RARRES1

Gene Summary

Gene:RARRES1; retinoic acid receptor responder (tazarotene induced) 1
Aliases: LXNL, TIG1, PERG-1
Location:3q25.32
Summary:This gene was identified as a retinoid acid (RA) receptor-responsive gene. It encodes a type 1 membrane protein. The expression of this gene is upregulated by tazarotene as well as by retinoic acid receptors. The expression of this gene is found to be downregulated in prostate cancer, which is caused by the methylation of its promoter and CpG island. Alternatively spliced transcript variant encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:retinoic acid receptor responder protein 1
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
RARRES1 is implicated in:
- integral to membrane
- negative regulation of cell proliferation
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

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

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Neoplasm Invasiveness
  • Antineoplastic Agents
  • Prostatic Hyperplasia
  • Cell Cycle Proteins
  • Tumor Suppressor Proteins
  • Esophageal Cancer
  • Histones
  • Gene Expression Profiling
  • Cancer Gene Expression Regulation
  • Prostate Cancer
  • Membrane Proteins
  • Lymphatic Metastasis
  • Receptors, Retinoic Acid
  • Messenger RNA
  • Breast Cancer
  • Polymerase Chain Reaction
  • Transcription
  • Retinol-Binding Proteins
  • DNA Methylation
  • Stomach Cancer
  • Retinoids
  • Tumor Markers
  • Tumor Suppressor Gene
  • Azacitidine
  • Neoplasm Proteins
  • Signal Transduction
  • RTPCR
  • Cell Proliferation
  • CpG Islands
  • Epigenetics
  • Transfection
  • Enzyme Inhibitors
  • Gene Silencing
  • GSTP1
  • Chromosome 3
  • Cancer DNA
  • Oligonucleotide Array Sequence Analysis
  • Proteins
  • Retinoic Acid
  • Promoter Regions
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: RARRES1 (cancer-related)

Moritz R, Ellinger J, Nuhn P, et al.
DNA hypermethylation as a predictor of PSA recurrence in patients with low- and intermediate-grade prostate cancer.
Anticancer Res. 2013; 33(12):5249-54 [PubMed] Related Publications
BACKGROUND: DNA CpG island hypermethylation causes gene silencing and is a common event in prostate carcinogenesis and progression. We investigated its role as a possible prognostic marker in patients with PCA Gleason score ≤7.
PATIENTS AND METHODS: We used a quantitative, methylation-specific PCR to analyze methylation patterns at five gene loci (APC, GSTP1, PTGS2, RARbeta and TIG1) in 84 prostate cancer (PCA) tissues (Gleason Score ≤7). Methylation was correlated with established clinico-pathological parameters (preoperative PSA, pathological Gleason score, extraprostatic extension, seminal vesicle penetration, lymph node involvement, surgical margins and age) and PSA recurrence.
RESULTS: DNA hypermethylation was frequently detected at APC (95.2%), GSTP1 (84.5%), PTGS2 (100%), RAR-beta (81.0%) and TIG1 (95.2%). DNA hypermethylation was correlated with Gleason Score (p=0.027; PTGS2) and lymph node involvement (p=0.024; RARbeta). High methylation levels at RARbeta (p=0.023) was a significant predictor of PSA recurrence following radical prostatectomy.
CONCLUSION: The analysis of DNA hypermethylation provides prognostic information in prognosis of low- and intermediate-grade PCA.

Chen XH, Wu WG, Ding J
Aberrant TIG1 methylation associated with its decreased expression and clinicopathological significance in hepatocellular carcinoma.
Tumour Biol. 2014; 35(2):967-71 [PubMed] Related Publications
Recently, it has been reported that tazarotene-induced gene 1 (TIG1) methylation was frequently detected in a variety of human cancers. However, the relationship between the TIG1 methylation and the characteristics of hepatocellular carcinoma (HCC) remains unknown. The aim of present study was to observe the promoter methylation of TIG1 in HCC tissues and assess its prognostic significance for HCC. Real-time quantitative polymerase chain reaction and methylation-specific polymerase chain reaction were used, respectively, to examine the mRNA expression and methylation status of TIG1 in 91 pairs of HCC and adjacent noncancerous tissues. The mRNA expression level of TIG1 was significantly lower in HCC tissues than in adjacent noncancerous tissues. The rate of TIG1 promoter methylation was significantly higher in HCC tissues than in adjacent noncancerous tissues (P < 0.001). A strong correlation between downregulation and promoter methylation was found in these tumors (P < 0.001). More importantly, TIG1 methylation status was related to tumor size (P = 0.015), histological differentiation (P = 0.004), and tumor stage (P < 0.001). Kaplan-Meier survival analysis showed that TIG1 promoter hypermethylation was associated with a worse outcome in patients with HCC. Further, Cox multivariate analysis indicated that TIG1 methylation status was an independent prognostic factor for the overall survival rate of HCC patients. In conclusion, our data suggested that epigenetic silencing of TIG1 gene expression by promoter hypermethylation may play an important role in HCC.

Rong G, Kang H, Wang Y, et al.
Candidate markers that associate with chemotherapy resistance in breast cancer through the study on Taxotere-induced damage to tumor microenvironment and gene expression profiling of carcinoma-associated fibroblasts (CAFs).
PLoS One. 2013; 8(8):e70960 [PubMed] Free Access to Full Article Related Publications
Recently, emerging evidence has suggested that carcinoma-associated fibroblasts (CAFs) could contribute to chemotherapy resistances in breast cancer treatment. The aim of this study is to compare the gene expression profiling of CAFs before and after chemotherapy and pick up candidate genes that might associate with chemotherapy resistance and could be used as predictors of treatment response. CAFs were cultured from surgically resected primary breast cancers and identified with immunohistochemistry (IHC) and Flow cytometry (FCM). MDA-MB-231 cells were cultured as the breast cancer cell line. Cell adhesion assay, invasion assay, and proliferation assay (MTT) were performed to compare the function of MDA-MB-231 cells co-cultured with CAFs and MDA-MB-231 cells without co-culture, after chemotherapy. Totally 6 pairs of CAFs were prepared for microarray analysis. Each pair of CAFs were obtained from the same patient and classified into two groups. One group was treated with Taxotere (regarded as after chemotherapy) while the other group was not processed with Taxotere (regarded as before chemotherapy). According to our study, the primary-cultured CAFs exhibited characteristic phenotype. After chemotherapy, MDA-MB-231 cells co-cultured with CAFs displayed increasing adhesion, invasiveness and proliferation abilities, compared with MDA-MB-231 cells without CAFs. Moreover, 35 differentially expressed genes (absolute fold change >2) were identified between CAFs after chemotherapy and before chemotherapy, including 17 up-regulated genes and 18 down-regulated genes. CXCL2, MMP1, IL8, RARRES1, FGF1, and CXCR7 were picked up as the candidate markers, of which the differential expression in CAFs before and after chemotherapy was confirmed. The results indicate the changes of gene expression in CAFs induced by Taxotere treatment and propose the candidate markers that possibly associate with chemotherapy resistance in breast cancer.

