IFITM1

Gene Summary

Gene:IFITM1; interferon induced transmembrane protein 1
Aliases: 9-27, CD225, IFI17, LEU13, DSPA2a
Location:11p15.5
Summary:-
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:interferon-induced transmembrane protein 1
Source:NCBIAccessed: 09 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 10 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Latest Publications: IFITM1 (cancer-related)

Ramanathan A, Ramanathan A
Interferon Induced Transmembrane Protein-1 Gene Expression as a Biomarker for Early Detection of Invasive Potential of Oral Squamous Cell Carcinomas.
Asian Pac J Cancer Prev. 2016; 17(4):2297-9 [PubMed] Related Publications
BACKGROUND: Early detection of malignant transformation with expression biomarkers has significant potential to improve the survival rate of patients as such biomarkers enable prediction of progression and assess sensitivity to chemotherapy. The expression of interferon inducible transmembrane protein 1 (IFITM1) has been associated with early invasion events in several carcinomas, including head and neck cancers, and hence has been proposed as a novel candidate biomarker. As the incidence of oral squamous cell carcinoma (OSCC) is highest in the Indian population, we sought to investigate: 1) the expression pattern of IFITM1 in OSCC tissue samples obtained from Indian patients of Dravidian origin; and 2) the possibility of using IFITM1 expression as a potential biomarker.
MATERIALS AND METHODS: Total RNA extracted from thirty eight OSCC biopsy samples was subjected to semi-quantitative RT-PCR with IFITM1 and GAPDH specific primers.
RESULTS: Of the thirty eight OSCC samples that were analyzed, IFITM1 overexpression was identified in fifteen (39%). Seven expressed a low level, while the remainder expressed high level of IFITM1.
CONCLUSIONS: The overexpression of IFITM1 in OSCC samples indicates that IFITM1 may be explored for the possibility of use as a high confidence diagnostic biomarker in oral cancers. To the best of our knowledge, this is the first time that IFITM1 overexpression is being reported in Indian OSCC samples.

Ogony J, Choi HJ, Lui A, et al.
Interferon-induced transmembrane protein 1 (IFITM1) overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a signal transducer and activator of transcription 2 (STAT2)-dependent manner.
Breast Cancer Res. 2016; 18(1):25 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Inflammatory breast cancer (IBC) is a very aggressive and lethal subtype of breast cancer that accounts for about 4 % of all breast cancers diagnosed in the United States. Despite the efforts of several investigators to identify the molecular factors driving the aggressive phenotype of IBC, a great deal is still unknown about the molecular underpinnings of the disease. In the present study, we investigated the role of interferon-induced transmembrane protein 1 (IFITM1), a well-known interferon-stimulated gene (ISG), in promoting the aggressiveness of SUM149 IBC cells.
METHODS: Western blot and real-time polymerase chain reaction analyses were performed to assess the protein and messenger RNA (mRNA) levels of IFITM1 and other ISGs in three IBC cell lines: SUM149, MDA-IBC-3, and SUM190. IFITM1 expression and cellular localization were assessed by using immunofluorescence, while the tumorigenic potential was assessed by performing cell migration, invasion, and colony formation assays. Small interfering RNA and short hairpin RNA knockdowns, enzyme-linked immunosorbent assays, and luciferase assays were performed to determine the functional significance of IFITM1 and signal transducers and activators of transcription 1 and 2 (STAT1/2) in SUM149 cells.
RESULTS: We found that IFITM1 was constitutively overexpressed at the mRNA and protein levels in triple-negative SUM149 IBC cells, but that it was not expressed in SUM190 and MDA-IBC-3 IBC cells, and that suppression of IFITM1 or blockade of the IFNα signaling pathway significantly reduced the aggressive phenotype of SUM149 cells. Additionally, we found that knockdown of STAT2 abolished IFITM1 expression and IFITM1 promoter activity in SUM149 cells and that loss of STAT2 significantly inhibited the ability of SUM149 cells to proliferate, migrate, invade, and form 2-D colonies. Notably, we found that STAT2-mediated activation of IFITM1 was particularly dependent on the chromatin remodeler brahma-related gene 1 (BRG1), which was significantly elevated in SUM149 cells compared with SUM190 and MDA-IBC-3 cells.
CONCLUSIONS: These findings indicate that overexpression of IFITM1 enhances the aggressive phenotype of triple-negative SUM149 IBC cells and that this effect is dependent on STAT2/BRG1 interaction. Further studies are necessary to explore the potential of IFITM1 as a novel therapeutic target and prognostic marker for some subtypes of IBCs.

Hingorani P, Missiaglia E, Shipley J, et al.
Clinical Application of Prognostic Gene Expression Signature in Fusion Gene-Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group.
Clin Cancer Res. 2015; 21(20):4733-9 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Pediatric rhabdomyosarcoma (RMS) has two common histologic subtypes: embryonal (ERMS) and alveolar (ARMS). PAX-FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology, whereas fusion gene-negative (FN) ARMS patients are clinically similar to ERMS patients. A five-gene expression signature (MG5) previously identified two diverse risk groups within the fusion gene-negative RMS (FN-RMS) patients, but this has not been independently validated. The goal of this study was to test whether expression of the MG5 metagene, measured using a technical platform that can be applied to routine pathology material, would correlate with outcome in a new cohort of patients with FN-RMS.
EXPERIMENTAL DESIGN: Cases were taken from the Children's Oncology Group (COG) D9803 study of children with intermediate-risk RMS, and gene expression profiling for the MG5 genes was performed using the nCounter assay. The MG5 score was correlated with clinical and pathologic characteristics as well as overall and event-free survival.
RESULTS: MG5 standardized score showed no significant association with any of the available clinicopathologic variables. The MG5 signature score showed a significant correlation with overall (N = 57; HR, 7.3; 95% CI, 1.9-27.0; P = 0.003) and failure-free survival (N = 57; HR, 6.1; 95% CI, 1.9-19.7; P = 0.002).
CONCLUSIONS: This represents the first, validated molecular prognostic signature for children with FN-RMS who otherwise have intermediate-risk disease. The capacity to measure the expression of a small number of genes in routine pathology material and apply a simple mathematical formula to calculate the MG5 metagene score provides a clear path toward better risk stratification in future prospective clinical trials.

Yu F, Xie D, Ng SS, et al.
IFITM1 promotes the metastasis of human colorectal cancer via CAV-1.
Cancer Lett. 2015; 368(1):135-43 [PubMed] Related Publications
Interferon-induced transmembrane protein 1 (IFITM1) is one of the interferon-induced transmembrane protein family members. In this study, we reported that the elevated IFITM1 expression in human colorectal cancer (CRC) significantly correlated with CRC lymph node and distance metastasis as well as a more advanced clinical stage. Importantly, elevated IFITM1 expression is an independent prognostic factor for poor survival. To investigate the molecular mechanisms, we showed that over-expression of IFITM1 in CRC cells promoted, whereas knockdown of IFITM1 expression inhibited, cell migration/invasion and tumorigenicity in vitro. Furthermore, we identified Caveolin-1 (CAV1) as a downstream target of IFITM1-induced cell invasion, as knockdown of CAV1 abrogated siIFITM1 mediated inhibition of cell invasion in CRC cells. In addition, in a CRC cohort of 229 patients, the expression of IFITM1 inversely correlated with the expression of CAV1. These results suggested that IFITM1 promotes the aggressiveness of CRC cells, and it is a potential prognostic marker and therapeutic target for CRC.

