ACCELERATED DISCOVERY |
Promoter Methylation and Silencing of the Retinoic Acid Receptor-ß Gene in Lung Carcinomas
Arvind K. Virmani,
Asha Rathi,
Sabine Zöchbauer-Müller,
Nicoletta Sacchi,
Yasuro Fukuyama,
David Bryant,
Anirban Maitra,
Shashank Heda,
Kwun M. Fong,
Frederik Thunnissen,
John D. Minna,
Adi F. Gazdar
Affiliations of authors: A. K. Virmani, A. Maitra, A. F. Gazdar, Hamon Center for Therapeutic Oncology Research and Department of Pathology, University of Texas Southwestern Medical Center, Dallas; A. Rathi, S. Zöchbauer-Müller, Y. Fukuyama, D. Bryant, S. Heda, Hamon Center for Therapeutic Oncology Research; N. Sacchi, Department of Biology, University of Milan, Italy; K. M. Fong, Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, Australia; F. Thunnissen, Department of Pathology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands; J. D. Minna, Hamon Center for Therapeutic Oncology Research and Departments of Pharmacology and Internal Medicine, University of Texas Southwestern Medical Center.
Correspondence to: Adi F. Gazdar, M.D., Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd., Dallas, TX 75390-8593 (e-mail: gazdar{at}simmons.swmed.edu).
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ABSTRACT
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Background: Retinoic acid plays an important role in lung development and differentiation, acting primarily via nuclear receptors encoded by the retinoic acid receptor-ß (RARß) gene. Because receptor isoforms RARß2 and RARß4 are repressed in human lung cancers, we investigated whether methylation of their promoter, P2, might lead to silencing of the RARß gene in human lung tumors and cell lines. Methods: Methylation of the P2 promoter from small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) cell lines and tumor samples was analyzed by the methylation-specific polymerase chain reaction (PCR). Expression of RARß2 and RARß4 was analyzed by reverse transcriptionPCR. Loss of heterozygosity (LOH) was analyzed by PCR amplification followed by electrophoretic separation of PCR products. Statistical differences were analyzed by Fisher's exact test with continuity correction. Results: The P2 promoter was methylated in 72% (63 of 87) of SCLC and in 41% (52 of 127) of NSCLC tumors and cell lines, and the difference was statistically significant (two-sided P<.001). By contrast, in 57 of 58 control samples, we observed only the unmethylated form of the gene. Four tumor cell lines with unmethylated promoter regions expressed both RARß2 and RARß4. Four tumor lines with methylated promoter regions lacked expression of these isoforms, but demethylation by exposure to 5-aza-2'-deoxycytidine restored their expression. LOH at chromosome 3p24 was observed in 100% (13 of 13) of SCLC lines and 67% (12 of 18) of NSCLC cell lines, and the difference was statistically significant (two-sided P = .028). Conclusions: Methylation of the RARß P2 promoter is one mechanism that silences RARß2 and RARß4 expression in many lung cancers, particularly SCLC. Chemical demethylation is a potential approach to lung cancer therapy.
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INTRODUCTION
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High frequencies of loss of heterozygosity (LOH) at chromosomal region 3p213p24 occur in several tumor types, suggesting the presence of one or more tumor suppressor genes in the short arm of chromosome 3 (15). Among the genes known to map within this frequently deleted region is the retinoic acid receptor-ß (RARß) gene.
Retinoids, analogues of vitamin A, are needed for normal lung development and differentiation (6,7). They can reverse preneoplastic lesions and prevent second primary tumors of the upper aerodigestive tract (8). These effects are mediated via nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which stimulate transcription factors in response to binding of a retinoic acid ligand. Each receptor group includes three subtypes (
, ß, and
). Receptors of the RAR family are differentially expressed during development and in adult life, and there is strong evidence that RARß plays a central role in growth regulation of epithelial cells and in tumorigenesis (911).
The human RARß gene generates multiple isoforms by use of promoters P1 and P2 and alternative splicing (12,13). P1 directs the transcription of isoform RARß1, whereas P2 promotes the transcription of isoforms RARß2 and RARß4 (14). Isoform RARß3 is expressed from the P1 promoter in mice, but it is absent in humans. These isoforms have been shown to vary in their ability to trans-activate retinoic acid-responsive promoters. It is thought that the receptors, through diversity in structure and patterns of expression, are able to control different subsets of retinoic acid-responsive genes to achieve the multiple effects of retinoic acid.
Repression of RARß occurs in non-small-cell lung cancers (NSCLCs) (5,15,16) as well as in other human malignancies. Human lung cancers show reduced expression of RARß2 and RARß4 messenger RNAs (mRNAs) and protein (5,15), and they exhibit resistance to retinoic acid (17,18). RARß2 plays an important role in suppression of murine lung tumorigenesis (19) and inhibits the growth of human lung cancer cells in vitro (18). These observations suggest that loss of expression of RARß, especially that of the RARß2 isoform, may be associated with lung carcinogenesis. In contrast, RARß1 is expressed in small-cell lung cancer (SCLC) cell lines (20).
