Polymerase Chain Reaction and Restriction Fragment Length Polymorphism (PCR-RFLP).
RESULTS: Our results showed that the distribution of polymorphisms can vary significantly according to the Brazilian region and ethnic groups. The distribution of allele and genotype frequencies of the polymorphism GSTA1 was statistically different between cases and controls. Genotypes (A / B + B / B) were associated with protection (OR = 0.61, 95% CI = 0.40-0.92) for PCa in comparison to genotype A / A.
CONCLUSION: The distribution of genotype frequencies of the polymorphism GSTA1 was statistically different between the case and control groups (p = 0.023), and the presence of genotypes A / B and B / B suggests a protective role against the risk of PCa compared to genotype A / A. This is the first study that reports the genotypic frequency of this polymorphism and its association with PCa in a Brazilian population sample.

Djansugurova L, Zhunussova G, Khussainova E, et al.
Association of DCC, MLH1, GSTT1, GSTM1, and TP53 gene polymorphisms with colorectal cancer in Kazakhstan.
Tumour Biol. 2015; 36(1):279-89 [PubMed] Related Publications
This study presents the first results of a molecular-genetic study of colorectal cancer (CRC) in Kazakhstan. Blood samples were collected from patients diagnosed with rectal or colon cancer (249 individuals) as well as a control cohort of healthy volunteers (245 individuals), taking into account the age, gender, ethnicity, and smoking habits of the CRC patients. Combined analysis of data obtained from individuals of either Kazakh or Russian decent showed a significant association with increased CRC risk in the following genotypes: DCC (32008376G/G and G/A versus A/A; OR = 3.45, 95 % confidence interval (95 %CI) = 1.75-6.81, χ (2) = 14.07, p < 0.0002), MLH1 (-93G/G versus G/A and A/A; OR = 1.45, 95 %CI = 1.02-2.07, χ (2) = 4.21, p < 0.04), TP53 (Pro72Pro; OR = 3.80, 95 %CI = 2.46-5.88, χ (2) = 61.27, p < 0.0001), combination GSTT1 deletions with heterozygotes versus normal homozygotes (OR = 1.43, 95 %CI = 1.00-2.04, χ (2) = 3.90, p < 0.05), and GSTM1 deletions (OR = 1.83, 95 %CI = 1.28-2.63, χ (2) = 11.04, p < .001). Analysis for ethnicity and smoking for each of the investigated polymorphisms showed that some genotypes can have a predictive value for susceptibility to CRC, at least those that demonstrate statistically significant ORs either for the combined mixed population of Kazakhstan or for both main ethnic groups separately (Kazakhs and Russians): TP53 Pro72Pro homozygous (for Kazakh-OR = 3.40, 95 %CI = 1.63-7.06, χ (2) = 11.35, p < 0.003; for Russian-OR = 4.69, 95 %CI = 2.53-8.66, χ (2) = 53.19, p < 0.0001) and GSTM1 deletions (for Kazakh-OR = 2.30, 95 %CI = 1.21-4.40, χ (2) = 8.42, p < 0.01; for Russian-OR = 1.64, 95 %CI = 1.01-2.66, χ (2) = 7.82, p < 0.02).