Qu Y, Dang S, Hou P
Gene methylation in gastric cancer.
Clin Chim Acta. 2013; 424:53-65 [PubMed] Related Publications
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.

Hauser S, Kogej M, Fechner G, et al.
Serum DNA hypermethylation in patients with bladder cancer: results of a prospective multicenter study.
Anticancer Res. 2013; 33(3):779-84 [PubMed] Related Publications
BACKGROUND: Cell-free serum DNA levels are increased in patients with cancer, and at least partially, these DNA fragments are derived from cancer cells. A few reports indicated that methylated serum DNA in patients with bladder cancer (BCA) is a useful non-invasive biomarker. The purpose of this prospective multicenter study was to validate earlier studies.
MATERIALS AND METHODS: In total, 227 consecutive participants (non-muscle invasive BCA, n=75; muscle-invasive BCA, n=20; transurethral bladder resection (TURB) without BCA, n=48; benign disease, n=31; healthy individuals, n=53), were recruited for this study. Cell-free serum DNA was isolated and digested with methylation-sensitive restriction-enzymes (Bsh1236I, HpaII and HinP1I) to quantify the amount of methylated (TIMP3, APC, RARB, TIG1, GSTP1, p14, p16, PTGS2 and RASSF1A) DNA fragments.
RESULTS: The amount of methylated DNA was usually small (<10%), and the methylation frequencies varied for different genes (e.g. frequent: TIMP3; moderate: APC, RARB, TIG1; infrequent: p16, PTGS2, p14, RASSF1A, GSTP1). Methylation levels at each gene site and the number of methylated genes were increased in BCA compared to healthy individuals, but were similar in BCA and patients with non-malignant disease. The number of methylated genes allowed for discrimination (62% sensitivity, 89% specificity) of BCA patients from healthy individuals. DNA hypermethylation was not correlated with advanced stage or grade in patients with BCA.
CONCLUSION: The detection of hypermethylated DNA in serum allows for discrimination of patients with BCA and healthy individuals, but there is no difference between patients with BCA and those with non-malignant disease, thereby limiting its value as a non-invasive biomarker.

Schwarzenbach H, Eichelser C, Kropidlowski J, et al.
Loss of heterozygosity at tumor suppressor genes detectable on fractionated circulating cell-free tumor DNA as indicator of breast cancer progression.
Clin Cancer Res. 2012; 18(20):5719-30 [PubMed] Related Publications
PURPOSE: LOH on circulating DNA may provide tumor-specific information on breast cancer. As identification of LOH on cell-free DNA is impeded by the prevalence of wild type DNA in blood of cancer patients, we fractionated plasma DNA, and determined the diagnostic and prognostic value of both fractions.
EXPERIMENTAL DESIGN: Our cohort of 388 patients with primary breast cancer before chemotherapy was selected from a multicenter study (SUCCESS). Postoperative plasma was fractionated in low- and high-molecular weight DNA by two different column systems. In both fractions, LOH was determined by a PCR-based microsatellite analysis using a panel of 8 polymorphic markers. Circulating tumor DNA in plasma from 30 patients after chemotherapy was additionally analyzed. The significance levels were adjusted for multiple comparisons.
RESULTS: More patients (38%) had LOH at all markers in the fraction containing short DNA fragments than in the fraction containing the long DNA molecules (28%, P = 0.0001). In both fractions 32.85% of LOH were concordant. LOH at the markers D3S1605, D10S1765, D12S1725, D13S218, and D17S855 significantly correlated with tumor stage, tumor size, and lymph node metastasis, positive progesterone, and HER2 receptor status. Most importantly, LOH at D12S1725 mapping to cyclin D2 correlated with shorter overall survival (P = 0.004).
CONCLUSIONS: The improved detection of LOH on cell-free DNA provides important information on DNA losses of tumor suppressor genes TIG1, PTEN, cyclin D2, RB1, and BRCA1 in breast cancer. In particular, loss of the cyclin D2 gene might become an important prognostic marker easily detectable in the peripheral blood.

Gu S, Tian Y, Chlenski A, et al.
Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma.
Anticancer Drugs. 2012; 23(10):1054-66 [PubMed] Free Access to Full Article Related Publications
Epigenetic aberrations and a CpG island methylator phenotype are associated with poor outcome in children with neuroblastoma (NB). Previously, we have shown that valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, exerts antitumor effects in an NB xenograft model. However, the underlying antitumor molecular mechanisms are largely unknown. In this study, we examined the role of HDAC in cell proliferation, cell cycle progression, gene expression patterns, and epigenome in NB. Cell proliferation, cell cycle progression, caspase activity, RNA and protein expression, quantitative methylation, and global DNA methylation were examined in NBL-W-N and LA1-55n NB cell lines. Our studies showed that inhibition of HDAC decreased NB proliferation, and induced caspase activity and G1 growth arrest. Expression patterns of cancer-related genes were modulated by VPA. The expression of THBS1, CASP8, SPARC, CDKN1A, HIC1, CDKN1B, and HIN1 was upregulated, and that of MYCN and TIG1 was downregulated. HDAC inhibition decreased methylation levels of THBS1 and RASSF1A promoters. Inhibition of HDAC increased acetylation of histone 4 and overall DNA methylation levels. Our studies showed that inhibition of HDAC blocked cell proliferation and cell cycle progression in relation to alteration in cancer-related genes, increased overall DNA methylation, and decreased methylation of tumor suppressor genes. Further studies examining the antitumor effects of VPA in NB are warranted.

Peng Z, Shen R, Li YW, et al.
Epigenetic repression of RARRES1 is mediated by methylation of a proximal promoter and a loss of CTCF binding.
PLoS One. 2012; 7(5):e36891 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The cis-acting promoter element responsible for epigenetic silencing of retinoic acid receptor responder 1 (RARRES1) by methylation is unclear. Likewise, how aberrant methylation interplays effectors and thus affects breast neoplastic features remains largely unknown.
METHODOLOGY/PRINCIPAL FINDINGS: We first compared methylation occurring at the sequences (-664~+420) flanking the RARRES1 promoter in primary breast carcinomas to that in adjacent benign tissues. Surprisingly, tumor cores displayed significantly elevated methylation occurring solely at the upstream region (-664~-86), while the downstream element (-85~+420) proximal to the transcriptional start site (+1) remained largely unchanged. Yet, hypermethylation at the former did not result in appreciable silencing effect. In contrast, the proximal sequence displayed full promoter activity and methylation of which remarkably silenced RARRES1 transcription. This phenomenon was recapitulated in breast cancer cell lines, in which methylation at the proximal region strikingly coincided with downregulation. We also discovered that CTCF occupancy was enriched at the unmethylayed promoter bound with transcription-active histone markings. Furthermore, knocking-down CTCF expression hampered RARRES1 expression, suggesting CTCF positively regulated RARRES1 transcription presumably by binding to unmethylated promoter poised at transcription-ready state. Moreover, RARRES1 restoration not only impeded cell invasion but also promoted death induced by chemotherapeutic agents, denoting its tumor suppressive effect. Its role of attenuating invasion agreed with data generated from clinical specimens revealing that RARRES1 was generally downregulated in metastatic lymph nodes compared to the tumor cores.
CONCLUSION/SIGNIFICANCE: This report delineated silencing of RARRES1 by hypermethylation is occurring at a proximal promoter element and is associated with a loss of binding to CTCF, an activator for RARRES1 expression. We also revealed the tumor suppressive roles exerted by RARRES1 in part by promoting breast epithelial cell death and by impeding cell invasion that is an important property for metastatic spread.