Analysis of lung cancer cell lines covering the entire open reading frame and the sequences of the retinoic acid response elements failed to show any mutations (17). Aberrant methylation of CpG islands was identified as an epigenetic mechanism for the transcriptional silencing (inactivation) of tumor suppressor genes (21,22). We investigated the role of aberrant methylation of the RARß gene promoter P2 in human lung cancers and cell lines.
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MATERIALS AND METHODS
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Cell Lines and Tumor Samples
All human lung cancer cell lines (66 SCLC lines and 78 NSCLC lines) and B-lymphoblastoid lines (n = 31) were established by us (23). The cells were grown in RPMI-1640 medium (Life Technologies, Inc. [GIBCO BRL], Rockville, MD) supplemented with 5% fetal bovine serum and were incubated in 5% CO2. Samples of tissue from 49 surgically resected primary NSCLC tumors, along with 24 samples of nonmalignant lung tissue from the same patients, were obtained from the Tumor and Tissue Repository at the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas. Formalin-fixed, paraffin-embedded sections of 21 SCLC tumors were obtained from The University of Texas M. D. Anderson Cancer Center, Houston, or from Canisius Wilhelmina Hospital, Nijmegen, The Netherlands. Archival paraffin sections of tumor-negative lymph nodes from 12 of the NSCLC patients were utilized as controls for the paraffin-embedded tumors. Epithelial cells from buccal swabs (n = 12) and peripheral blood lymphocytes (n = 10) were collected from 22 healthy volunteers and served as negative controls for the frozen tissues. Appropriate Institutional Review Board permission was obtained from all participating centers, and written informed consent was obtained from all volunteers before usage of prospectively collected fresh samples. Institutional guidelines do not require written permission for the use of anonymous archival paraffin-embedded specimens.
Genomic DNA was obtained from cell lines, primary tumors, and nonmalignant cells by digestion with 200 µg/mL proteinase K (Life Technologies, Inc.) for 1 day at 37 °C, followed by two extractions with phenolchloroform (1 : 1) (24). DNA was extracted from paraffin sections after precise laser-capture microdissection of the tumor cells or lymph nodes, as described previously (25).
Methylation-Specific Polymerase Chain Reaction
The methylation-specific polymerase chain reaction (PCR) employs an initial bisulfite reaction to modify the DNA. As a result, all unmethylated cytosines are deaminated and converted to uracils, while 5-methylcytosines remain unaltered. Thus, after bisulfite treatment, alleles that were originally methylated have DNA sequences different from those of their corresponding unmethylated alleles, and these differences can be used to design PCR primers that are specific for methylated or unmethylated alleles.
DNA was treated with sodium bisulfite as described previously (26). Briefly, 1 µg of DNA was denatured by incubation with 0.2 M NaOH for 10 minutes at 37 °C. Aliquots of 10 mM hydroquinone (30 µL) (Sigma Chemical Co., St. Louis, MO) and 3 M sodium bisulfite (pH 5.0, 520 µL) (Sigma Chemical Co.) were added, and the solution was incubated at 50 °C for 16 hours. Treated DNA was purified by use of a Wizard DNA Purification System (Promega Corp., Madison, WI). Modified DNA was stored at -70 °C until used.
Amplification of bisulfite-modified DNA for RARß gene promoter P2 was performed by PCR as described by Côté et al. (27) with primers that were specific for either methylated or unmethylated RARß sequences. Primers used to amplify the methylated RARß gene were 5'-TCGAGAACGCGAGCGATTCG-3' (sense) and 5'-GACCAATCCAACCGAAACGA-3' (antisense). Primers used to amplify the unmethylated RARß gene were 5'-TTGAGAATGTGAGTGATTTGA-3' (sense) and 5'-AACCAATCCAACCAAAACAA-3' (antisense). Normal lymphocyte DNA was treated with SssI DNA methyltransferase (New England Biolabs, Inc., Beverly, MA), subjected to bisulfite modification, and used as a positive-control DNA for each PCR reaction (28). Negative control samples without DNA were included for each set of PCR. PCR of DNA from nonmalignant tissues and samples from healthy volunteers served as negative (unmethylated) controls. PCR products were analyzed on 2% agarose gels containing ethidium bromide (Life Technologies, Inc.). Conversion of all unmethylated Cs to Ts was confirmed by sequencing eight individual PCR products.