Uvirova M, Simova J, Kubova B, et al.
Comparison of the prevalence of KRAS-LCS6 polymorphism (rs61764370) within different tumour types (colorectal, breast, non-small cell lung cancer and brain tumours). A study of the Czech population.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015; 159(3):466-71 [PubMed] Related Publications
AIMS: A germline SNP (rs61764370) is located in a let-7 complementary site (LCS6) in the 3'UTR of KRAS oncogene, and it was found to alter the binding capability of the mature let-7 microRNA to the KRAS mRNA. The aim of the study was to evaluate the frequency of the KRAS-LCS6 variant allele in different cancer types that included patients with colorectal cancer (CRC), breast cancer (BC), non-small cell lung cancer (NSCLC) and brain tumour patient subgroups from the Czech Republic. The occurrence of this genetic variant was correlated with the presence of selected somatic mutations representing predictive biomarkers in the respective tumours.
METHODS: DNA of tumour tissues was isolated from 428 colorectal cancer samples, 311 non-small cell lung cancer samples, 195 breast cancer samples and 151 samples with brain tumour. Analysis of SNP (rs61764370) was performed by the PCR+RFLP method and direct sequencing. KRAS, BRAF and EGFR mutation status was assessed using real-time PCR. The status of the HER2 gene was assessed using the FISH method.
RESULTS: The KRAS-LCS6 TG genotype has been detected in 16.4% (32/195) of breast cancer cases (in HER2 positive breast cancer 3.3%, in HER2 negative breast cancer 20.1%), in 12.4% (53/428) of CRC cases (KRAS/BRAF wild type CRC in 10.6%, KRAS mutant CRC in 10.1%, BRAF V600E mutant CRC in 18.5%), in 13.2% (41/311) of NSCLC samples, (EGFR mutant NSCLC patients in 8%, EGFR wild type NSCLC in 12.9%), and 17.9% (27/151) of brain tumour cases. The KRAS-LCS6 TG genotype was not significantly different across the studied tumours. In our study, the GG genotype has not been found among the cancer samples.
CONCLUSIONS: Based on the findings, it is concluded that the occurrence of the KRAS-LCS6 TG genotype was statistically significantly different in association with status of the HER2 gene in breast cancer. Furthermore, significant association between the mutation status of analysed somatic variants in genes of the EGFR signalling pathway (KRAS, BRAF, EGFR) and the KRAS-LCS6 genotype in colorectal cancer and NSCLC has not been established.

Xie SB, He XX, Yao SK
Matrine-induced autophagy regulated by p53 through AMP-activated protein kinase in human hepatoma cells.
Int J Oncol. 2015; 47(2):517-26 [PubMed] Related Publications
Matrine, one of the main extract components of Sophora flavescens, has been shown to exhibit inhibitory effects on some tumors through autophagy. However, the mechanism underlying the effect of matrine remains unclear. The cultured human hepatocellular carcinoma cell line HepG2 and SMMC‑7721 were treated with matrine. Signal transduction and gene expression profile were determined. Matrine stimulated autophagy in SMMC‑7721 cells in a mammalian target of rapamycin (mTOR)-dependent manner, but in an mTOR-independent manner in HepG2 cells. Next, in HepG2 cells, autophagy induced by matrine was regulated by p53 inactivation through AMP-activated protein kinase (AMPK) signaling transduction, then AMPK suppression switched autophagy to apoptosis. Furthermore, the interferon (IFN)-inducible genes, including interferon α-inducible protein 27 (IFI27) and interferon induced transmembrane protein 1 (IFITM1), which are downstream effector of p53, might be modulated by matrine-induced autophagy. In addition, we found that the p53 protein isoforms, p53β, p53γ, ∆133p53, and ∆133p53γ, due to alternative splicing of intron 9, might be regulated by the p53-mediated autophagy. These results show that matrine induces autophagy in human hepatoma cells through a novel mechanism, which is p53/AMPK signaling pathway involvement in matrine-promoted autophagy.

Choi HJ, Lui A, Ogony J, et al.
Targeting interferon response genes sensitizes aromatase inhibitor resistant breast cancer cells to estrogen-induced cell death.
Breast Cancer Res. 2015; 17:6 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Estrogen deprivation using aromatase inhibitors (AIs) is currently the standard of care for postmenopausal women with hormone receptor-positive breast cancer. Unfortunately, the majority of patients treated with AIs eventually develop resistance, inevitably resulting in patient relapse and, ultimately, death. The mechanism by which resistance occurs is still not completely known, however, recent studies suggest that impaired/defective interferon signaling might play a role. In the present study, we assessed the functional role of IFITM1 and PLSCR1; two well-known interferon response genes in AI resistance.
METHODS: Real-time PCR and Western blot analyses were used to assess mRNA and protein levels of IFITM1, PLSCR1, STAT1, STAT2, and IRF-7 in AI-resistant MCF-7:5C breast cancer cells and AI-sensitive MCF-7 and T47D cells. Immunohistochemistry (IHC) staining was performed on tissue microarrays consisting of normal breast tissues, primary breast tumors, and AI-resistant recurrence tumors. Enzyme-linked immunosorbent assay was used to quantitate intracellular IFNα level. Neutralizing antibody was used to block type 1 interferon receptor IFNAR1 signaling. Small interference RNA (siRNA) was used to knockdown IFITM1, PLSCR1, STAT1, STAT2, IRF-7, and IFNα expression.
RESULTS: We found that IFITM1 and PLSCR1 were constitutively overexpressed in AI-resistant MCF-7:5C breast cancer cells and AI-resistant tumors and that siRNA knockdown of IFITM1 significantly inhibited the ability of the resistant cells to proliferate, migrate, and invade. Interestingly, suppression of IFITM1 significantly enhanced estradiol-induced cell death in AI-resistant MCF-7:5C cells and markedly increased expression of p21, Bax, and Noxa in these cells. Significantly elevated level of IFNα was detected in AI-resistant MCF-7:5C cells compared to parental MCF-7 cells and suppression of IFNα dramatically reduced IFITM1, PLSCR1, p-STAT1, and p-STAT2 expression in the resistant cells. Lastly, neutralizing antibody against IFNAR1/2 and knockdown of STAT1/STAT2 completely suppressed IFITM1, PLSCR1, p-STAT1, and p-STAT2 expression in the resistant cells, thus confirming the involvement of the canonical IFNα signaling pathway in driving the overexpression of IFITM1 and other interferon-stimulated genes (ISGs) in the resistant cells.
CONCLUSION: Overall, these results demonstrate that constitutive overexpression of ISGs enhances the progression of AI-resistant breast cancer and that suppression of IFITM1 and other ISGs sensitizes AI-resistant cells to estrogen-induced cell death.