Kloth M, Goering W, Ribarska T, et al.
The SNP rs6441224 influences transcriptional activity and prognostically relevant hypermethylation of RARRES1 in prostate cancer.
Int J Cancer. 2012; 131(6):E897-904 [PubMed] Related Publications
Epigenetic aberrations are frequent in prostate cancer and could be useful for detection and prognostication. However, the underlying mechanisms and the sequence of these changes remain to be fully elucidated. The tumor suppressor gene RARRES1 (TIG1) is frequently hypermethylated in several cancers. Having noted changes in the expression of its paralogous neighbor gene LXN at 3q25.32, we used pyrosequencing to quantify DNA methylation at both genes and determine its relationship with clinicopathological parameters in 86 prostate cancer tissues from radical prostatectomies. Methylation at LXN and RARRES1 was highly correlated. Increasing methylation was associated with worse clinical features, including biochemical recurrence, and decreased expression of both genes. However, expression of three neighboring genes was unaffected. Intriguingly, RARRES1 methylation was influenced by the genotype of the rs6441224 single-nucleotide polymorphism (SNP) in its promoter. We found that this SNP is located within an ETS-family-response element and that the more strongly methylated allele confers lower activity in reporter assays. Concomitant methylation of RARRES1 and LXN in cancerous tissues was also detected in prostate cancer cell lines and was shown to be associated with repressive histone modifications and transcriptional downregulation. In conclusion, we found that genotype-associated hypermethylation of the ETS-family target gene RARRES1 influences methylation at its neighbor gene LXN and could be useful as a prognostic biomarker.

Tsai FM, Wu CC, Shyu RY, et al.
Tazarotene-induced gene 1 inhibits prostaglandin E2-stimulated HCT116 colon cancer cell growth.
J Biomed Sci. 2011; 18:88 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The tazarotene-induced gene 1 (TIG1) is a putative tumor suppressor gene. We have recently demonstrated both TIG1A and TIG1B isoforms inhibited cell growth and induced the expression of G protein-coupled receptor kinase 5 (GRK5) in colon cancer cells. Because elevated prostaglandin E2 (PGE2) signaling plays a significant role in colorectal carcinogenesis, the objective of this study was to explore the effect of TIG1 on PGE2-induced cellular proliferation and signaling in colon cancer cells.
METHODS: HCT116 cells as well as TIG1A and TIG1B stable cells established from HCT116 colon cancer cells using the GeneSwitch system were used. TIG1 isoform expression was induced by mifepristone treatment in stable cells. Cell growth was determined using the WST-1 cell proliferation assay. Activation of β-catenin/TCF and cyclic adenosine monophosphate (cAMP)/CREB signaling pathways were determined using luciferase reporter assays. Expression and subcellular distribution of β-catenin were analyzed using Western blot and confocal microscope. Levels of cAMP were measured using an enzyme immunoassay. RNA interference was used to examine the effects of TIG1- and GRK5-mediated changes.
RESULTS: PGE2-stimulated cell growth was reduced in inducible TIG1A- and TIG1B-stable HCT116 cells. GRK5 expression was upregulated by both TIG1A and TIG1B isoforms, and its expression suppressed PGE2-stimulated HCT116 cell growth. GRK5, TIG1A, and TIG1B expression significantly inhibited PGE2-stimulated β-catenin/TCF and cAMP signaling pathway reporters and cAMP. Also, PGE2-stimulated nuclear localization of β-catenin was inhibited by expression of TIG1A and TIG1B, which was ameliorated by both TIG1 and GRK5 siRNAs.
CONCLUSIONS: TIG1 suppressed PGE2-stimulated Wnt and cAMP signaling pathways in colon cancer cells through GRK5.

Davidson B, Stavnes HT, Risberg B, et al.
Gene expression signatures differentiate adenocarcinoma of lung and breast origin in effusions.
Hum Pathol. 2012; 43(5):684-94 [PubMed] Related Publications
Lung and breast adenocarcinoma at advanced stages commonly involve the serosal cavities, giving rise to malignant effusions. The aim of the present study was to compare the global gene expression patterns of metastases from these 2 malignancies, to expand and improve the diagnostic panel of biomarkers currently available for their differential diagnosis, as well as to define type-specific biological targets. Gene expression profiles of 7 breast and 4 lung adenocarcinoma effusions were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time polymerase chain reaction and immunohistochemistry. Unsupervised hierarchical clustering using all 54,675 genes in the array separated lung from breast adenocarcinoma samples. We identified 289 unique probes that were significantly differentially expressed in the 2 cancers by greater than 2-fold using moderated t statistics, of which 65 and 224 were overexpressed in breast and lung adenocarcinoma, respectively. Genes overexpressed in breast adenocarcinoma included TFF1, TFF3, FOXA1, CA12, PITX1, RARRES1, CITED4, MYC, TFAP2A, EFHD1, TOB1, SPDEF, FASN, and TH. Genes overexpressed in lung adenocarcinoma included TITF1, SFTPG, MMP7, EVA1, GPR116, HOP, SCGB3A2, and MET. The differential expression of 15 genes was validated by quantitative real-time PCR, and differences in 8 gene products were confirmed by immunohistochemistry. Expression profiling distinguishes breast adenocarcinoma from lung adenocarcinoma and identifies genes that are differentially expressed in these 2 tumor types. The molecular signatures unique to these cancers may facilitate their differential diagnosis and may provide a molecular basis for therapeutic target discovery.

Vasiljević N, Wu K, Brentnall AR, et al.
Absolute quantitation of DNA methylation of 28 candidate genes in prostate cancer using pyrosequencing.
Dis Markers. 2011; 30(4):151-61 [PubMed] Free Access to Full Article Related Publications
Aberrant DNA methylation plays a pivotal role in carcinogenesis and its mapping is likely to provide biomarkers for improved diagnostic and risk assessment in prostate cancer (PCa). We quantified and compared absolute methylation levels among 28 candidate genes in 48 PCa and 29 benign prostate hyperplasia (BPH) samples using the pyrosequencing (PSQ) method to identify genes with diagnostic and prognostic potential. RARB, HIN1, BCL2, GSTP1, CCND2, EGFR5, APC, RASSF1A, MDR1, NKX2-5, CDH13, DPYS, PTGS2, EDNRB, MAL, PDLIM4, HLAa, ESR1 and TIG1 were highly methylated in PCa compared to BPH (p < 0.001), while SERPINB5, CDH1, TWIST1, DAPK1, THRB, MCAM, SLIT2, CDKN2a and SFN were not. RARB methylation above 21% completely distinguished PCa Separation based on methylation level of SFN, SLIT2 and SERPINB5 distinguished low and high Gleason score cancers, e.g. SFN and SERPINB5 together correctly classified 81% and 77% of high and low Gleason score cancers respectively. Several genes including CDH1 previously reported as methylation markers in PCa were not confirmed in our study. Increasing age was positively associated with gene methylation (p < 0.0001).Accurate quantitative measurement of gene methylation in PCa appears promising and further validation of genes like RARB, HIN1, BCL2, APC and GSTP1 is warranted for diagnostic potential and SFN, SLIT2 and SERPINB5 for prognostic potential.