Reverse Transcription-PCR Analysis
Four tumor cell lines in which RARß P2 promoter had been identified as being methylated were incubated in culture medium with and without 5-aza-2'-deoxycytidine (Aza-CdR) at a concentration of 2 µg/mL for 6 days, with medium changes on days 1, 3, and 5 (29). Cells were harvested at the end of the 6th day for extraction of mRNA with a polyadenylic acid tail [poly(A) RNA]. Reverse transcription (RT) was performed on poly(A) RNA with the SuperScript II First-Strand Synthesis System (Life Technologies, Inc.), with the use of RARß2-gene-specific reverse primer (29). One microliter of the RT reaction mixture was used as template for PCR with primer set 1 (29) to produce a 256-base-pair (bp) RARß2 gene product. A separate PCR was performed on the same RT product by use of primer set 2, which consists of forward primer 110-FP (30) and the above-described RT reverse primer, to amplify RARß2 (623-bp product) and RARß4 (264-bp product) simultaneously. One-step RTPCR (Life Technologies, Inc.) was performed with primers for glyceraldehyde-3-phosphate dehydrogenase, a housekeeping gene (sense primer: 5'-ACAGTCCATGCCATCACTGCC-3'; antisense primer: 5'-GCCTGCTCCACCACCTTCTTG-3'), to confirm the integrities of the poly(A) RNAs. PCR products were analyzed on 2% agarose gels.
Analysis of LOH
Fourteen polymorphic microsatellite markers (see Table 2
) that are located in chromosome region 3p24 and flank the RARß gene (31) were selected for LOH analysis. DNA from 13 SCLC and 18 NSCLC tumor cell lines and their corresponding B-lymphoblastoid lines (constitutional DNA) were analyzed as described previously (23). Briefly, 20 ng of genomic DNA was amplified by PCR in the presence of [
-32P]cytidine 5'-triphosphate by use of the microsatellite markers. The PCR products were separated by electrophoresis in 6% polyacrylamide gels containing 7 M urea and were visualized by autoradiography. Markers that identified two bands of different size but of similar intensity in the lane having normal DNA were termed "informative" (i.e., heterozygous). Markers that gave only a single major band in the normal DNA lane were termed "noninformative." LOH was defined as a loss of a band corresponding to an allele present in informative cases.
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Table 2. Loss of heterozygosity (LOH) at chromosome locus 3p24 in small-cell lung cancer (SCLC) and in non-small-cell lung cancer (NSCLC) cell lines
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Statistical Analysis
Statistical differences between groups were examined by use of Fisher's exact test with continuity correction. All P values are two-sided. Values of P<.05 were considered to be statistically significant.
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RESULTS
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Methylation-specific PCR was performed on bisulfite-modified control and tumor DNA samples by simultaneous use of primers for the methylated and unmethylated forms of the RARß gene promoter P2. As detailed in Table 1
, 72% of (63 of 87) of SCLC and 41% (52 of 127) of NSCLC samples showed methylation of RARß gene promoter P2. The difference in incidence of methylation of all 87 SCLC samples compared with all 127 NSCLC samples was statistically significant (P<.001). The incidences of RARß promoter gene methylation between adenocarcinomas (26 of 71 [37%]) and squamous cell carcinomas (13 of 24 [54%]), the major subtypes of NSCLCs, were not statistically significantly different.
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Table 1. Incidence of methylation of the RARß gene promoter P2 in lung tumors, tumor cell lines, and control tissues
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Tumor cell lines are pure tumor populations that are free of nonmalignant cells, and 95% (137 of 144) of the tumor cell lines that we examined were homozygous for either methylated or unmethylated RARß promoter gene sequences. Five percent (seven of 144) were heterozygous and showed amplification of both methylated and unmethylated RARß promoter gene sequences. Sample gels are shown in Fig. 1
, A.

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Fig. 1. Methylation of the retinoic acid receptor-ß (RARß) P2 promoter and expression of RARß isoforms in lung cancers. A) Examples of methylation-specific polymerase chain reaction (PCR) analysis of the RARß P2 promoter region. DNA from five small-cell lung cancer (SCLC) cell lines (H209, H1399, H2107, H1607, and H2195) and five non-small-cell lung cancer (NSCLC) cell lines (H1395, H1437, H2009, H2347, and H2122) was treated with bisulfite and amplified by PCR, as described in the text, by use of primers specific for unmethylated or methylated DNA. The resulting products were analyzed by gel electrophoresis. A visible product in the RAR(U) gel indicates that the RARß gene is unmethylated in the corresponding DNA; a visible product in the RAR(M) gel indicates that the gene is methylated. Product in both gels indicates that both methylated and unmethylated forms of the gene are present. Lanes C1 and C2 show the products of PCR analysis of identically treated DNA from normal lymphocytes and buccal epithelial cells, respectively. Lanes B1 and B2 are negative PCR controls (no template DNA). B) Reverse transcription (RT)PCR analysis of expression of RARß2. Tumor cell lines H1607, HCC15, H2087, and HCC1171 were incubated with (+ lanes) or without ( lanes) 5-aza-2'-deoxycytidine (5 Aza-CdR) for 6 days. Their messenger RNA (mRNA) was extracted, and complementary DNAs were produced by RT for use as templates for PCR analysis, as described in the text. The resulting products were analyzed by gel electrophoresis. Panel a shows the results obtained by use of primer set 1, which produces a 256-base-pair (bp) product that indicates that the transcript of RARß2 was present (i.e., the gene was expressed). Panel b shows the results obtained by use of primer set 2, which produces 623-bp and 264-bp products that indicate that the transcripts of RARß2 and RARß4, respectively, were present (i.e., the genes were expressed). Panel c shows the results obtained after one-step RTPCR analysis with primers for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a housekeeping gene that produces a 266-bp product (to demonstrate the integrities of the extracted mRNAs). Size markers are shown in the marker lane of each gel. Blank lanes are RT control (no enzyme added) and PCR control (no RT template added).