Ali RH, Al-Safi R, Al-Waheeb S, et al.
Molecular characterization of a population-based series of endometrial stromal sarcomas in Kuwait.
Hum Pathol. 2014; 45(12):2453-62 [PubMed] Related Publications
Endometrial stromal sarcomas (ESSs) frequently harbor genetic fusions, including JAZF1-SUZ12 and equivalent fusions in low-grade ESS (LGESS) and YWHAE-NUTM2 in high-grade ESS (HGESS). This study aims to classify a population-based series of ESSs in Kuwait based on the 2014 World Health Organization classification system and to assess the diagnostic use of interferon-induced transmembrane protein 1 (IFITM1) immunomarker for ESSs. Twenty ESSs including 19 LGESSs and 1 HGESS treated during the period between 2002 and 2013 were identified, and the cases were reviewed and characterized using fluorescence in situ hybridization and immunohistochemical studies. Thirteen (81.3%) of 16 LGESSs with interpretable results showed JAZF1 and/or PHF1 genetic rearrangements by fluorescence in situ hybridization, and the only HGESS in the series showed YWHAE genetic rearrangement. All LGESSs with interpretable results showed positive immunostaining for CD10 compared with 11 (61%) of 18 that showed positive immunostaining for IFITM1; 4 of 7 IFITM1-negative LGESSs showed JAZF1 and/or PHF1 rearrangements. A series of uterine leiomyomas, leiomyosarcomas, adenosarcomas, and carcinosarcomas were included for comparison, and positive IFITM1 staining was found in 1 of 10 leiomyomas, 3 of 13 leiomyosarcomas, 3 of 4 adenosarcomas, and 3 of 8 carcinosarcomas, compared to 0 of 10 leiomyomas, 9 of 13 leiomyosarcomas, 3 of 4 adenosarcomas, and 5 of 8 carcinosarcomas that were positive for CD10. Our results demonstrated characteristic genetic rearrangements in a high percentage of LGESSs in this Middle Eastern population, and IFITM1 antibody appears to be less sensitive than CD10 for LGESS.

Sun X, Sandhu R, Figueroa JD, et al.
Benign breast tissue composition in breast cancer patients: association with risk factors, clinical variables, and gene expression.
Cancer Epidemiol Biomarkers Prev. 2014; 23(12):2810-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast tissue composition (epithelium, non-fatty stroma, and adipose) changes qualitatively and quantitatively throughout the lifespan, and may mediate relationships between risk factors and breast cancer initiation. We sought to identify relationships between tissue composition, risk factors, tumor characteristics, and gene expression.
METHODS: Participants were 146 patients from the Polish Breast Cancer Study, with data on risk factor and clinicopathological characteristics. Benign breast tissue composition was evaluated using digital image analysis of histologic sections. Whole-genome microarrays were performed on the same tissue blocks.
RESULTS: Mean epithelial, non-fatty stromal, and adipose proportions were 8.4% (SD = 4.9%), 27.7% (SD = 24.0%), and 64.0% (SD = 24.0%), respectively. Among women <50 years old, stroma proportion decreased and adipose proportion increased with age, with approximately 2% difference per year (P < 0.01). The variation in epithelial proportion with age was modest (0.1% per year). Higher epithelial proportion was associated with obesity (7.6% in nonobese vs. 10.1% in obese; P = 0.02) and with poorly differentiated tumors (7.8% in well/moderate vs. 9.9% in poor; P = 0.05). Gene expression signatures associated with epithelial and stromal proportion were identified and validated. Stroma-associated genes were in metabolism and stem cell maintenance pathways, whereas epithelial genes were enriched for cytokine and immune response pathways.
CONCLUSIONS: Breast tissue composition was associated with age, body mass index, and tumor grade, with consequences for breast gene expression.
IMPACT: Breast tissue morphologic factors may influence breast cancer etiology. Composition and gene expression may act as biomarkers of breast cancer risk and progression.

Boeckx C, Weyn C, Vanden Bempt I, et al.
Mutation analysis of genes in the EGFR pathway in Head and Neck cancer patients: implications for anti-EGFR treatment response.
BMC Res Notes. 2014; 7:337 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Targeted therapy against the Epidermal Growth Factor Receptor (EGFR) is among the most promising molecular therapeutics for Head and Neck Squamous Cell Carcinoma (HNSCC). However, drug resistance limits the clinical efficacy of anti-EGFR monoclonal antibodies and no predictive biomarker has entered the clinic yet.
METHODS: A retrospective clinical study was performed utilizing pathological specimens from 52 newly diagnosed HNSCC patients. These patients were screened for mutations in EGFR and KRAS. Tyrosine kinase mutations in EGFR and KRAS mutations were evaluated by high resolution melting analysis (HRMA), whereas EGFRvIII was determined using one-step real-time PCR. Finally, patient samples were screened for HPV-DNA by GP5+/6+ PCR. Survival analysis was performed using Kaplan-Meier analysis and significance was calculated using log-rank statistic.
RESULTS: In our study population no EGFRvIII mutations were present. However, two silent mutations were found; T785T in exon 20 and R836R in exon 21 of the EGFR gene. Additionally, HRMA revealed an abnormal KRAS melting pattern in 7.0% of the samples. However, the KRAS StripAssay could confirm only one sample with a G12S mutation and none of these samples could be confirmed by direct sequencing. HPV DNA was present in 3/25 larynx and 9/27 oropharynx tumors.
CONCLUSION: The low rate of EGFR and KRAS mutations in this Belgian HNSCC population suggests that these genes will probably not play a major role in predicting response to anti-EGFR therapy in HNSCC. Hence, other predictive markers need to be discovered in order to optimize EGFR targeting therapy.

Tymoszuk P, Charoentong P, Hackl H, et al.
High STAT1 mRNA levels but not its tyrosine phosphorylation are associated with macrophage infiltration and bad prognosis in breast cancer.
BMC Cancer. 2014; 14:257 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: STAT1 has been attributed a function as tumor suppressor. However, in breast cancer data from microarray analysis indicated a predictive value of high mRNA expression levels of STAT1 and STAT1 target genes belonging to the interferon-related signature for a poor response to therapy. To clarify this issue we have determined STAT1 expression levels and activation by different methods, and investigated their association with tumor infiltration by immune cells. Additionally, we evaluated the interrelationship of these parameters and their significance for predicting disease outcome.
METHODS: Expression of STAT1, its target genes SOCS1, IRF1, CXCL9, CXCL10, CXCL11, IFIT1, IFITM1, MX1 and genes characteristic for immune cell infiltration (CD68, CD163, PD-L1, PD-L2, PD-1, CD45, IFN-γ, FOXP3) was determined by RT-PCR in two independent cohorts comprising 132 breast cancer patients. For a subset of patients, protein levels of total as well as serine and tyrosine-phosphorylated STAT1 were ascertained by immunohistochemistry or immunoblotting and protein levels of CXCL10 by ELISA.
RESULTS: mRNA expression levels of STAT1 and STAT1 target genes, as well as protein levels of total and serine-phosphorylated STAT1 correlated with each other in neoplastic tissue. However, there was no association between tumor levels of STAT1 mRNA and tyrosine-phosphorylated STAT1 and between CXCL10 serum levels and CXCL10 expression in the tumor. Tumors with increased STAT1 mRNA amounts exhibited elevated expression of genes characteristic for tumor-associated macrophages and immunosuppressive T lymphocytes. Survival analysis revealed an association of high STAT1 mRNA levels and bad prognosis in both cohorts. A similar prognostically relevant correlation with unfavorable outcome was evident for CXCL10, MX1, CD68, CD163, IFN-γ, and PD-L2 expression in at least one collective. By contrast, activation of STAT1 as assessed by the level of STAT1-Y701 phosphorylation was linked to positive outcome. In multivariate Cox regression, the predictive power of STAT1 mRNA expression was lost when including expression of CXCL10, MX1 and CD68 as confounders.
CONCLUSIONS: Our study confirms distinct prognostic relevance of STAT1 expression levels and STAT1 tyrosine phosphorylation in breast cancer patients and identifies an association of high STAT1 levels with elevated expression of STAT1 target genes and markers for infiltrating immune cells.