Satoh K, Nimura S, Aoki M, et al.
Tumor budding in colorectal carcinoma assessed by cytokeratin immunostaining and budding areas: possible involvement of c-Met.
Cancer Sci. 2014; 105(11):1487-95 [PubMed] Related Publications
Tumor budding/sprouting has been shown to be an independent adverse prognostic factor in T1 and T3N0 colorectal carcinomas, however, its assessment could be improved by more accurate identification of budding carcinoma cells and consideration of budding areas. Moreover, tumor budding mechanisms are yet to be defined. In this study, we evaluated the identification of budding tumor cells by either H&E staining alone or H&E with immunohistochemistry and developed a scoring system based on budding grades and areas. We examined whether the budding score correlated with clinicopathologic features and prognosis and the association between tumor budding/sprouting and c-Met protein expression and phosphorylation and MET gene copy numbers because c-Met is known to play an important role in colorectal carcinoma tumorigenesis. Cytokeratin immunohistochemistry could identify tumors with shorter disease-free survival (DFS) from the low-grade budding group assessed with H&E alone. High budding scores based on budding grade and area were more significantly correlated with DFS than scores obtained using the budding grade alone. In tumors with a high budding score, c-Met expression and phosphorylation levels and MET gene copy numbers were significantly increased at the invasive front compared with those in superficial tumor portions. This study showed for the first time that high levels of phospho-c-Met at the invasive front were significantly associated with a high budding score and shorter DFS. In conclusion, a budding score assessed by budding grades and budding-positive areas correlates highly with clinicopathologic aggressive features of colorectal carcinoma.

Sun X, Guo M, Sun Q, et al.
The existence and role of microchimerism after microtransplantion.
Leuk Res. 2014; 38(11):1285-90 [PubMed] Related Publications
AIM: To study microchimerism's role and function after microtransplantation and identify novel genetic markers for microchimerism detection.
METHODS: Analyzing microchimerisms from patients microtransplanted to determine the presence of GSTT1, GSTM1, SRY and other genetic markers by real-time PCR.
RESULTS: Microchimerism could be detected for a short time after microtransplantation simultaneously with hematopoietic recovery. In conclusion, microchimerism might accelerate hematopoietic recovery and GSTT1 and GSTM1 genes could be used as genetic markers to differentiate donor cells.
DISCUSSION: Microchimerism could exist for a short time after microtransplantation and appears to function in hematopoietic recovery. According to published reports, cytokines secreted from microchimerisms could be detected in recipients and exhibit some function on the host. Therefore, cytokines secreted from donor cells are hypothesized to accelerate hematopoietic recovery. The evidence to prove a longer existence for microchimerism is insufficient and needs supports by additional experiments; however, we cannot deny its existence just because of the limited sensitivity of methods.

Jóźwicki W, Brożyna AA, Siekiera J
Expression of OCT4A: the first step to the next stage of urothelial bladder cancer progression.
Int J Mol Sci. 2014; 15(9):16069-82 [PubMed] Article available free on PMC after 03/03/2016 Related Publications
OCT4 (octamer-binding transcription factor) is a transcription factor responsible for maintaining the pluripotent properties of embryonic stem cells. In this paper, we present the results of studies to investigate the role of the OCT4 splicing variant in urothelial bladder cancer and the relationship between the OCT4 phenotype and the morphological parameters of tumor malignancy. Ninety patients who received a cystectomy for bladder cancer were enrolled. The expression of OCT4 protein was analyzed by immunohistochemistry. The ratio of OCT4-positive cells was the lowest in pT1 (pathological assessment (p)--tumor extent confined to mucosa (T1)) tumors and the highest in pTis (non-papillary tumor extent confined to urothelium) and pT2 (tumor extent including muscularis propria) tumors. Information about the percentage of OCT4A-positive tumor cells could facilitate choosing the treatment mode in borderline pTis-pT1 (crossing the border of the basement membrane; the first stage of progression) and pT1-pT2 (crossing the border of the muscularis propria; the second stage of progression) cases: a higher percentage of OCT4A-positive cells should support more radical therapy. A significantly higher percentage of cases with moderate OCT4 intensity was found in metastasizing (the third stage of progression) cases with >2 positive lymph nodes. The percentage of OCT4-positive cells was significantly higher for cancers with a high grade, higher non-classic differentiation number and greater aggressiveness of invasion. The differentiation, maturation and aggressiveness of tumor invasion appear to depend on the expression of the OCT4 phenotype in cancer cells, similar to the successive stages of malignancy progression in urothelial cancer.