Mithani SK, Smith IM, Califano JA
Use of integrative epigenetic and cytogenetic analyses to identify novel tumor-suppressor genes in malignant melanoma.
Melanoma Res. 2011; 21(4):298-307 [PubMed] Free Access to Full Article Related Publications
The objective of this study was to identify novel tumor-suppressor genes in melanoma, using an integrative genomic approach. Data from: (i) earlier reports of DNA loss and gain in malignant melanoma accompanied by comparative genomic hybridization high-definition array data of the entire human genome; (ii) microarray expression data from melanoma-derived cell lines identifying genes with significantly increased expression due to methylation using a pharmacologic demethylating strategy; and (iii) publicly available RNA expression microarray data of primary tumors and benign nevi were integrated using statistical tools to define a population of candidate tumor-suppressor genes. Twenty-seven genes were identified in areas of deletion that demonstrated diminished expression in primary melanomas relative to benign nevi and were significantly increased in expression by 5-Aza treatment. Seven genes of these 27 genes demonstrated methylation and deletion in a validation cohort of 14 separate primary tumors. These were: CHRDL1, SFRP1, TMEM47, LPL, RARRES1, PLCXD1, and KOX15. All of these genes demonstrated growth-suppressive properties with transfection into melanoma-derived cell lines. Seven putative tumor-suppressor genes in malignant melanoma were identified using a novel integrative technique.

Wu CC, Tsai FM, Shyu RY, et al.
G protein-coupled receptor kinase 5 mediates Tazarotene-induced gene 1-induced growth suppression of human colon cancer cells.
BMC Cancer. 2011; 11:175 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tazarotene-induced gene 1 (TIG1) is a retinoid-inducible type II tumour suppressor gene. The B isoform of TIG1 (TIG1B) inhibits growth and invasion of cancer cells. Expression of TIG1B is frequently downregulated in various cancer tissues; however, the expression and activities of the TIG1A isoform are yet to be reported. Therefore, this study investigated the effects of the TIG1A and TIG1B isoforms on cell growth and gene expression profiles using colon cancer cells.
METHODS: TIG1A and TIG1B stable clones derived from HCT116 and SW620 colon cancer cells were established using the GeneSwitch system; TIG1 isoform expression was induced by mifepristone treatment. Cell growth was assessed using the WST-1 cell proliferation and colony formation assays. RNA interference was used to examine the TIG1 mediating changes in cell growth. Gene expression profiles were determined using microarray and validated using real-time polymerase chain reaction, and Western blot analyses.
RESULTS: Both TIG1 isoforms were expressed at high levels in normal prostate and colon tissues and were downregulated in colon cancer cell lines. Both TIG1 isoforms significantly inhibited the growth of transiently transfected HCT116 cells and stably expressing TIG1A and TIG1B HCT116 and SW620 cells. Expression of 129 and 55 genes was altered upon induction of TIG1A and TIG1B expression, respectively, in stably expressing HCT116 cells. Of the genes analysed, 23 and 6 genes were upregulated and downregulated, respectively, in both TIG1A and TIG1B expressing cells. Upregulation of the G-protein-coupled receptor kinase 5 (GRK5) was confirmed using real-time polymerase chain reaction and Western blot analyses in both TIG1 stable cell lines. Silencing of TIG1A or GRK5 expression significantly decreased TIG1A-mediated cell growth suppression.
CONCLUSIONS: Expression of both TIG1 isoforms was observed in normal prostate and colon tissues and was downregulated in colon cancer cell lines. Both TIG1 isoforms suppressed cell growth and stimulated GRK5 expression in HCT116 and SW620 cells. Knockdown of GRK5 expression alleviated TIG1A-induced growth suppression of HCT116 cells, suggesting that GRK5 mediates cell growth suppression by TIG1A. Thus, TIG1 may participate in the downregulation of G-protein coupled signaling by upregulating GRK5 expression.

Tamura G, So K, Miyoshi H, et al.
Quantitative assessment of gene methylation in neoplastic and non-neoplastic gastric epithelia using methylation-specific DNA microarray.
Pathol Int. 2009; 59(12):895-9 [PubMed] Related Publications
A fiber-type DNA microarray was used to calculate methylation rates (MR) of four tumor suppressor genes, lysyl oxidase (LOX), p16, RUNX3, and tazarotene-induced gene 1 (TIG1). MR were calculated in 26 primary gastric cancers and corresponding non-neoplastic gastric epithelia, and the results were compared to those of conventional methylation-specific polymerase chain reaction (MSP). MR ranged from 0.1% to 69.1% (mean, 18.3%) for LOX, 0.5-74.1% (mean, 15.7%) for p16, 0.2-76.5% (mean, 22.7%) for RUNX3, and 0.6-41.2% (mean, 5.8%) for TIG1 in primary gastric cancers, and from 0.1% to 25.8% (mean, 8.7%) for LOX, 1.0- 23.2% (mean, 10.3%) for p16, 0.7-25.1% (mean, 5.5%) for RUNX3, and 1.8-27.6% (mean, 11.4%) for TIG1 in corresponding non-neoplastic gastric epithelia. Although MR varied significantly across different samples for both neoplastic and non-neoplastic gastric epithelia, high-level methylation (MR >40%) was cancer specific and was observed in 19.2%, 19.2%, 30.8%, and 3.8% of primary gastric cancers for LOX, p16, RUNX3, and TIG1, respectively. All samples with high-level methylation, as well as some samples with low MR (particularly <10%) were judged to be methylation positive on conventional MSP. Quantitative analysis of gene methylation using methylation-specific DNA microarray is a promising method for cancer diagnosis.