Riehmer V, Gietzelt J, Beyer U, et al.
Genomic profiling reveals distinctive molecular relapse patterns in IDH1/2 wild-type glioblastoma.
Genes Chromosomes Cancer. 2014; 53(7):589-605 [PubMed] Related Publications
Molecular changes associated with the progression of glioblastoma after standard radiochemotherapy remain poorly understood. We compared genomic profiles of 27 paired primary and recurrent IDH1/2 wild-type glioblastomas by genome-wide array-based comparative genomic hybridization. By bioinformatic analysis, primary and recurrent tumor profiles were normalized and segmented, chromosomal gains and losses identified taking the tumor cell content into account, and difference profiles deduced. Seven of 27 (26%) pairs lacked DNA copy number differences between primary and recurrent tumors (equal pairs). The recurrent tumors in 9/27 (33%) pairs contained all chromosomal imbalances of the primary tumors plus additional ones, suggesting a sequential acquisition of and/or selection for aberrations during progression (sequential pairs). In 11/27 (41%) pairs, the profiles of primary and recurrent tumors were divergent, i.e., the recurrent tumors contained additional aberrations but had lost others, suggesting a polyclonal composition of the primary tumors and considerable clonal evolution (discrepant pairs). Losses on 9p21.3 harboring the CDKN2A/B locus were significantly more common in primary tumors from sequential and discrepant (nonequal) pairs. Nonequal pairs showed ten regions of recurrent genomic differences between primary and recurrent tumors harboring 46 candidate genes associated with tumor recurrence. In particular, copy numbers of genes encoding apoptosis regulators were frequently changed at progression. In summary, approximately 25% of IDH1/2 wild-type glioblastoma pairs have stable genomic imbalances. In contrast, approximately 75% of IDH1/2 wild-type glioblastomas undergo further genomic aberrations and alter their clonal composition upon recurrence impacting their genomic profile, a process possibly facilitated by 9p21.3 loss in the primary tumor. © 2014 Wiley Periodicals, Inc.

Kim NH, Sung HY, Choi EN, et al.
Aberrant DNA methylation in the IFITM1 promoter enhances the metastatic phenotype in an intraperitoneal xenograft model of human ovarian cancer.
Oncol Rep. 2014; 31(5):2139-46 [PubMed] Related Publications
A lack of reliable biomarkers for the early detection and risk of metastatic recurrences makes ovarian cancer the most lethal gynecological cancer. To understand the molecular mechanisms involved in ovarian cancer metastasis in vivo, we analyzed the transcriptional expression pattern in metastatic implants of human ovarian carcinoma xenografts in mice. The expression of 937 genes was significantly different, by at least 2-fold, in the xenografts compared with that in SK-OV-3 cells. We investigated the mechanisms that regulate the expression of one of the profoundly upregulated genes, interferon-induced transmembrane protein 1 (IFITM1), in the metastatic implants. Specific CpG sites within the IFITM1 promoter were hypomethylated in the metastatic implants relative to those in the wild-type SK-OV-3 cells. Treating wild-type SK-OV-3 cells with the demethylating agent 5-aza-2'-deoxycytidine enhanced IFITM1 expression in a dose-dependent manner, implying transcriptional regulation by promoter methylation. We also found that IFITM1 overexpression caused increased migration and invasiveness in SK-OV-3 cells. Our results demonstrate that IFITM1 could be a novel metastasis-promoting gene that enhances the metastatic phenotype in ovarian cancer via epigenetic transcriptional regulation. Our findings also suggest that the status of DNA methylation within the IFITM1 promoter region could be a biomarker indicating metastatic progression in ovarian cancer.

Han SJ, Rolston JD, Molinaro AM, et al.
Phase II trial of 7 days on/7 days off temozolmide for recurrent high-grade glioma.
Neuro Oncol. 2014; 16(9):1255-62 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A phase II trial was performed to evaluate the efficacy of a dose-dense, 7 days on/7 days off schedule of temozolomide for patients with recurrent high-grade gliomas (HGG).
METHODS: Sixty patients with recurrent HGG received temozolomide at 150 mg/m(2)/day on days 1-7 and days 15-21 during each 4-week cycle. The primary endpoint was 6-month progression-free survival (PFS-6), with a secondary endpoint of overall survival (OS). A further exploratory objective included the investigation of whether methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter within tumor tissue predicted outcomes.
RESULTS: Among patients with glioblastoma (n = 40), PFS-6 was 10% (95% CI, 3%-24%) with median OS of 21.6 weeks (95% CI, 16.9-30.6 weeks). PFS-6 for grade III glioma patients (n = 20) was 50% (95% CI, 27%-73%), and median OS was 100.6 weeks (95% CI, 67 weeks to not reached). There were trends towards longer PFS and OS with MGMT promoter methylation (log-rank test; P = .06 for PFS; P = .07 for OS). Additionally, bevacizumab-naïve glioblastoma patients had significantly longer PFS and OS (median PFS was 8.07 weeks [95% CI, 8 weeks to not reached] vs 7.57 weeks [95% CI, 7.29-8.29 weeks], log-rank test, P < .001; median OS was 62 weeks [26.1 weeks to not reached] vs 18.2 weeks [13.9-27.3 weeks], log-rank test, P < .001).
CONCLUSIONS: The dose-dense temozolomide regimen was well tolerated, although it has no significant activity in this population. Clinical trials.gov identified. NCT00619112 (available at http://clinicaltrials.gov/ct2/show/NCT00619112).