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In tumor samples, most of which consist of mixtures of tumor cells and nonmalignant cells, either the band that corresponds to unmethylated RARß only or the bands that correspond to both methylated and unmethylated RARß were present. In 57 of 58 control samples, we observed only the unmethylated form of the gene (Table 1
). Only one of the microdissected samples from a histologically normal lymph node that was used as control for paraffin-fixed samples had both methylated and unmethylated DNA. The presence of unmethylated RARß promoter sequences in all control tissues confirmed the integrity of the DNA in these samples.
Four each of methylation-positive and methylation-negative cell line mRNAs were selected for RARß2 and RARß4 gene expression studies. NSCLC cell lines HCC44, HCC193, and HCC515 and SCLC cell line H209, in which the RARß promoter was unmethylated, contained both RARß2 and RARß4 transcripts (data not shown). SCLC cell line H1607 and NSCLC cell lines HCC15, H2087, and HCC1171, in which the RARß promoters were methylated, lacked both transcripts (Fig 1
, B). After demethylation with Aza-CdR, these four cell lines were positive for both transcripts (Fig.1
, B), although the intensity of the bands varied in the different cell lines.
We analyzed a panel of 31 SCLC or NSCLC tumor cell lines that were paired with corresponding B-lymphoblastoid cell lines (Table 2
) for LOH at or around the RARß gene by use of 14 polymorphic markers. We found LOH in at least one of the markers in all 13 SCLC cell lines (100%) and in 67% (12 of 18) of the NSCLC cell lines. Marker D3S1567 had a low informative rate (i.e., was seldom heterozygous) but showed 100% loss in both SCLC and NSCLC cell lines. Markers D3S1583, D3S2336, D3S2335, and D3S2337, which are centromeric to D3S1567, showed statistically significant differences in the incidences of LOH in SCLC compared with NSCLC cell lines. Although the precise location of the RARß gene relative to these loci (31) is not known, the region bounded by these markers may be within or close to the gene. While there was no apparent relationship between LOH for any specific marker and methylation status, LOH at one or more markers was present in 89% (16 of 18) of the tumor lines in which the RARß gene promoter was methylated.
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DISCUSSION
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RARß may be the member of the RAR receptor family that is primarily responsible for mediating the effects of retinoic acid (32). Reduced expression of RARß has been reported in lung cancer (33) and in other solid tumors (29). Geradts et al. (17) reported loss of RARß expression in 75% of SCLC tumor lines and in 53% of NSCLC lines. Xu et al. (15) observed reduced expression of RARß2 in NSCLC tumors. A marked decrease in the expression of RARß, as well as a high frequency of LOH at 3p24, was also observed in non-neoplastic lesions (5). Only two reports addressed expression of RARß4. Sommer et al. (30) demonstrated that the ratio of RARß4 to RARß2 is elevated in breast tumor cell lines. In mice that carry an RARß4-like transgene, RARß4-like expression showed tissue-specific variation (34) and was reduced in lung tissue. These data support the hypothesis that one or more isoforms of the RARß gene may exert tumor-suppressive effects.
Aberrant methylation of the RARß promoter gene has been observed previously in breast and colon cancers (29,35,36). Our observations demonstrate a high frequency of aberrant DNA methylation of the RARß P2 promoter gene in lung cancers, particularly in SCLC. In the eight cell lines that we tested, there was complete concordance between aberrant methylation of the P2 promoter and silencing of both RARß2 and RARß4 transcripts. Furthermore, treatment with Aza-CdR restored transcript expression, indicating that methylation is one of the mechanisms responsible for loss of expression. Allelic losses at or around 3p24, the chromosomal location of RARß, were more frequent in SCLC (100%) than in NSCLC (67%). The high frequency of LOH at 3p24, combined with the presence of only methylated sequences in most cell lines, fulfills the criteria for Knudson's two-hit hypothesis for tumor suppressor gene inactivation (37). While strong circumstantial evidence exists for the role of inactivation of the RARß gene in lung cancer pathogenesis, the possibility that other genes at 3p are responsible for or contribute to lung cancer pathogenesis must be considered.