Davies A, Giannoudis A, Zhang JE, et al.
Dual glutathione-S-transferase-θ1 and -μ1 gene deletions determine imatinib failure in chronic myeloid leukemia.
Clin Pharmacol Ther. 2014; 96(6):694-703 [PubMed] Related Publications
Approximately 40% of patients with chronic myeloid leukemia (CML) receiving imatinib fail treatment. There is an increased risk of CML in subjects with (i) deletions of genes encoding glutathione-S-transferase (GST)-θ1 (GSTT1) and -μ1, (GSTM1) and (ii) the GST-π1 (GSTP1) single-nucleotide polymorphism (SNP) Ile105Val (GSTP1*B; rs1695); however, their effects on imatinib treatment outcome are not known. Here, we assess the role of these GSTs in relation to imatinib treatment outcome in 193 CML patients. Deletion of GSTT1 alone, or in combination with deletion of the GSTM1 gene, significantly increased the likelihood of imatinib failure (P = 0.021 and P < 0.001, respectively). The GSTP1*B SNP was not associated with time to imatinib failure. Losses of the GSTT1 and GSTM1 genes are therefore important determinants of imatinib failure in CML. Screening for GSTT1 and GSTM1 gene deletions during diagnosis may identify patients who may be better treated using an alternative therapy.

He HR, You HS, Sun JY, et al.
Glutathione S-transferase gene polymorphisms and susceptibility to acute myeloid leukemia: meta-analyses.
Jpn J Clin Oncol. 2014; 44(11):1070-81 [PubMed] Related Publications
OBJECTIVE: A large body of evidence has shown the possible relevance of polymorphisms of the genes that encode glutathione S-transferase μ, π and θ (GSTM1, GSTP1 and GST1, respectively) to the susceptibility of acute myeloid leukemia, but the exact association still remains uncertain. Therefore, we performed a meta-analysis to derive a more precise estimation of the relationship.
METHODS: A comprehensive literature search of PubMed and Web of Knowledge electronic databases was conducted to collect relevant studies until 20 February 2014. References of the retrieved articles were also screened. The extracted data were statistically analyzed, and pooled odds ratios with 95% confidence intervals were calculated to estimate the association strength using Review Manager version 5.2.
RESULTS: Twenty-nine studies were included in the meta-analysis. The pooled analyses revealed that the GSTM1-null genotype was associated with an increased risk of acute myeloid leukemia in East Asians (P = 0.01; odds ratio = 1.22; 95% confidence interval = 1.05-1.42), and GSTT1-null genotype in Caucasians (P < 0.0001; odds ratio = 1.48; 95% confidence interval = 1.29-1.69). There was also a predilection towards the female gender for both of these polymorphisms. For GSTP1 Ile105Val polymorphism, no significant association was found under any contrast model. In addition, the presence of the double-null genotypes increased the risk of acute myeloid leukemia in both Caucasians and East Asians.
CONCLUSIONS: This meta-analysis suggested that heritable GST status could influence the risk of developing acute myeloid leukemia.