Xu CZ, Shi RJ, Chen D, et al.
Potential biomarkers for paclitaxel sensitivity in hypopharynx cancer cell.
Int J Clin Exp Pathol. 2013; 6(12):2745-56 [PubMed] Free Access to Full Article Related Publications
Paclitaxel has been proved to be active in treatment and larynx preservation of HNSCC, however, the fact that about 20-40% patients do not respond to paclitaxel makes it urgent to figure out the biomarkers for paclitaxel-based treatment in Hypopharynx cancer (HPC) patients to improve the therapy effect. In this work, Fadu cells, treated or untreated with low dose of paclitaxel for 24 h, were applied to DNA microarray chips. The differential expression in mRNAs and miRs was analyzed and the network between expression-altered mRNAs and miRs was constructed. Differentially expressed genes were mainly enriched in superpathway of cholesterol biosynthesis (ACAT2, MSMO1, LSS, FDFT1 and FDPS etc.), complement system (C3, C1R, C1S, CFR and CFB etc.), interferon signaling (IFIT1, IFIT3, IFITM1 and MX1 etc.), mTOR signaling (MRAS, PRKAA2, PLD1, RND3 and EIF4A1 etc.) and IGF1 signaling (MRAS, IGFBP7, JUN and FOS etc.), most of these pathways are implicated in tumorigenesis or chemotherapy resistance. The first three pathways were predicted to be suppressed, while the last two pathways were predicted to be induced by paclitaxel, suggesting the combination therapy with mTOR inhibition and paclitaxel might be better than single one. The dramatically expression-altered miRs were miR-112, miR-7, miR-1304, miR-222*, miR-29b-1* (these five miRs were upregulated) and miR-210 (downregulated). The 26 putative target genes mediated by the 6 miRs were figured out and the miR-gene network was constructed. Furthermore, immunoblotting assay showed that ERK signaling in Fadu cells was active by low dose of paclitaxel but repressed by high dose of paclitaxel. Collectively, our data would provide potential biomarkers and therapeutic targets for paclitaxel-based therapy in HPC patients.

Park HS, Park JM, Park S, et al.
Subcellular localization of Mdm2 expression and prognosis of breast cancer.
Int J Clin Oncol. 2014; 19(5):842-51 [PubMed] Related Publications
BACKGROUND: Mouse double minute 2 (Mdm2) is a negative regulator of the tumor suppressor p53. The p53-Mdm2 pathway may play a role in cancer development and prognosis, although the role of p53-Mdm2 in breast cancer remains unclear.
METHODS: p53 and Mdm2 expressions were determined by immunohistochemistry of tissue microarrays of 865 breast cancer patients who underwent surgery. Clinicopathological characteristics and survival data were analyzed. Mdm2 expression was categorized into four groups: negative, cytoplasm positive, nucleus positive, and concurrent nuclear and cytoplasm positive (N+&C+).
RESULTS: Negative, cytoplasm-positive, nucleus-positive, and N+&C+ expressions of Mdm2 were observed in 59.2, 10.9, 27.8, and 2.1 % of patients, respectively. The N+&C+ group was associated with larger tumor size, higher grade, negativity for estrogen and progesterone receptors, HER2 positivity, high Ki-67 index, p53 positivity, and triple negative breast cancer. p53-positive tumors showed poorer overall survival than p53-negative tumors. The nucleus-positive and N+&C+ groups showed poorer disease-free survival than the negative and cytoplasm-positive groups. In multivariate analysis, nuclear Mdm2 expression including the N+&C+ group was significantly related to poor prognosis.
CONCLUSIONS: Concurrent nuclear and cytoplasmic Mdm2 expression was an independent prognostic factor in patients with breast cancer. Subcellular localization of Mdm2 expression should be considered in the evaluation of Mdm2 in breast cancer.

Lee HR, No HK, Ryu CJ, Park HJ
Brahma‑related gene 1-associated expression of 9-27 and IFI-27 is involved in acquired cisplatin resistance of gastric cancer cells.
Mol Med Rep. 2013; 8(3):747-50 [PubMed] Related Publications
In order to investigate the mechanism of cisplatin resistance, a cisplatin-resistant human gastric cancer cell line was established. Subsequent to the exposure of the YCC-3 gastric cancer cell line to equal concentrations of cis-diammine-dichloroplatinum (II) (cisplatin, CDDP) for 6 months, a cisplatin-resistant cell line was established (YCC-3/R). To determine the molecular mechanism of cisplatin resistance in YCC-3/R cells, differentially expressed genes (DEGs) were investigated between YCC-3 and YCC-3/R by annealing control primer-based reverse transcriptase-polymerase chain reaction (ACP RT-PCR) technology. Eleven DEGs were successfully identified and sequenced. Among them, interferon-induced transmembrane protein 1 (9-27) and interferon α-inducible protein 27 (IFI-27) were markedly increased in YCC-3/R cells. In addition, western blot analysis demonstrated that the Brahma-related gene 1 (BRG1), which was observed to selectively activate 9-27 and IFI-27 genes, was overexpressed in YCC-3/R cells. The results suggested that the BRG1‑associated expression of 9-27 and IFI-27 is involved in cisplatin resistance in gastric cancer cells.

Davidson JA, Cromwell I, Ellard SL, et al.
A prospective clinical utility and pharmacoeconomic study of the impact of the 21-gene Recurrence Score® assay in oestrogen receptor positive node negative breast cancer.
Eur J Cancer. 2013; 49(11):2469-75 [PubMed] Related Publications
PURPOSE: The primary purpose of this study was to measure the impact of the 21-gene Recurrence Score® result on systemic treatment recommendations and to perform a prospective health economic analysis in stage I-II, node-negative, oestrogen receptor positive (ER+) breast cancer.
METHODS: Consenting patients with ER+ node negative invasive breast cancer and their treating medial oncologists were asked to complete questionnaires about treatment preferences, level of confidence in those preferences and a decisional conflict scale (patients only) after a discussion of their diagnosis and risk without knowledge of the Recurrence Score. At a subsequent visit, the assay result and final treatment recommendations were discussed prior to both parties completing a second set of questionnaires. A Markov health state transition model was constructed, simulating the costs and outcomes experienced by a hypothetical 'assay naïve' population and an 'assay informed' population.
RESULTS: One hundred and fifty-six patients across two cancer centres were enrolled. Of the 150 for whom successful assay results were obtained, physicians changed their chemotherapy recommendations in 45 cases (30%; 95% confidence interval (CI) 22.8-38.0%); either to add (10%; 95% CI 5.7-16.0%) or omit (20%; 95% CI 13.9-27.3%) adjuvant chemotherapy. There was an overall significant improvement in physician confidence post-assay (p<0.001). Patient decisional conflict also significantly decreased following the assay (p<0.001). The simulation model found an incremental cost-effectiveness ratio of Canadian Dollars (CAD) $6630/quality-adjusted life years (QALY).
CONCLUSION: Within the context of a publicly funded health care system, the Recurrence Score assay significantly affects adjuvant treatment recommendations and is cost effective in ER+ node negative breast cancer.