Several genes are known to be inactivated in lung cancers by aberrant methylation (38). The frequencies of aberrant methylation of the RARß gene reported herein are among the highest for any gene described to date in lung cancers (38). Ayoub et al. (39) have reported frequent repression of both RARß2 and RARß4 in the bronchial epithelium of smokers. Their finding and those of other investigators (33,40) suggest that alteration in RAR expression is an early event in lung cancer pathogenesis. Tumor cells may release their DNA into the circulation, which would allow detection of aberrant methylation in DNA from the sera of lung cancer patients (38). Chemical reversal of methylation-related gene silencing (an epigenetic phenomenon) is a potential therapeutic approach (41). Our findings indicate that aberrant methylation of the RARß gene is a frequent abnormality in lung cancers and may have clinical applications for risk assessment, for diagnosis, and for novel therapeutic approaches.
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NOTES
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Supported by Public Health Service Specialized Program of Research Excellence (SPORE) Developmental grant 4P50CA7097-0452 (to A. K. Virmani) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
We thank Dr. James Herman for assistance with the methodology for methylation-specific polymerase chain reaction, Dr. Chun X. Huang and Mr. Thomas Cunningham for technical help, and PALGA (the National Dutch Pathology Laboratory Files System) for support.
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REFERENCES
|
---|
1
Rabbitts P, Bergh J, Douglas J, Collins F, Waters J. A submicroscopic homozygous deletion at the D3S3 locus in a cell line isolated from a small cell lung carcinoma. Genes Chromosomes Cancer 1990;2:2318.[Medline]
2
Daly MC, Xiang RH, Buchhagen D, Hensel CH, Garcia DK, Killary AM, et al. A homozygous deletion on chromosome 3 in a small cell lung cancer cell line correlates with a region of tumor suppressor activity. Oncogene 1993;8:17219.[Medline]
3
Wistuba II, Behrens C, Virmani AK, Mele G, Milchgrub S, Girard L, et al. High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res 2000;60:194960.[Abstract/Free Full Text]
4
Sekido Y, Ahmadian M, Wistuba, II, Latif F, Bader S, Wei MH, et al. Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene. Oncogene 1998;16:31517.[Medline]
5
Picard E, Seguin C, Monhoven N, Rochette-Egly C, Siat J, Borrelly J, et al. Expression of retinoid receptor genes and proteins in non-small-cell lung cancer. J Natl Cancer Inst 1999;91:105966.[Abstract/Free Full Text]
6
Grummer MA, Thet LA, Zachman RD. Expression of retinoic acid receptor genes in fetal and newborn rat lung. Pediatr Pulmonol 1994;17:2348.[Medline]
7
Mendelsohn C, Lohnes D, Decimo D, Lufkin T, LeMeur M, Chambon P, et al. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development 1994;120:274971.[Abstract/Free Full Text]
8
Lippman SM, Spitz MR, Huber MH, Hong WK. Strategies for chemoprevention study of premalignancy and second primary tumors in the head and neck. Curr Opin Oncol 1995;7:23441.[Medline]
9
Roman SD, Clarke CL, Hall RE, Alexander IE, Sutherland RL. Expression and regulation of retinoic acid receptors in human breast cancer cells. Cancer Res 1992;52:223642.[Abstract]
10
Seewaldt VL, Johnson BS, Parker MB, Collins SJ, Swisshelm K. Expression of retinoic acid receptor beta mediates retinoic acid-induced growth arrest and apoptosis in breast cancer cells. Cell Growth Differ 1995;6:107788.[Abstract]
11
Swisshelm K, Ryan K, Lee X, Tsou HC, Peacocke M, Sager R. Down-regulation of retinoic acid receptor beta in mammary carcinoma cell lines and its up-regulation in senescing normal mammary epithelial cells. Cell Growth Differ 1994;5:13341.[Abstract]
12
Giguere V. Retinoic acid receptors and cellular retinoid binding proteins: complex interplay in retinoid signaling. Endocr Rev 1994;15:6179.[Medline]
13
Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J 1996;10:94054.[Abstract/Free Full Text]
14
Toulouse A, Morin J, Pelletier M, Bradley WE. Structure of the human retinoic acid receptor beta 1 gene. Biochim Biophys Acta 1996;1309:14.[Medline]
15
Xu XC, Sozzi G, Lee JS, Lee JJ, Pastorino U, Pilotti S, et al. Suppression of retinoic acid receptor beta in non-small-cell lung cancer in vivo: implications for lung cancer development. J Natl Cancer Inst 1997;89:6249.[Abstract/Free Full Text]
16
Houle B, Leduc F, Bradley WE. Implication of RARß in epidermoid (Squamous) lung cancer. Genes Chromosomes Cancer 1991;3:35866.[Medline]
17
Geradts J, Chen JY, Russell EK, Yankaskas JR, Nieves L, Minna JD. Human lung cancer cell lines exhibit resistance to retinoic acid treatment. Cell Growth Differ 1993;4:799809.[Abstract]
18
Toulouse A, Morin J, Dion PA, Houle B, Bradley WE. RARbeta2 specificity in mediating RA inhibition of growth of lung cancer-derived cells. Lung Cancer 2000;28:12737.[Medline]
19
Berard J, Laboune F, Mukuna M, Masse S, Kothary R, Bradley WE. Lung tumors in mice expressing an antisense RARbeta2 transgene. FASEB J 1996;10:10917.[Abstract/Free Full Text]
20
Houle B, Pelletier M, Wu J, Goodyer C, Bradley WE. Fetal isoform of human retinoic acid receptor beta expressed in small cell lung cancer lines. Cancer Res 1994;54:3659.[Abstract]
21
Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 1998;72:14196.[Medline]
22
Schmutte C, Jones PA. Involvement of DNA methylation in human carcinogenesis. Biol Chem 1998;379:37788.