Son MS, Kang MJ, Park HC, et al.
Expression and mutation analysis of TIG1 (tazarotene-induced gene 1) in human gastric cancer.
Oncol Res. 2009; 17(11-12):571-80 [PubMed] Related Publications
Tazarotene-induced gene 1 (TIG1) has been known to function as a cell adhesion molecule, which leads to better cell to cell contact and reduced proliferation. We investigated expression and mutation status of TIG1 in primary gastric tumors and cell lines to explore the candidacy of the gene as a tumor suppressor. A total of 172 gastric tissue specimes, including 80 primary adenocarcinomas, 12 benign tumors, and 80 adjacent normal mucosa, and 15 gastric cancer cell lines were used. TIG1 expression was analyzed by semiquantitative RT-PCR and immunoblot analysis. To screen for the presence of somatic mutations, RT-PCR-SSCP analysis was carried out. The effect of 5-aza-2'-deoxycytidine treatment was examined to elicit whether TIG1 reduction is associated with abnormal DNA hypermethylation. Compared to noncancerous tissues, a substantial reduction of TIG1 expression was observed in 73.3% (11115) cancer cell lines, and seven of these exhibited nearly undetectable levels of expression. Decreased expression of TIG1 was also found in 62 (77.5%) primary carcinoma tissues compared to adjacent noncancerous tissues, indicating a tumor-specific reduction of TIG1. Expression levels of TIG1 were significantly low in primary carcinomas and cancer cell lines compared to those of normal tissues. Moreover, loss or reduction of TIG1 was significantly high in advanced tumors compared to early tumors and more frequent in poorly differentiated tumors than well or moderately differentiated tumors. TIG1 expression was reactivated or its level was elevated following 5-aza-2'-deoxycytidine treatment, indicating that TIG1 expression is transcriptionally silenced in these cancer cells by abnormal DNA hypermethylation. These data indicate that TIG1 undergoes frequent epigenetic inactivation due to aberrant DNA hypermethylation in gastric cancers, and its altered expression is associated with the malignant progression of tumors.

Kwok WK, Pang JC, Lo KW, Ng HK
Role of the RARRES1 gene in nasopharyngeal carcinoma.
Cancer Genet Cytogenet. 2009; 194(1):58-64 [PubMed] Related Publications
Nasopharyngeal carcinoma (NPC) is a unique type of head and neck cancer that is most prevalent in southern China. Previous studies have suggested that genetic susceptibility, environmental carcinogens, and Epstein-Barr virus (EBV) infection contribute to the etiology of NPC. Our group has identified the retinoic acid receptor responder (tazarotene induced) 1 gene (RARRES1; alias TIG1) to be transcriptionally silenced by promoter hypermethylation in approximately 90% of NPC cases, suggesting that its inactivation may be important in NPC formation. The aim of this study was to explore the functional role of the RARRES1 protein (alias TIG1) in NPC cells with EBV infection (HK1-EBV) and without (HK1). Cellular proliferation analysis, as measured by 5-bromo-2'-deoxyuridine (BrdU) incorporation, showed that knockdown and overexpression of TIG1 in HK1 led, respectively, to significantly increased (P = 0.005) and reduced (P = 0.027) proportions of BrdU-labeled cells, compared with control cells. In contrast, knockdown or overexpression of TIG1 had no significant effect on cellular proliferation in HK1-EBV cells. Invasion chamber assay showed that TIG1 knockdown in HK1-EBV cells resulted in significant enhancement of invasive capacity of HK1-EBV cells (P = 0.006). HK1 cells were not invasive, regardless of TIG1 status. These findings suggest that TIG1 may play a role in cellular proliferation and invasion in NPC cells and that its function may be dependent on the EBV status.

Sun J, Chen Z, Zhu T, et al.
Hypermethylated SFRP1, but none of other nine genes "informative" for western countries, is valuable for bladder cancer detection in Mainland China.
J Cancer Res Clin Oncol. 2009; 135(12):1717-27 [PubMed] Related Publications
PURPOSE: A 11-gene set by methylation-specific PCR in urine sediments for sensitive/specific detection of bladder cancer has been identified previously. In this study, we have evaluated 10 DNA methylation biomarkers that have been reported informative in western countries for bladder cancer diagnosis for a better set.
MATERIALS AND METHODS: The promoter CpG Islands of the following 10 genes: CDH1, FANCF, LOXL1, LOXL4, p16INK4, SFRP1, SOX9, TIG1, TIMP3, and XAF1 have been subjected to methylation-specific PCR analysis in the DNA of 2 bladder cancer cell lines, 2 normal bladder tissues and urine sediments of 82 bladder cancer patients, 15 non-cancerous urogenital patients and 5 healthy volunteers.
RESULTS: Both XAF1 and LOXL1 genes were heterozygously methylated in the normal bladder tissues, showing no cancer state specificity. While the hypermethylated states were detected in urine sediments of bladder cancer at a frequency not less than 2.4% (2/82 cases), nine genes were also methylated in the patients of the non-cancerous urogenital diseases. The methylated SFRP1 was detected in 36.6% (30/82 cases) of bladder cancer and 6.7% (1/15 cases) of non-cancerous urogenital diseases, showing the bladder cancer specificity.
CONCLUSIONS: Inclusion of the SFRP1 gene into a set of 11 genes has improved the bladder cancer detection. The insufficiency of predicting disease onset in this study with the previously recommended targets in western countries suggests a possible disease disparity between these two populations. Alternatively, the tissue-specific methylation might be mistaken as the cancer specific in the studies where no non-cancerous lesion controls were involved.

Bonazzi VF, Irwin D, Hayward NK
Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma.
Genes Chromosomes Cancer. 2009; 48(1):10-21 [PubMed] Related Publications
Tumor suppressor genes (TSGs) are sometimes inactivated by transcriptional silencing through promoter hypermethylation. To identify novel methylated TSGs in melanoma, we carried out global mRNA expression profiling on a panel of 12 melanoma cell lines treated with a combination of 5-Aza-2-deoxycytidine (5AzadC) and an inhibitor of histone deacetylase, Trichostatin A. Reactivation of gene expression after drug treatment was assessed using Illumina whole-genome microarrays. After qRT-PCR confirmation, we followed up 8 genes (AKAP12, ARHGEF16, ARHGAP27, ENC1, PPP1R3C, PPP1R14C, RARRES1, and TP53INP1) by quantitative DNA methylation analysis using mass spectrometry of base-specific cleaved amplification products in panels of melanoma cell lines and fresh tumors. PPP1R3C, ENC1, RARRES1, and TP53INP1, showed reduced mRNA expression in 35-59% of the melanoma cell lines compared to melanocytes and which was correlated with a high proportion of promoter methylation (>40-60%). The same genes also showed extensive promoter methylation in 6-25% of the tumor samples, thus confirming them as novel candidate TSGs in melanoma.