Zhu X, Dent S, Paquet L, et al.
Factors influencing Oncotype DX use in the management of early breast cancer: a single centre experience.
Eur J Cancer. 2014; 50(15):2544-9 [PubMed] Related Publications
BACKGROUND: Oncotype DX recurrence score is a multi-gene assay which quantifies the risk of distant recurrence in patients with hormone receptor-positive (HR+) early breast cancer (EBC) treated with tamoxifen, and predicts the magnitude of clinical benefit of adjuvant chemotherapy. This retrospective study examined factors that were associated with use of Oncotype DX assay at a tertiary care cancer centre in Ottawa, Canada.
METHODS: One hundred consecutive patients (pts) diagnosed with HR+, HER2/neu negative EBC (stage I-II), who underwent Oncotype DX testing (Test Group) between 1st April 2010, and 30th June 2011 were included in the study. A second cohort of 100 randomly selected patients with HR+, HER2/neu negative EBC diagnosed from the same time period who did not receive Oncotype DX testing were used as the control group (Control Group). Demographic and clinicopathologic data were obtained from review of charts. Logistic regression was performed to identify variables associated with Oncotype DX usage.
FINDINGS: Median age was 58 years (r: 26-77) in Test Group and 63 years (r: 30-81) in Control Group. Sixty-two patients in the Test Group had T1 tumours, compared with 71 in the Control Group. The median 10-year recurrence risks from Adjuvant! Online were 19% and 12% in the Test Group and Control Group, respectively. Factors significantly associated with the utilisation of Oncotype DX assay on multivariate analysis include age 50-64 (p=0.049), tumour size 10.1-20mm (p=0.008) and grade 2 histological grade (p=0.004).
INTERPRETATION: Usage of Oncotype DX assay is associated with several clinicopathological factors. These factors reflect the clinical uncertainty of benefit from chemotherapy in these subpopulations of patients and suggest how Oncotype DX assay could complement clinicopathological factors in helping clinicians on treatment selection.

Yin B, Zeng Y, Wang X, et al.
Expression and clinical significance of cancer-testis genes in clear cell renal cell carcinoma.
Int J Clin Exp Pathol. 2014; 7(7):4112-9 [PubMed] Article available free on PMC after 03/03/2016 Related Publications
Cancer-testis (CT) antigens, which are encoded by CT genes, have been recognized as a group of highly attractive targets for cancer immunotherapy. However, the expression and clinical relevance of CT genes in clear cell renal cell carcinoma (ccRCC) remains largely unknown. The present study aims to analyze the expression profile of 6 individual CT genes including MAGE-A1, MAGE-A3, MAGE-A12, cTAGE-1, cTAGE-2, and NY-ESO-1 in ccRCC and further investigate their possible correlations with clinicopathologic characteristics. The mRNA expressions of these CT genes were detected using reverse transcriptase-polymerase chain reaction (RT-PCR) in 105 ccRCC tissue samples (T1-2 in 70 samples, T3-4 in 35 samples; G1-2 in 65 samples, G3-4 in 40 samples) as well as the paired adjacent normal tissues. The most frequently expressed CT gene was MAGE-A3 (27.6%), followed by MAGE-A12 (23.8%), NY-ESO-1 (21%), MAGE-A1 (20%), cTAGE-1 (17.1%), and cTAGE-2 (14.3%). In contrast, no expression of CT genes was detected in the paired adjacent normal tissues. Furthermore, the MAGE-A3 protein expression was determined by Western blot and immunohistochemistry. MAGE-A3 protein was expressed in 21.9% ccRCC samples with a cytoplasmic staining pattern. No MAGE-A3 protein expression was found in the paired adjacent normal tissues. There was a significant correlation between MAGE-A3 expression at both mRNA (P =0.045) and protein (P = 0.03) levels with advanced stages of the disease. Taken together, CT genes may serve as promising targets of specific immunotherapy for ccRCC and particularly, MAGE-A3 may serve as a potential prognostic marker for ccRCC patients.

Chuang HC, Yang LP, Fitzgerald AL, et al.
The p53-reactivating small molecule RITA induces senescence in head and neck cancer cells.
PLoS One. 2014; 9(8):e104821 [PubMed] Article available free on PMC after 03/03/2016 Related Publications
TP53 is the most commonly mutated gene in head and neck cancer (HNSCC), with mutations being associated with resistance to conventional therapy. Restoring normal p53 function has previously been investigated via the use of RITA (reactivation of p53 and induction of tumor cell apoptosis), a small molecule that induces a conformational change in p53, leading to activation of its downstream targets. In the current study we found that RITA indeed exerts significant effects in HNSCC cells. However, in this model, we found that a significant outcome of RITA treatment was accelerated senescence. RITA-induced senescence in a variety of p53 backgrounds, including p53 null cells. Also, inhibition of p53 expression did not appear to significantly inhibit RITA-induced senescence. Thus, this phenomenon appears to be partially p53-independent. Additionally, RITA-induced senescence appears to be partially mediated by activation of the DNA damage response and SIRT1 (Silent information regulator T1) inhibition, with a synergistic effect seen by combining either ionizing radiation or SIRT1 inhibition with RITA treatment. These data point toward a novel mechanism of RITA function as well as hint to its possible therapeutic benefit in HNSCC.