Shibata MA, Ambati J, Shibata E, et al.
Mammary cancer gene therapy targeting lymphangiogenesis: VEGF-C siRNA and soluble VEGF receptor-2, a splicing variant.
Med Mol Morphol. 2012; 45(4):179-84 [PubMed] Related Publications
Metastasis contributes significantly to cancer mortality, and the most common pathway of initial dissemination is via the afferent ducts of the lymphatics. Overexpression of vascular endothelial growth factor (VEGF)-C has been associated with lymphangiogenesis and lymph node metastasis in a multitude of human neoplasms, including breast cancers. We recently reported that both VEGF-C siRNA and endogenous soluble vascular endothelial growth factor receptor-2 (esVEGFR-2, a new splicing variant) inhibit VEGF-C function and metastasis in a mouse model of metastatic mammary cancer. Here we briefly review our previous experimental work, specifically targeting tumor lymphangiogenesis, in which metastatic mouse mammary cancers received direct intratumoral injections of either expression vectors VEGF-C siRNA or esVEGFR-2, or the empty plasmid vector, once a week for 6 or 8 weeks, followed by in vivo gene electrotransfer of the injected tumors. Throughout our study, both tumor lymphangiogenesis and the multiplicity of lymph node metastasis were significantly inhibited, with an overall reduction in tumor growth, by both VEGF-C siRNA and esVEGFR-2; further, a significant reduction in the number of dilated lymphatic vessels containing intraluminal cancer cells was observed with both treatments. Thus, therapeutic strategies targeting lymphangiogenesis may have great clinical significance for the treatment of metastatic human breast cancer.

Pinheiro H, Carvalho J, Oliveira P, et al.
Transcription initiation arising from E-cadherin/CDH1 intron2: a novel protein isoform that increases gastric cancer cell invasion and angiogenesis.
Hum Mol Genet. 2012; 21(19):4253-69 [PubMed] Related Publications
Disruption of E-cadherin (CDH1 gene) expression, subcellular localization or function arises during initiation and progression of almost 90% of all epithelial carcinomas. Nevertheless, the mechanisms through which this occurs are largely unknown. Previous studies showed the importance of CDH1 intron 2 sequences for proper gene and protein expression, supporting these as E-cadherin cis-modulators. Through RACE and RT-PCR, we searched for transcription events arising from CDH1 intron 2 and discovered several new transcripts. One, named CDH1a, with high expression in spleen and absent from normal stomach, was demonstrated to be translated into a novel isoform, differing from canonical E-cadherin in its N-terminal, as determined by mass spectrometry. Quantitative and functional assays showed that when overexpressed in an E-cadherin negative context, CDH1a replaced canonical protein interactions and functions. However, when co-expressed with canonical E-cadherin, CDH1a increased cell invasion and angiogenesis. Further, interferon-induced gene IFITM1 and IFI27 levels were increased upon CDH1a overexpression. Effects on invasion and IFITM1 and IFI27 expression were reverted upon CDH1a-specific knockdown. Importantly, CDH1a was de novo expressed in gastric cancer cell lines. This study presents a new mechanism by which E-cadherin functions are impaired by cis-regulatory mechanisms possibly with the involvement of inflammatory machinery. If confirmed in other cancer models, our data enclose potential for designing targeted therapies to rescue E-cadherin function.

Imajoh M, Hashida Y, Taniguchi A, et al.
Novel human polyomaviruses, Merkel cell polyomavirus and human polyomavirus 9, in Japanese chronic lymphocytic leukemia cases.
J Hematol Oncol. 2012; 5:25 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chronic lymphocytic leukemia (CLL) is the rarest adult leukemia in Japan, whereas it is the most common leukemia in the Western world. Recent studies from the United States and Germany suggest a possible etiological association between Merkel cell polyomavirus (MCPyV) and CLL, although no data have been reported from Eastern countries. To increase the volume of relevant data, this study investigated the prevalence and DNA loads of MCPyV and human polyomavirus 9 (HPyV9), another lymphotropic polyomavirus, in Japanese CLL cases.
FINDINGS: We found that 9/27 CLL cases (33.3 %) were positive for MCPyV using quantitative real-time polymerase chain reaction analysis. The viral DNA loads ranged from 0.000017 to 0.0012 copies per cell. All cases were negative for HPyV9. One MCPyV-positive CLL case was evaluated by mutational analysis of the large T (LT) gene, which indicated the presence of wild-type MCPyV without a nucleotide deletion. DNA sequence analysis of the entire small T (ST) gene and the partial LT gene revealed that a Japanese MCPyV isolate, designated CLL-JK, had two nucleotide gaps when compared with the reference sequence of the North American isolate MCC350.
CONCLUSIONS: This study provides the first evidence that MCPyV is present in a subset of Japanese CLL cases with low viral DNA loads. MCPyV and HPyV9 are unlikely to contribute directly to the development of CLL in the majority of Japanese cases. MCPyV isolated from the Japanese CLL cases may constitute an Asian group and its pathogenicity needs to be clarified in future studies.

Ma Z, Guo W, Niu HJ, et al.
Transcriptome network analysis reveals potential candidate genes for esophageal squamous cell carcinoma.
Asian Pac J Cancer Prev. 2012; 13(3):767-73 [PubMed] Related Publications
The esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with a poor prognosis. Understanding molecular changes in ESCC should improve identification of risk factors with different molecular subtypes and provide potential targets for early detection and therapy. Our study aimed to obtain a molecular signature of ESCC through the regulation network based on differentially expressed genes (DEGs). We used the GSE23400 series to identify potential genes related to ESCC. Based on bioinformatics we constructed a regulation network. From the results, we could establish that many transcription factors and pathways closely related with ESCC were linked by our method. STAT1 also arose as a hub node in our transcriptome network, along with some transcription factors like CCNB1, TAP1, RARG and IFITM1 proven to be related with ESCC by previous studies. In conclusion, our regulation network provided information on important genes which might be useful in investigating the complex interacting mechanisms underlying the disease.

Lee J, Goh SH, Song N, et al.
Overexpression of IFITM1 has clinicopathologic effects on gastric cancer and is regulated by an epigenetic mechanism.
Am J Pathol. 2012; 181(1):43-52 [PubMed] Related Publications
In an effort to identify novel genes related to the prognosis of gastric cancer, we performed gene expression profiling and found overexpressed levels of human interferon-induced transmembrane protein 1 (IFITM1). We validated the gastric cancer-specific up-regulation of IFITM1 and its association with cancer progression. We also studied its epigenetic regulation and tumorigenesis-related functions. Expression of IFITM1 was evaluated in various human gastric cancer cells and in 35 patient tumor tissues by quantitative RT-PCR and Western blot analyses. The results showed highly up-regulated IFITM1 in cancer cell lines and tissues. Furthermore, IHC studies were performed on 151 patient tissues, and a significant correlation was revealed between higher IFITM1 expression and Lauren's intestinal type (P = 0.007) and differentiated adenocarcinoma (P = 0.025). Quantitative studies of DNA methylation for 27 CpG sites in the regulatory region showed hypermethylation in cells expressing low levels of IFITM1. Methylation-dependent IFITM1 expression was confirmed further by in vitro demethylation using 5-aza-2'-deoxycytidine and luciferase assays. The functional analysis of IFITM1 by silencing of its expression with small-interfering RNA showed decreased migration and invasiveness of cancer cells, whereas its overexpression exhibited the opposite results. In this study, we demonstrated gastric cancer-specific overexpression of IFITM1 regulated by promoter methylation and the role of IFITM1 in cancer prognosis.