Ellinger J, Bastian PJ, Jurgan T, et al.
CpG island hypermethylation at multiple gene sites in diagnosis and prognosis of prostate cancer.
Urology. 2008; 71(1):161-7 [PubMed] Related Publications
OBJECTIVES: CpG island hypermethylation causes gene silencing and could be decisive in prostate carcinogenesis and progression. We investigated its role at multiple gene sites during prostate carcinogenesis.
METHODS: A quantitative, methylation-specific polymerase chain reaction was used to analyze the hypermethylation patterns at nine gene loci (Annexin2, APC, EDNRB, GSTP1, PTGS2, MDR1, RARbeta, Reprimo, and TIG1) in 80 patients with prostate cancer (PCa) and 26 patients with benign prostatic hyperplasia (BPH).
RESULTS: Hypermethylation was more frequent in PCa than in BPH tissues (EDNRB, 100% versus 88%; TIG1, 96% versus 12%; RARbeta, 95% versus 35%; GSTP1, 93% versus 15%; APC, 80% versus 50%; MDR1, 80% versus 31%; PTGS2, 68% versus 15%; Reprimo, 59% versus 19%; and Annexin2, 4% versus 0%). TIG1 and GSTP1 hypermethylation distinguished between PCa and BPH with a specificity of greater than 85% and sensitivity of greater than 93%. Hypermethylation at a single gene locus did not correlate with any clinicopathologic variables. In contrast, hypermethylation at two genes (eg, APC and TIG1, APC and GSTP1, APC and PTGS2, APC or MDR, GSTP1 or PTGS2) correlated significantly with the pathologic stage and/or Gleason score (P = 0.033 to 0.045). Hypermethylation at APC and Reprimo, as well as DNA hypermethylation at more than five genes, correlated significantly with the rate of prostate-specific antigen recurrence after radical prostatectomy (P = 0.0078 and P = 0.0074, respectively).
CONCLUSIONS: Our results have confirmed that the hypermethylation patterns are helpful in the diagnosis and prognosis of PCa. Increases in CpG island hypermethylation at multiple gene sites occur during PCa progression and indicate early biochemical recurrence after radical prostatectomy.

Ellinger J, El Kassem N, Heukamp LC, et al.
Hypermethylation of cell-free serum DNA indicates worse outcome in patients with bladder cancer.
J Urol. 2008; 179(1):346-52 [PubMed] Related Publications
PURPOSE: CpG island hypermethylation is a frequent event in bladder carcinogenesis and progression. We investigated the diagnostic and prognostic value of hypermethylation in cell-free serum DNA of patients with bladder cancer.
MATERIALS AND METHODS: The study cohort consisted of 45 patients with bladder cancer undergoing cystectomy and 45 with histologically confirmed benign prostatic hyperplasia serving as controls. Hypermethylation at APC, DAPK, GSTP1, PTGS2, TIG1 and Reprimo was analyzed using real-time polymerase chain reaction following methylation sensitive restriction endonuclease treatment.
RESULTS: Hypermethylation at the APC and GSTP1 promoter was detected in 59% of cases, whereas TIG1 (32%), PTGS2 (24%) and DAPK (2%) were less frequently hypermethylated. In the benign prostatic hyperplasia group 3 patients also harbored methylated GSTP1 DNA, whereas none of the other gene sites was methylated. Hypermethylation at APC, GSTP1 or TIG1 distinguished patients with bladder cancer and controls most accurately with 80% sensitivity and 93% specificity. Hypermethylation significantly correlated with prognostic unfavorable clinicopathological parameters, including APC with pT stage, GSTP1, or GSTP1 or TIG1 with multifocal bladder cancer and APC, or APC or TIG1 with surgical margin positivity. Bladder cancer specific mortality was significantly increased in patients with APC hypermethylation.
CONCLUSIONS: The detection of hypermethylation in cell-free serum DNA provides valuable diagnostic and prognostic information that can still be improved by combining the results of 3 gene sites (APC, GSTP1 and TIG1). The presence of hypermethylated DNA in the serum of patients with bladder cancer is associated with a worse outcome. Our results suggest that measuring hypermethylation in the serum of patients with bladder cancer is a useful biomarker.

Ellinger J, Haan K, Heukamp LC, et al.
CpG island hypermethylation in cell-free serum DNA identifies patients with localized prostate cancer.
Prostate. 2008; 68(1):42-9 [PubMed] Related Publications
BACKGROUND: One of the earliest and most common epigenetic events in prostate carcinogenesis is DNA CpG island (CGI) hypermethylation. Our aim was to analyze the diagnostic and prognostic possibilities of multigene methylation analysis in cell-free serum DNA of prostate cancer (PCA) patients.
METHODS: We analyzed serum samples from 226 consecutive patients (168 PCA; 42 benign prostatic hyperplasia (BPH); 5 incidental PCA; 11 healthy individuals). Cell-free DNA was digested with methylation-sensitive restriction endonucleases (HpaII and HinP1I). Subsequently, CGI hypermethylation at GSTP1, PTGS2, Reprimo, and TIG1 was assessed using real-time PCR.
RESULTS: CGI hypermethylation at GSTP1, TIG1, PTGS2, and Reprimo was more frequent in PCA (42.3%, 9.5%, 2.4%, and 1.2%, respectively) compared to BPH (7.7%, 0%, 0%, and 0%, respectively) and healthy individuals (all 0%) with a statistical significant difference of GSTP1 (P < 0.0001) and TIG1 (P = 0.038). GSTP1 hypermethylation was also detected in four patients with incidental PCA. Hypermethylation in serum DNA at GSTP1 and hypermethylation at any gene site distinguished between PCA and BPH patients in a highly specific (92%) but less sensitive (42-47%) manner. Neither CGI hypermethylation at a single gene loci nor the combination of multiple gene sites was correlated to the pathological stage, grade or biochemical recurrence following radical prostatectomy.
CONCLUSIONS: The detection of aberrant hypermethylation in cell-free serum DNA allows the highly specific diagnosis of PCA. A test based on GSTP1 hypermethylation in serum samples of patients with suspected PCA may help to identify men with increased risk of harboring PCA despite negative prostate biopsy.

Yanatatsaneejit P, Chalermchai T, Kerekhanjanarong V, et al.
Promoter hypermethylation of CCNA1, RARRES1, and HRASLS3 in nasopharyngeal carcinoma.
Oral Oncol. 2008; 44(4):400-6 [PubMed] Related Publications
In search for putative tumor suppressor genes critical of nasopharyngeal carcinoma (NPC), we analyzed the available information from the expression profiling in conjunction with the comprehensive alleotyping published data relevant to this malignancy. Integration of this information suggested eight potential candidate tumor suppressor genes, CCNA1, HRASLS3, RARRES1, CLMN, EML1, TSC22, LOH11CR2A and MCC. However, to confirm the above observations, we chose to investigate if promoter hypermethylation of these candidate genes would be one of the mechanisms responsible for the de-regulation of gene expression in NPC in addition to the loss of genetic materials. In this study, we detected consistent hypermethylation of the 5' element of CCNA1, RARRES1, and HRASLS in NPC tissues with prevalence of 48%, 51%, and 17%, respectively. Moreover, we found a similar profile of promoter hypermethylation in primary cultured NPC cells but none in normal nasopharyngeal epithelium or leukocytes, which further substantiate our hypothesis. Our data indicate that CCNA1, RARRES1, and HRASLS3 may be the putative tumor suppressor genes in NPC.