Moulik NR, Parveen F, Kumar A, Agrawal S
Glutathione-S-transferase polymorphism and acute lymphoblastic leukemia (ALL) in north Indian children: a case-control study and meta-analysis.
J Hum Genet. 2014; 59(9):529-35 [PubMed] Related Publications
Various studies on association of glutathione S-transferase (GST) polymorphisms and childhood acute lymphoblastic leukemia (ALL) have yielded conflicting results. We examined this association among north Indian children and conducted an updated meta-analysis to overcome sample size-related limitations. GSTM1, GSTP1 and GSTT1 genotypes in 100 children with ALL and 300 healthy controls were compared. GSTT1 null mutation (odds ratio (OR) 2.54, 95% confidence interval (CI) 1.50-4.32) and GSTP1 homozygous mutation (OR 3.13, 95%CI 1.48-6.59) were found to increase the risk of childhood ALL, while GSTM1 did not alter the risk. Meta-analysis included 22, 10 and 20 studies examining the association of childhood ALL with GSTM1, GSTP1 and GSTT1 genotypes, respectively. Only GSTM1 genotype (OR 1.29, 95%CI 1.10-1.62) was associated with increased risk in the overall analysis. However, both GSTM1 (OR 1.54, 95%CI 1.12-2.10) and GSTT1 (OR 1.63, 95%CI 1.32-1.99) null genotypes were associated with increased risk in Asian subjects. The risk of developing childhood ALL was not associated with GSTP1 genotype.

Dong W, van Ginkel JW, Au KY, et al.
ORCA-010, a novel potency-enhanced oncolytic adenovirus, exerts strong antitumor activity in preclinical models.
Hum Gene Ther. 2014; 25(10):897-904 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Improving the antitumor potency of current oncolytic adenoviruses represents one of the major challenges in development of these viruses for clinical use. We have generated an oncolytic adenovirus carrying the safety-enhancing E1AΔ24 deletion, the potency-enhancing T1 mutation, and the infectivity-enhancing fiber RGD modification. The results of in vitro cytotoxicity assays on 15 human cancer cell lines derived from different tumor types demonstrated that ORCA-010 is more potent than Ad5-Δ24RGD or ONYX-015. As ORCA-010 will initially be developed for the treatment of prostate cancer, selectivity experiments were performed using primary human prostate cells. ORCA-010 killed cancer cells more effectively than these primary human cells. In both primary prostate fibroblasts and epithelial cells, ORCA-010 was as safe as Ad5-Δ24RGD. Evaluation of ORCA-010 in in vivo xenograft tumor models in nude mice showed that ORCA-010 significantly inhibited growth of prostate, lung, and ovarian tumors and conferred prolonged survival of tumor-bearing animals. Furthermore, we observed a substantial increase in infectious viral particles in tumors injected with ORCA-010. The number of infectious viral particles increased after treatment and infectious particles remained present up to at least 4 weeks posttreatment. Intratumoral virus replication was associated with substantial necrosis and fibrosis. In conclusion, ORCA-010 is more potent than earlier generation oncolytic adenoviruses, without demonstrating increased toxicity. ORCA-010 exerted strong in vivo antitumor activity and is therefore a suitable candidate for clinical evaluation.