23
Virmani AK, Fong KM, Kodagoda D, McIntire D, Hung J, Tonk V, et al. Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types. Genes Chromosomes Cancer 1998;21:30819.[Medline]
24
Herrmann BG, Frischauf AM. Isolation of genomic DNA. Methods Enzymol 1987;152:1803.[Medline]
25
Maitra A, Wistuba II, Virmani AK, Sakaguchi M, Park I, Stucky A, et al. Enrichment of epithelial cells for molecular studies. Nat Med 1999;5:45963.[Medline]
26
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 1996;93:98216.[Abstract/Free Full Text]
27
Cote S, Sinnett D, Momparler RL. Demethylation by 5-aza-2'-deoxycytidine of specific 5-methylcytosine sites in the promoter region of the retinoic acid receptor beta gene in human colon carcinoma cells. Anticancer Drugs 1998;9:74350.[Medline]
28
Esteller M, Corn PG, Urena JM, Gabrielson E, Baylin SB, Herman JG. Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. Cancer Res 1998;58:45158.[Abstract]
29
Sirchia SM, Ferguson AT, Sironi E, Subramanyan S, Orlandi R, Sukmar S, et al. Evidence of epigenetic changes affecting the chromatin state of the retinoic acid receptor beta2 promoter in breast cancer cells. Oncogene 2000;19:155663.[Medline]
30
Sommer KM, Chen LI, Treuting PM, Smith LT, Swisshelm K. Elevated retinoic acid receptor beta(4) protein in human breast tumor cells with nuclear and cytoplasmic localization. Proc Natl Acad Sci U S A 1999;96:86516.[Abstract/Free Full Text]
31
Unigene. Bethesda (MD): National Institutes of Health, National Library of Medicine, National Center for Biotechnology Information. (URL:http://www.ncbi.nlm.nih.gov/UniGene/clust.cgi?ORG=Hs&CID=171495).
32
Clifford JL, Petkovich M, Chambon P, Lotan R. Modulation by retinoids of mRNA levels for nuclear retinoic acid receptors in murine melanoma cells. Mol Endocrinol 1990;4:154655.[Abstract]
33
Lotan R. Aberrant expression of retinoid receptors and lung carcinogenesis. J Natl Cancer Inst 1999;91:98991.[Free Full Text]
34
Berard J, Gaboury L, Landers M, De Repentigny Y, Houle B, Kothary R, et al. Hyperplasia and tumours in lung, breast and other tissues in mice carrying a RAR beta 4-like transgene. EMBO J 1994;13:557080.[Abstract]
35
Widschwendter M, Berger J, Hermann M, Muller HM, Amberger A, Zeschnigk M, et al. Methylation and silencing of the retinoic acid receptor-ß2 gene in breast cancer. J Natl Cancer Inst 2000;92:82632.[Abstract/Free Full Text]
36
Cote S, Momparler RL. Activation of the retinoic acid receptor beta gene by 5-aza-2'-deoxycytidine in human DLD-1 colon carcinoma cells. Anticancer Drugs 1997;8:5661.[Medline]
37
Knudson AG Jr. Hereditary cancers disclose a class of cancer genes. Cancer 1989;63:188891.[Medline]
38
Esteller M, Sanchez-Cespedes M, Rosell R, Sidransky D, Baylin SB, Herman JG. Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. Cancer Res 1999;59:6770.[Abstract/Free Full Text]
39
Ayoub J, Jean-Francois R, Cormier Y, Meyer D, Ying Y, Major P, et al. Placebo-controlled trial of 13-cis-retinoic acid activity on retinoic acid receptor-beta expression in a population at high risk: implications for chemoprevention of lung cancer. J Clin Oncol 1999;17:354652.[Abstract/Free Full Text]
40
Sun SY, Kurie JM, Yue P, Dawson MI, Shroot B, Chandraratna RA, et al. Differential responses of normal, premalignant, and malignant human bronchial epithelial cells to receptor-selective retinoids. Clin Cancer Res 1999;5:4317.[Abstract/Free Full Text]
41
Sporn MB. Retinoids and demethylating agentslooking for partners [editorial]. J Natl Cancer Inst 2000;92:7801.[Free Full Text]
Manuscript received April 28, 2000;
revised June 27, 2000;
accepted July 10, 2000.
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[Abstract]
[Full Text]
-
Hutt, J. A., Vuillemenot, B. R., Barr, E. B., Grimes, M. J., Hahn, F. F., Hobbs, C. H., March, T. H., Gigliotti, A. P., Seilkop, S. K., Finch, G. L., Mauderly, J. L., Belinsky, S. A.