Kim BH, Cho NY, Choi M, et al.
Methylation profiles of multiple CpG island loci in extrahepatic cholangiocarcinoma versus those of intrahepatic cholangiocarcinomas.
Arch Pathol Lab Med. 2007; 131(6):923-30 [PubMed] Related Publications
CONTEXT: CpG island hypermethylation is attracting attention because of its importance as a tumor marker and its potential mechanism for the development of human cancers. Extrahepatic cholangiocarcinoma has been poorly investigated with respect to CpG island hypermethylation, and the number of genes known to be methylated in extrahepatic cholangiocarcinomas is fewer than 20.
OBJECTIVE: To generate methylation profiles of 24 CpG island loci in extrahepatic cholangiocarcinomas, to correlate methylation findings with clinicopathologic findings, and to compare these findings with those of intrahepatic cholangiocarcinomas.
DESIGN: Sixty-three extrahepatic cholangiocarcinomas and 48 intrahepatic cholangiocarcinomas were investigated for hypermethylation in 24 CpG island loci by using methylation-specific polymerase chain reaction.
RESULTS: A total of 61 (96.8%) of 63 extrahepatic cholangiocarcinomas showed hypermethylation in at least one of the examined loci, and a high methylation frequency was seen in HOXA1 (95.2%), HPP1 (69.8%), and NEUROG1 (61.9%). The number of methylated CpG island loci was greater in extrahepatic cholangiocarcinomas with nodal metastasis than in those without nodal metastasis (P = .047), and hypermethylation of TIG1 was closely associated with nodal metastasis of extrahepatic cholangiocarcinomas (P = .007). CDH1 and NEUROG1 were more frequently methylated in extrahepatic cholangiocarcinoma than in intrahepatic cholangiocarcinoma, whereas CHFR, GSTP1, IGF2, MGMT, MINT31, p14, and RBP1 were more frequently methylated in intrahepatic cholangiocarcinoma: the differences was statistically significant (P < .05).
CONCLUSIONS: A close relationship exists between CpG island hypermethylation and nodal metastasis of extrahepatic cholangiocarcinomas. Methylation profiles of extrahepatic cholangiocarcinomas are somewhat similar to but distinct from those of intrahepatic cholangiocarcinomas.

Jeronimo C, Monteiro P, Henrique R, et al.
Quantitative hypermethylation of a small panel of genes augments the diagnostic accuracy in fine-needle aspirate washings of breast lesions.
Breast Cancer Res Treat. 2008; 109(1):27-34 [PubMed] Related Publications
PURPOSE: We hypothesized that comprehensive breast cancer methylation profiling might provide biomarkers for diagnostic assessment of suspicious breast lesions using fine needle aspiration biopsy (FNA).
EXPERIMENTAL DESIGN: Twenty-three gene promoters were surveyed by quantitative methylation-specific PCR in bisulfite-modified DNA from 66 breast carcinomas (BCa), 31 fibroadenomas (FB) and 12 normal breast (NT) samples to define a set of genes differentially methylated in malignant and non-malignant tissues. This set was tested in 78 FNA washings obtained pre-operatively (66 malignant, 12 benign), with histopathological diagnosis. Receiver operator characteristic (ROC) curve analysis identified a gene panel which might distinguish cancer from non-cancerous lesions. Finally, this panel was validated in an independent series of FNA washings (45 cases) in which cytomorphology did not reach definitive diagnosis.
RESULTS: In tissue samples, 14-3-3-sigma, DAPK, CCND2, RASSF1A, CALCA, APC, HIN1, RARbeta2, TIG1, and GSTP1 methylation levels differed significantly among BCa, FB, and NT. ROC curve analysis identified a panel of four gene loci (CCND2, RASSF1A, APC, and HIN1) that discriminated BCa from benign lesions in a set of 78 FNA washings from histologically characterized breast lesions. When this panel was tested in the validation dataset of 45 FNA washings, breast cancer was identified with perfect specificity (100%) when 3 of 4 gene loci tested positive, providing estimated added information of 91% over cytomorphologic evaluation alone.
CONCLUSIONS: Our data provide evidence that multigene methylation analysis augments diagnostic accuracy of cytological assessment of suspicious breast lesions, and might be a valuable ancillary tool for breast cancer diagnosis.

Cho NY, Kim BH, Choi M, et al.
Hypermethylation of CpG island loci and hypomethylation of LINE-1 and Alu repeats in prostate adenocarcinoma and their relationship to clinicopathological features.
J Pathol. 2007; 211(3):269-77 [PubMed] Related Publications
Promoter CpG island hypermethylation is an important carcinogenic event in prostate adenocarcinoma. Regardless of tissue type, human cancers have in common both focal CpG island hypermethylation and global genomic hypomethylation. The present study evaluated CpG island loci hypermethylation and LINE-1 and Alu repeat hypomethylation in prostate adenocarcinoma, analysed the relationship between them, and correlated these findings with clinicopathological features. We examined 179 cases of prostate adenocarcinoma and 30 cases of benign prostate hypertrophy for the methylation status of 22 CpG island loci and the methylation levels of LINE-1 and Alu repeats using methylation-specific polymerase chain reaction and combined bisulphite restriction analysis, respectively. The following 16 CpG island loci were found to display cancer-related hypermethylation: RASSF1A, GSTP1, RARB, TNFRSF10C, APC, BCL2, MDR1, ASC, TIG1, RBP1, COX2, THBS1, TNFRSF10D, CD44, p16, and RUNX3. Except for the last four CpG island loci, hypermethylation of each of the remaining 12 CpG island loci displayed a close association with one or more of the prognostic parameters (ie preoperative serum prostate specific antigen level, Gleason score sum, and clinical stage). Prostate adenocarcinoma with hypermethylation of each of ASC, COX2, RARB, TNFRSF10C, MDR1, TIG1, RBP1, NEUROG1, RASSF1A, and GSTP1 showed a significantly lower methylation level of Alu or LINE-1 than prostate adenocarcinoma without hypermethylation. In addition, hypomethylation of Alu or LINE-1 was closely associated with one or more of the above prognostic parameters. These data suggest that in tumour progression a close relationship exists between CpG island hypermethylation and the hypomethylation of repetitive elements, and that CpG island hypermethylation and DNA hypomethylation contribute to cancer progression.

So K, Tamura G, Honda T, et al.
Multiple tumor suppressor genes are increasingly methylated with age in non-neoplastic gastric epithelia.
Cancer Sci. 2006; 97(11):1155-8 [PubMed] Related Publications
A number of tumor suppressor and tumor-related genes are silenced by promoter hypermethylation in gastric cancer. Hypermethylation is not restricted to cancer cells, but is also present in non-neoplastic cells during aging. Such age-related methylation in non-neoplastic gastric epithelia is postulated to constitute a field defect that increases the risk for development of gastric cancer. To quantitatively evaluate age-related methylation in non-neoplastic gastric epithelia, we used a fiber-type DNA microarray on which methylated and unmethylated sequence probes were mounted. After bisulfite modification, a part of the promoter CpG island of four tumor suppressor genes, lysyl oxidase (LOX), p16, RUNX3 and tazarotene-induced gene 1 (TIG1), were amplified by PCR using Cy5 end labeled primers. Methylation rates (MRs) were calculated as the ratio of the fluorescence intensity of a methylated sequence probe to the total fluorescence intensity of methylated and unmethylated probes. Non-neoplastic gastric mucosa was obtained from 24 non-cancer-bearing stomachs at autopsy. MRs ranged from 0.0% to 77.2% (mean, 15.8%) for LOX, 0.0% to 45.8% (mean, 10.0%) for p16, 0.0% to 83.8% (mean, 9.0%) for RUNX3, and 0.0% to 46.1% (mean, 6.6%) for TIG1, and significantly correlated with aging (P < 0.01). The regression curves were: y = 0.013x(2) - 0.6184x + 4.0512, R(2) = 0.5728 (P < 0.001) for LOX; y = 0.0107x(2) - 0.6055x + 5.2943, R(2) = 0.7891 (P < 0.00001) for p16; y = 0.0182x(2) - 1.2234x + 11.566, R(2) = 0.5595 (P < 0.001) for RUNX3; and y = 0.0068 x(2) - 0.3586 x + 2.4306, R(2) = 0.4670 (P < 0.01) for TIG1. Thus, our present results are consistent with the notion that age-related methylation is associated with cancer susceptibility in the elderly. Quantitative analysis of DNA methylation using DNA microarrays is a promising method for risk assessment in the development of gastric cancer.