Chen J, Zhao J, Ma R, et al.
Prognostic significance of E-cadherin expression in hepatocellular carcinoma: a meta-analysis.
PLoS One. 2014; 9(8):e103952 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUNDS: Hepatocellular Carcinoma (HCC) is one of the most common malignancy of liver and HCC-related morbidity and mortality remains at high level. Researchers had investigated whether and how reduced E-cadherin expression impacted the prognosis of patients with HCC but the results reported by different teams remain inconclusive.
METHODS: A systematic literature search was performed in all available databases to retrieve eligible studies and identify all relevant data, which could be used to evaluate the correlation between reduced E-cadherin expression and clinicopathological features and prognosis for HCC patients. A fixed or random effects model was used in this meta-analysis to calculate the pooled odds ratios (OR) and weighted mean differences (WMD) with 95% confidence intervals (CI).
RESULTS: Total 2439 patients in thirty studies matched the selection criteria. Aggregation of the data suggested that reduced E-cadherin expression in HCC patients correlated with poor 1-, 3- and 5-year overall survival. The combined ORs were 0.50 (n = 13 studies, 95% CI: 0.37-0.67, Z = 4.49, P<0.00001), 0.39 (n = 13 studies, 95% CI: 0.28-0.56, Z = 5.12, P<0.00001), 0.40 (n = 11 studies, 95% CI: 0.25-0.64, Z = 3.82, P = 0.0001), respectively. Additionally, the pooled analysis denoted that reduced E-cadherin expression negatively impacts recurrence-free survival (RSF) with no significant heterogeneity. The pooled ORs for 1-, 3- and 5- year RSF affected by down-regulated E-cadherin were 0.73 (n = 6 studies, 95% CI: 0.54-1.00, Z = 1.95, P = 0.05), 0.70 (n = 6 studies, 95% CI: 0.52-0.95, Z = 2.32, P = 0.02), 0.66 (n = 5 studies, 95% CI: 0.48-0.90, Z = 2.64, P = 0.008). And what's more, reduced E-cadherin expression tended to be significantly associated with metastasis (OR = 0.31, 95% CI: 0.16-0.60, Z = 3.50, P = 0.0005), vascular invasion (OR = 0.76, 95% CI: 0.59-0.98, Z = 2.14, P = 0.03), advanced differentiation grade (OR = 0.31, 95% CI: 0.21-0.45, Z = 6.04, P<0.00001) and advanced TMN stage (T3/T4 versus T1/T2) (OR = 0.61,95% CI:0.38-0.98, Z = 2.05, P = 0.04).
CONCLUSIONS: Reduced E-cadherin expression indicates a poor prognosis for patients with HCC, and it may have predictive potential for prognosis of HCC patients.

Hemdan T, Lindén M, Lind SB, et al.
The prognostic value and therapeutic target role of stathmin-1 in urinary bladder cancer.
Br J Cancer. 2014; 111(6):1180-7 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
BACKGROUND: The oncoprotein-18/stathmin 1 (STMN1), involved in cell progression and migration, is associated with clinical outcome in breast cancer. Here we aim to investigate its clinical significance in urinary bladder cancer and its possibilities as a therapeutic target.
METHODS: Immunohistochemical analyses of STMN1 protein expression were performed in three patient cohorts: cohort I (n=115 Ta, n=115 T1, n=112 T2-4 stages), cohort II, based on randomised controlled trials (n=239 T1-T4), and cohort III of primary tumour/matched metastasis (n=90 T1-T4). The effects of STMN1 on cell proliferation and migration were evaluated in the urinary bladder cancer cell line, T24, by inhibiting STMN1-cellular expression using siRNA.
RESULTS: In cohort I, high STMN1 expression correlated to shorter disease-specific survival hazard ratio (HR)=2.04 (95% confidence interval (CI) 1.13-3.68; P=0.02), elevated p53- (P<0.001) and Ki67-protein levels (P<0.001). The survival result was validated in cohort II: HR=1.76 (95% CI 1.04-2.99; P=0.03). In the metastatic bladder cancer material, 70% of the patients were STMN1-positive in both the primary tumour and matched metastases. In vitro, the growth and migration of the T24 cells were significantly reduced (P<0.01, P<0.0001, respectively), when transfecting the cells with STMN1-siRNA.
CONCLUSIONS: STMN1 protein expression has prognostic significance but is primarily a potential treatment target in urinary bladder cancer.