(2005). Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways. Carcinogenesis
26: 1999-2009
[Abstract]
[Full Text]
-
Belinsky, S. A.
(2005). Silencing of genes by promoter hypermethylation: key event in rodent and human lung cancer. Carcinogenesis
26: 1481-1487
[Abstract]
[Full Text]
-
Touma, S. E., Goldberg, J. S., Moench, P., Guo, X., Tickoo, S. K., Gudas, L. J., Nanus, D. M.
(2005). Retinoic Acid and the Histone Deacetylase Inhibitor Trichostatin A Inhibit the Proliferation of Human Renal Cell Carcinoma in a Xenograft Tumor Model. Clin Cancer Res
11: 3558-3566
[Abstract]
[Full Text]
-
Kim, Y. T., Lee, S. H., Sung, S. W., Kim, J. H.
(2005). Can Aberrant Promoter Hypermethylation of CpG Islands Predict the Clinical Outcome of Non-Small Cell Lung Cancer After Curative Resection?. Ann. Thorac. Surg.
79: 1180-1188
[Abstract]
[Full Text]
-
Meuwissen, R., Berns, A.
(2005). Mouse models for human lung cancer. Genes & Dev.
19: 643-664
[Abstract]
[Full Text]
-
Mongan, N. P., Gudas, L. J.
(2005). Valproic acid, in combination with all-trans retinoic acid and 5-aza-2'-deoxycytidine, restores expression of silenced RAR{beta}2 in breast cancer cells. Mol Cancer Ther
4: 477-486
[Abstract]
[Full Text]
-
Brabender, J., Metzger, R., Salonga, D., Danenberg, K. D., Danenberg, P. V., Holscher, A. H., Schneider, P. M.
(2005). Comprehensive expression analysis of retinoic acid receptors and retinoid X receptors in non-small cell lung cancer: implications for tumor development and prognosis. Carcinogenesis
26: 525-530
[Abstract]
[Full Text]
-
Fujiwara, K., Fujimoto, N., Tabata, M., Nishii, K., Matsuo, K., Hotta, K., Kozuki, T., Aoe, M., Kiura, K., Ueoka, H., Tanimoto, M.
(2005). Identification of Epigenetic Aberrant Promoter Methylation in Serum DNA Is Useful for Early Detection of Lung Cancer. Clin Cancer Res
11: 1219-1225
[Abstract]
[Full Text]
-
Srinivas, H., Juroske, D. M., Kalyankrishna, S., Cody, D. D., Price, R. E., Xu, X.-C., Narayanan, R., Weigel, N. L., Kurie, J. M.
(2005). c-Jun N-Terminal Kinase Contributes to Aberrant Retinoid Signaling in Lung Cancer Cells by Phosphorylating and Inducing Proteasomal Degradation of Retinoic Acid Receptor {alpha}. Mol. Cell. Biol.
25: 1054-1069
[Abstract]
[Full Text]
-
Rigas, J. R., Dragnev, K. H.
(2005). Emerging Role of Rexinoids in Non-Small Cell Lung Cancer: Focus on Bexarotene. Oncologist
10: 22-33
[Abstract]
[Full Text]
-
Arce, J. D.-C., Soto, U., van Riggelen, J., Schwarz, E., Hausen, H. z., Rosl, F.
(2004). Ectopic Expression of Nonliganded Retinoic Acid Receptor {beta} Abrogates AP-1 Activity by Selective Degradation of c-Jun in Cervical Carcinoma Cells. J. Biol. Chem.
279: 45408-45416
[Abstract]
[Full Text]
-
Takahashi, T., Shivapurkar, N., Riquelme, E., Shigematsu, H., Reddy, J., Suzuki, M., Miyajima, K., Zhou, X., Bekele, B. N., Gazdar, A. F., Wistuba, I. I.
(2004). Aberrant Promoter Hypermethylation of Multiple Genes in Gallbladder Carcinoma and Chronic Cholecystitis. Clin Cancer Res
10: 6126-6133
[Abstract]
[Full Text]
-
Khuri, F. R., Lotan, R.
(2004). Retinoids in Lung Cancer: Friend, Foe, or Fellow Traveler?. J Clin Oncol
22: 3435-3437
[Full Text]
-
Kim, J. S., Lee, H., Kim, H., Shim, Y. M., Han, J., Park, J., Kim, D.-H.
(2004). Promoter Methylation of Retinoic Acid Receptor Beta 2 and the Development of Second Primary Lung Cancers in Non-Small-Cell Lung Cancer. J Clin Oncol
22: 3443-3450
[Abstract]
[Full Text]
-
Hirsch, F.R., Merrick, D.T., Franklin, W.A.