Wu CC, Shyu RY, Chou JM, et al.
RARRES1 expression is significantly related to tumour differentiation and staging in colorectal adenocarcinoma.
Eur J Cancer. 2006; 42(4):557-65 [PubMed] Related Publications
Retinoic acid receptor responder 1 (RARRES1) is a retinoid regulated gene. Its expression is frequently down-regulated through DNA hypermethylation in several types of malignant tissues. This study investigated the clinical significance of RARRES1 protein and its association with RARRES3 protein expression in 161 (26 adenoma, 13 distal normal mucosa and 122 primary colorectal adenocarcinoma) paraffin-embedded colorectal tissues by immunohistochemistry. RARRES1 protein was detected at the highest levels in terminally differentiated cells of normal mucosal tissues and all 26 adenoma tissues. Among 122 colorectal adenocarcinomas, the poorly differentiated adenocarcinomas and Dukes' stage D tumours showed a significant decrease in RARRES1 expression (P < 0.001 and P < 0.01, respectively). RARRES1 expression was significantly (P < 0.001) correlated with RARRES3 expression, which was positively associated with tumour differentiation (P < 0.001). Difference in expression of RARRES1 among 119 patients had no apparent effect on patient survival. Our results suggest the role of RARRES1 in colorectal epithelial differentiation, and the down-regulation of RARRES1 is related to stage D progression.

Rosenbaum E, Hoque MO, Cohen Y, et al.
Promoter hypermethylation as an independent prognostic factor for relapse in patients with prostate cancer following radical prostatectomy.
Clin Cancer Res. 2005; 11(23):8321-5 [PubMed] Related Publications
PURPOSE: To analyze the prognostic significance of six epigenetic biomarkers (APC, Cyclin D2, GSTP1, TIG1, Rassf1A, and RARbeta2 promoter hypermethylation) in a homogeneous group of prostate cancer patients, following radical prostatectomy alone.
PATIENTS AND METHODS: Biomarker analyses were done retrospectively on tumors from 74 prostate cancer patients all with a Gleason score of 3 + 4 = 7 and minimum follow-up period of 7 years. Using quantitative methylation-specific PCR, we analyzed six gene promoters in primary prostate tumor tissues. Time to any progression was the primary end point, and development of metastatic disease and/or death from prostate cancer was a secondary point. The association of clinicopathologic and biomolecular risk factors to recurrence was done using the log-rank test and Cox proportional hazards model for multivariate analysis. To identify independent prognostic factors, a stepwise selection method was used.
RESULTS: At a median follow-up time of 9 years, 37 patients (50%) had evidence of recurrence: biochemical/prostate-specific antigen relapse, metastases, or death from prostate cancer. In the final multivariate analysis for time to progression (TTP), the significant factors were age > 60 [hazard ratio (HR), 0.4; 95% confidence interval (95% CI), 0.2-0.8; P = 0.01], hypermethylation of GSTP1 (HR, 0.23; 95% CI; 0.09-0.64; P = 0.004), and hypermethylation of APC (HR, 3.0; 95% CI, 1.42-6.32; P = 0.004). In another multivariate analysis, a profile of hypermethylation of APC and cyclin D2 hypermethylation was significant as well: if either any one was hypermethylated (HR, 1.84; 95% CI, 0.92-3.72; P = 0.09) or if both were hypermethylated (HR, 4.3; 95% CI, 1.52-12.33; P = 0.01).
CONCLUSIONS: Methylation status of selected genes in the prostate cancer specimen may predict for time to recurrence in Gleason 3 + 4 = 7 patients undergoing prostatectomy. These results should be validated in a larger and unselected cohort.

Shutoh M, Oue N, Aung PP, et al.
DNA methylation of genes linked with retinoid signaling in gastric carcinoma: expression of the retinoid acid receptor beta, cellular retinol-binding protein 1, and tazarotene-induced gene 1 genes is associated with DNA methylation.
Cancer. 2005; 104(8):1609-19 [PubMed] Related Publications
BACKGROUND: Hypermethylation of CpG islands has been associated with silencing of various tumor suppressor genes, and the retinoid acid receptor beta (RARbeta), cellular retinol-binding protein 1 (CRBP1), and tazarotene-induced gene 1 (TIG1) genes have been associated with retinoic acid signaling. To the authors' knowledge, little is known regarding the involvement of these three genes in gastric carcinoma (GC). In this study, the authors investigated the methylation status of these genes and analyzed the role of their DNA methylation in GC.
METHODS: DNA methylation of 3 retinoic acid-associated genes was analyzed in 42 samples of GC from 42 patients and in 8 GC cell lines by methylation-specific polymerase chain reaction (PCR) analysis. The mRNA expression levels for these three genes were measured by quantitative reverse transcription-PCR.
RESULTS: In 7 of 8 GC cell lines, the CRBP1 gene was hypermethylated, and CRBP1 transcription was inactive. In 6 of 8 GC cell lines, the TIG1 gene was hypermethylated, and TIG1 transcription was inactive. Treatment with demethylating agent 5-aza-2'-deoxycytidine restored both CRBP1 and TIG1 transcription. DNA methylation of the RARbeta, CRBP1, and TIG1 genes was detected in 15 of 42 GC samples (36%), 14 of 42 GC samples (33%), and 4 of 42 GC samples (10%), respectively, and in 6 of 30 samples (20%), 0 of 30 samples (0%), and 1 of 30 samples (3%) of corresponding nonneoplastic mucosa. None of the 10 normal gastric mucosa samples from young, healthy individuals demonstrated hypermethylation of any of these genes. DNA methylation of each gene was associated significantly with low mRNA expression of the respective gene. Twenty-four of 42 GC samples (57%) demonstrated hypermethylation of at least 1 of the 3 genes. However, no significant, concordant hypermethylation of these genes was observed.
CONCLUSIONS: The results suggested that gastric carcinogenesis involves transcriptional inactivation by aberrant DNA methylation of genes related to retinoid signaling.

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