Leong KJ, Beggs A, James J, et al.
Biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation.
Br J Surg. 2014; 101(10):1299-309 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
BACKGROUND: Total mesorectal excision (TME) remains commonplace for T1-2 rectal cancer owing to fear of undertreating a small proportion of patients with node-positive disease. Molecular stratification may predict cancer progression. It could be used to select patients for organ-preserving surgery if specific biomarkers were validated.
METHODS: Gene methylation was quantified using bisulphite pyrosequencing in 133 unirradiated rectal cancer TME specimens. KRAS mutation and microsatellite instability status were also defined. Molecular parameters were correlated with histopathological indices of disease progression. Predictive models for nodal metastasis, lymphovascular invasion (LVI) and distant metastasis were constructed using a multilevel reverse logistic regression model.
RESULTS: Methylation of the retinoic acid receptor β gene, RARB, and that of the checkpoint with forkhead and ring finger gene, CHFR, was associated with tumour stage (RARB: 51·9 per cent for T1-2 versus 33·9 per cent for T3-4, P < 0·001; CHFR: 5·5 per cent for T1-2 versus 12·6 per cent for T3-4, P = 0·005). Gene methylation associated with nodal metastasis included RARB (47·1 per cent for N- versus 31·7 per cent for N+; P = 0·008), chemokine ligand 12, CXCL12 (12·3 per cent for N- versus 8·9 per cent for N+; P = 0·021), and death-associated protein kinase 1, DAPK1 (19·3 per cent for N- versus 12·3 per cent for N+; P = 0·022). RARB methylation was also associated with LVI (45·1 per cent for LVI- versus 31·7 per cent for LVI+; P = 0·038). Predictive models for nodal metastasis and LVI achieved sensitivities of 91·1 and 85·0 per cent, and specificities of 55·3 and 45·3 per cent, respectively.
CONCLUSION: This methylation biomarker panel provides a step towards accurate discrimination of indolent and aggressive rectal cancer subtypes. This could offer an improvement over the current standard of care, whereby fit patients are offered radical surgery.

Clark DA, Dhesy-Thind S, Ellis P, Ramsay J
The CD200-tolerance signaling molecule associated with pregnancy success is present in patients with early-stage breast cancer but does not favor nodal metastasis.
Am J Reprod Immunol. 2014; 72(5):435-9 [PubMed] Related Publications
PROBLEM: The CD200-tolerance signaling molecule prevents pregnancy failure and is also expressed by a wide variety of malignant tumors. The effect of CD200 mRNA expression on progression of human tumors has been variable.
METHOD OF STUDY: A cross-sectional study was performed to examine the correlation between CD200 protein expression in the primary tumors from postoperative Stage I-IIIA human breast cancer and the likelihood of regional lymph node metastasis.
RESULTS: Fifty-eight percentage of patients had strong CD200(+) tumor staining (71% of Stage I and 53% Stage II-IIIA). Strong staining was associated with large T2-3 primary tumors compared to T1 tumors (64 versus 50%) and T2-3 N(+) versus T1 N(-) tumors (70 versus 63%), but this was not statistically significant. Nodal metastases were not more frequent in patients with strong CD200(+) staining (57% compared to 58% for weak/negative staining cases), and the metastatic tumor cells in regional lymph nodes were often CD200(-) when the primary tumor was CD200(+).
CONCLUSION: CD200 expression by early-stage human breast cancer cells in primary tumors did not correlate with increased regional lymph node metastasis.

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