Yang G, Rao L, Tian L, Cai X
An association between EGF and EGFR gene polymorphisms with gastric cancer in a Chinese Han population.
Hepatogastroenterology. 2012 Nov-Dec; 59(120):2668-71 [PubMed] Related Publications
BACKGROUND/AIMS: The epidermal growth factor and its receptor play an important role in the development of gastric cancer. We investigate the potential association between epidermal growth factor and its receptor gene polymorphisms with gastric cancer in a Chinese Han population.
METHODOLOGY: Polymerase chain reaction restriction fragment length polymorphism strategies were used to genotype EGF +61 G/A and EGFR+2073 A/T in 207 gastric cancer cases and 318 healthy controls.
RESULTS: The A allele of EGF +61 G/A was less frequently in gastric cancer patients than in controls(OR=0.73, 95%CI=0.55-0.95, p=0.02). The A allele frequency was also associated with deeper tumor invasion(OR=1.74, 95%CI=1.05-2.89, p=0.03), increased lymph node metastasis (OR=1.74, 95%CI=1.08-2.82, p=0.02)and shorter survival time (95%CI=9.27-16.72, p=0.038).A T allele frequency in the EGFR +2073 A/T polymorphism was associated with increased lymph node metastasis in gastric cancer (OR=1.62, 95%CI=1.06-2.47,p=0.03).
CONCLUSIONS: Our results suggest that the A allele of EGF +61 G/A polymorphism decreases the risk of gastric cancer. However, the presence of either the A allele of EGF +61 G/A or the EGFR +2073 T allele indicated a poor prognosis for gastric cancer patients.

He JD, Luo HL, Li J, et al.
Influences of the interferon induced transmembrane protein 1 on the proliferation, invasion, and metastasis of the colorectal cancer SW480 cell lines.
Chin Med J (Engl). 2012; 125(3):517-22 [PubMed] Related Publications
BACKGROUND: Interferon-induced transmembrane protein 1 (IFITM1) has been identified as a molecular marker of the colorectal tumors; however its influences on the biological behaviors of the colorectal cancer cells are currently unknown. We aimed to study the influences of IFITM1 on the proliferation, invasion, and metastasis of the colorectal cancer SW480 cell lines.
METHODS: We constructed IFITM1/pEGFP-C3 recombinant plasmids and transfected them into the colorectal cancer SW480 cell lines. IFITM1/pEGFP-C3 recombinant plasmids were identified by means of immunofluorescence, laser confocal scanning microscopy, and reverse transcription polymerase chain reaction. IFITM1/SW480 cells with stable over-expression of IFITM1 were confirmed by G418 screening. The influences of IFITM1 on the proliferation of the SW480 cell lines were investigated by MTT assay and tumor transplantation experiments in nude mice. Cell invasion experiments were performed to determine the invasion capacity of the IFITM1/SW480 cells. Matrix metalloproteinase 2 (MMP-2) and MMP-9 activities were detected by the gelatin zymographic analysis, and MMP-9 expression by the Western blotting analysis.
RESULTS: IFITM1/pEGFP-C3 recombinant plasmids were successfully constructed in this study, and the IFITM1/SW480 cells with stable IFITM1 gene over-expression were confirmed by G418 screening. MTT results showed that the proliferation of the IFITM1/SW480 cells was significantly enhanced (P < 0.01). Tumors were harvested from four weeks old mice. Tumor volumes were (1347.00 ± 60.94) mm(3), (1032.40 ± 111.38) mm(3) and (1018.78 ± 28.83) mm(3); and tumor weights were (1522.34 ± 62.76) mg, (1137.78 ± 97.22) mg and (1155.76 ± 133.31) mg for mice inoculated with the IFITM1/SW480 cells, pEGFP-C3/SW480 cells and SW480 cells, respectively. Tumor volumes and weights from mice inoculated with the IFITM1/SW480 cells were significantly increased (P < 0.01). In addition, the numbers of the SW480 cells and IFITM1/SW480 cells that migrated through Matrigel were 448.64 ± 38.09 and 540.45 ± 44.61, respectively; so the invasive ability of the SW480 cells transfected with IFITM1 gene was significantly greater than that of the SW480 cells (P < 0.01). Gelatin zymographic analysis showed that MMP-9 and MMP-2 protein activities in the IFITM1/SW480 cells were significantly enhanced, and Western blotting analysis showed that MMP-9 expression in the IFITM1/SW480 cells was also increased.
CONCLUSION: IFITM1 can enhance the proliferation, invasion, and metastasis of the colorectal cancer SW480 cell lines.

Melaiu O, Cristaudo A, Melissari E, et al.
A review of transcriptome studies combined with data mining reveals novel potential markers of malignant pleural mesothelioma.
Mutat Res. 2012 Apr-Jun; 750(2):132-40 [PubMed] Related Publications
Malignant pleural mesothelioma (MPM), a cancer of the serosal pleural cavities, is one of the most aggressive human tumors. In order to identify genes crucial for the onset and progression of MPM, we performed an extensive literature review focused on transcriptome studies (RTS). In this kind of studies a great number of transcripts are analyzed without formulating any a priori hypothesis, thus preventing any bias coming from previously established knowledge that could lead to an over-representation of specific genes. Each study was thoroughly analyzed paying particular attention to: (i) the employed microarray platform, (ii) the number and type of samples, (iii) the fold-change, and (iv) the statistical significance of deregulated genes. We also performed data mining (DM) on MPM using three different tools (Coremine, SNPs3D, and GeneProspector). Results from RTS and DM were compared in order to restrict the number of genes potentially deregulated in MPM. Our main requirement for a gene to be a "mesothelioma gene" (MG) is to be reproducibly deregulated among independent studies and confirmed by DM. A list of MGs was thus produced, including PTGS2, BIRC5, ASS1, JUNB, MCM2, AURKA, FGF2, MKI67, CAV1, SFRP1, CCNB1, CDK4, and MSLN that might represent potential novel biomarkers or therapeutic targets for MPM. Moreover, it was found a sub-group of MGs including ASS1, JUNB, PTGS2, EEF2, SULF1, TOP2A, AURKA, BIRC5, CAV1, IFITM1, PCNA, and PKM2 that could explain, at least in part, the mechanisms of resistance to cisplatin, one first-line chemotherapeutic drug used for the disease. Finally, the pathway analysis showed that co-regulation networks related to the cross-talk between MPM and its micro-environment, in particular involving the adhesion molecules, integrins, and cytokines, might have an important role in MPM. Future studies are warranted to better characterize the role played by these genes in MPM.

Zhang H, Zheng X, Ji T, et al.
Comparative screening of K-ras mutations in colorectal cancer and lung cancer patients using a novel real-time PCR with ADx-K-ras kit and Sanger DNA sequencing.
Cell Biochem Biophys. 2012; 62(3):415-20 [PubMed] Related Publications
We determined frequency/types of K-ras mutations in colorectal/lung cancer. ADx-K-ras kit (real-time/double-loop probe PCR) was used to detect somatic tumor gene mutations compared with Sanger DNA sequencing using 583 colorectal and 244 lung cancer paraffin-embedded clinical samples. Genomic DNA was used in both methods; mutation rates at codons 12/13 and frequency of each mutation were detected and compared. The data show that 91.4% colorectal and 59.0% lung carcinoma samples were detected conclusively by DNA sequencing, whereas 100% colorectal and lung samples were detected by ADx-K-ras kit. K-ras gene mutations were detected in 32.9-27.4% colorectal samples using kit and sequencing methods, respectively. Whereas 10.6-8.3% lung cancer samples were positively detected by kit and sequencing methods, respectively. Notably, 172/677 showed mutations and 467/677 showed wild type by both methods; 38 samples showed mutations with kit but wild type with sequencing. Mutations in colorectal samples were as follows: GGT → GAT/codon-12 (35.1%); GGC → GAC/codon-13 (26.6%); GGT → GTT/codon-12 (18.2%); and GGT → GCT/codon-12 (1.6%). Mutations in lung samples were as follows: GGT > GTT/codon-12 (40.9%) and GGT > GCT/codon-12 (4.5%). In conclusion, K-ras mutations involved 32.2% colorectal and 10.6% lung samples among this cohort. ADx-K-ras real-time PCR showed higher detection rates (P < 0.05). The kit method has good clinical applicability as it is simple, fast, less prone to contamination and hence can be used effectively and reliably for clinical screening of somatic tumor gene mutations.

Deraz EM, Kudo Y, Yoshida M, et al.
MMP-10/stromelysin-2 promotes invasion of head and neck cancer.
PLoS One. 2011; 6(10):e25438 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Periostin, IFN-induced transmembrane protein 1 (IFITM1) and Wingless-type MMTV integration site family, member 5B (Wnt-5b) were previously identified as the invasion promoted genes of head and neck squamous cell carcinoma (HNSCC) by comparing the gene expression profiles between parent and a highly invasive clone. We have previously reported that Periostin and IFITM1 promoted the invasion of HNSCC cells. Here we demonstrated that Wnt-5b overexpression promoted the invasion of HNSCC cells. Moreover, stromelysin-2 (matrix metalloproteinase-10; MMP-10) was identified as a common up-regulated gene among Periostin, IFITM1 and Wnt-5b overexpressing HNSCC cells by using microarray data sets. In this study, we investigated the roles of MMP-10 in the invasion of HNSCC.
METHODS AND FINDINGS: We examined the expression of MMP-10 in HNSCC cases by immunohistochemistry. High expression of MMP-10 was frequently observed and was significantly correlated with the invasiveness and metastasis in HNSCC cases. Next, we examined the roles of MMP-10 in the invasion of HNSCC cells in vitro. Ectopic overexpression of MMP-10 promoted the invasion of HNSCC cells, and knockdown of MMP-10 suppressed the invasion of HNSCC cells. Moreover, MMP-10 knockdown suppressed Periostin and Wnt-5b-promoted invasion. Interestingly, MMP-10 overexpression induced the decreased p38 activity and MMP-10 knockdown induced the increased p38 activity. In addition, treatment with a p38 inhibitor SB203580 in HNSCC cells inhibited the invasion.
CONCLUSIONS: These results suggest that MMP-10 plays an important role in the invasion and metastasis of HNSCC, and that invasion driven by MMP-10 is partially associated with p38 MAPK inhibition. We suggest that MMP-10 can be used as a marker for prediction of metastasis in HNSCC.

Bahnassy AA, Zekri AR, Loutfy SA, et al.
The role of cyclins and cyclin dependent kinases in development and progression of hepatitis C virus-genotype 4-associated hepatitis and hepatocellular carcinoma.
Exp Mol Pathol. 2011; 91(2):643-52 [PubMed] Related Publications
UNLABELLED: Altered cell cycle regulatory genes expression contributes to HCV-associated liver disease. We sought to assess the role of cyclins and cyclin dependent kinases (CDKs) in HCV-associated CH and HCC. Aberrant expression of cyclins A, E, D1, CDK2 and CDK4 was assessed by immunohistochemistry and differential PCR in HCV-associated CH and HCC with pericarcinomatous foci (PCF). S phase fraction (SPF) was determined by flow cytometry. Results were correlated with overall survival (OS) in HCC patients. In HCC, cyclins A, E, D1, CDK2 and CDK4 protein overexpression was detected in 52.8%, 52.8%, 69%, 47% and 58% compared to 36.1%, 33%, 56%, 27.8%, 55.6% for CH and 36.1%, 27%, 30.6%, 27%, 50% for PCF. Gene amplification was detected in 38.9%, 33% 66%, 33%, 44% of HCC compared to 27.8%, 25%, 44%, 27.8%, 36% in CH and 25%, 22.2%, 38.9%, 27%, 33% in PCF. A significant difference was reported between HCC, CH, NHT regarding cyclins A, E, D1, CDK2 (p=0.007, p=0.002, p=0.047, p=0.002) protein expression (ADD) and cyclin D1 amplification (p=0.009). Cyclins A, E, CDK2 expression was associated with fibrosis in CH (p=0.004, p=0.02, p=0.012). Reduced OS was (ADD) associated with cyclin D1 and cyclin A, grade, stage and metastasis (p=0.001, p=0.02, p=0.018, p=0.01, p=0.001).
CONCLUSIONS: Increased cyclins A, E, D1, CDK2 and CDK4 expression is important for HCV-associated CH and HCC. Cyclin D1 and cyclin A are prognostic biomarkers associated with reduced OS in HCC. Cyclin D1 aberration could identify high risk groups of CH patients prone to develop HCC.

Payne K, Wright P, Grant JW, et al.
BIOMED-2 PCR assays for IGK gene rearrangements are essential for B-cell clonality analysis in follicular lymphoma.
Br J Haematol. 2011; 155(1):84-92 [PubMed] Related Publications
B-cell clonality analysis is commonly performed by polymerase chain reaction (PCR) targeting the IGH genes although a high false-negative rate is recognized for germinal centre/post-germinal centre B-cell malignancies, especially follicular lymphoma. We assessed the diagnostic value of BIOMED-2 IGK assays and investigated the cause of IGH PCR failure in 77 patients with follicular lymphoma. Using the full set of BIOMED-2 reactions, clonal immunoglobulin gene rearrangements were detected in 74 (96%) cases. The clonality detection rate was 86% by two IGK reactions but only 68% by five IGH reactions (P < 0·001). Sequencing of the clonal PCR products showed significantly fewer somatic mutations in the rearranged IGKV (9/27 cases, 33%, mean mutation rate 0·5%) than IGHV (17/17 cases, 100%, rate 11·0%) (P < 0·01). All IGHV-IGHJ PCR failures occurred in cases with at least one mutation at the corresponding IGHV primer binding sites. t(14:18)(q32:q21)/IGH-BCL2 was detected in 50 of 71 (70%) cases and the presence of the translocation was not associated with the poor performance of IGH assays. Our results showed that BIOMED-2 IGK assays are significantly more sensitive than IGH assays in follicular lymphoma due to the fact that the rearranged IGKV is less frequently targeted by somatic hypermutation than IGHV, and therefore, are essential in routine clonality analysis of these lymphomas.

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