(2002). Role of biomarkers for early detection of lung cancer and chemoprevention. Eur Respir J
19: 1151-1158
[Abstract]
[Full Text]
-
Jeronimo, C., Henrique, R., Hoque, M. O., Ribeiro, F. R., Oliveira, J., Fonseca, D., Teixeira, M. R., Lopes, C., Sidransky, D.
(2004). Quantitative RAR{beta}2 Hypermethylation: A Promising Prostate Cancer Marker. Clin Cancer Res
10: 4010-4014
[Abstract]
[Full Text]
-
Takahashi, T., Shivapurkar, N., Reddy, J., Shigematsu, H., Miyajima, K., Suzuki, M., Toyooka, S., Zochbauer-Muller, S., Drach, J., Parikh, G., Zheng, Y., Feng, Z., Kroft, S. H., Timmons, C., McKenna, R. W., Gazdar, A. F.
(2004). DNA Methylation Profiles of Lymphoid and Hematopoietic Malignancies. Clin Cancer Res
10: 2928-2935
[Abstract]
[Full Text]
-
Topaloglu, O., Hoque, M. O., Tokumaru, Y., Lee, J., Ratovitski, E., Sidransky, D., Moon, C.-s.
(2004). Detection of Promoter Hypermethylation of Multiple Genes in the Tumor and Bronchoalveolar Lavage of Patients with Lung Cancer. Clin Cancer Res
10: 2284-2288
[Abstract]
[Full Text]
-
Dragnev, K. H., Pitha-Rowe, I., Ma, Y., Petty, W. J., Sekula, D., Murphy, B., Rendi, M., Suh, N., Desai, N. B., Sporn, M. B., Freemantle, S. J., Dmitrovsky, E.
(2004). Specific Chemopreventive Agents Trigger Proteasomal Degradation of G1 Cyclins: Implications for Combination Therapy. Clin Cancer Res
10: 2570-2577
[Abstract]
[Full Text]
-
Dote, H., Toyooka, S., Tsukuda, K., Yano, M., Ouchida, M., Doihara, H., Suzuki, M., Chen, H., Hsieh, J.-T., Gazdar, A. F., Shimizu, N.
(2004). Aberrant Promoter Methylation in Human DAB2 Interactive Protein (hDAB2IP) Gene in Breast Cancer. Clin Cancer Res
10: 2082-2089
[Abstract]
[Full Text]
-
Vuillemenot, B. R., Pulling, L. C., Palmisano, W. A., Hutt, J. A., Belinsky, S. A.
(2004). Carcinogen exposure differentially modulates RAR-{beta} promoter hypermethylation, an early and frequent event in mouse lung carcinogenesis. Carcinogenesis
25: 623-629
[Abstract]
[Full Text]
-
Zheng, S., Ma, X., Zhang, L., Gunn, L., Smith, M. T., Wiemels, J. L., Leung, K., Buffler, P. A., Wiencke, J. K.
(2004). Hypermethylation of the 5' CpG Island of the FHIT Gene Is Associated with Hyperdiploid and Translocation-Negative Subtypes of Pediatric Leukemia. Cancer Res
64: 2000-2006
[Abstract]
[Full Text]
-
Youssef, E. M., Lotan, D., Issa, J.-P., Wakasa, K., Fan, Y.-H., Mao, L., Hassan, K., Feng, L., Lee, J. J., Lippman, S. M., Hong, W. K., Lotan, R.
(2004). Hypermethylation of the Retinoic Acid Receptor-{beta}2 Gene in Head and Neck Carcinogenesis. Clin Cancer Res
10: 1733-1742
[Abstract]
[Full Text]
-
Liu, Y., An, Q., Li, L., Zhang, D., Huang, J., Feng, X., Cheng, S., Gao, Y.
(2003). Hypermethylation of p16INK4a in Chinese lung cancer patients: biological and clinical implications. Carcinogenesis
24: 1897-1901
[Abstract]
[Full Text]
-
Thunnissen, F B J M
(2003). Sputum examination for early detection of lung cancer. J Clin Pathol
56: 805-810
[Abstract]
[Full Text]
-
Fong, K M, Sekido, Y, Gazdar, A F, Minna, J D
(2003). Lung cancer * 9: Molecular biology of lung cancer: clinical implications. Thorax
58: 892-900
[Abstract]
[Full Text]
-
Jeronimo, C., Costa, I., Martins, M. C., Monteiro, P., Lisboa, S., Palmeira, C., Henrique, R., Teixeira, M. R., Lopes, C.
(2003). Detection of Gene Promoter Hypermethylation in Fine Needle Washings from Breast Lesions. Clin Cancer Res
9: 3413-3417
[Abstract]
[Full Text]
-
Villar-Garea, A., Fraga, M. F., Espada, J., Esteller, M.
(2003). Procaine Is a DNA-demethylating Agent with Growth-inhibitory Effects in Human Cancer Cells. Cancer Res
63: 4984-4989
[Abstract]
[Full Text]
-
Segura-Pacheco, B., Trejo-Becerril, C., Perez-Cardenas, E., Taja-Chayeb, L., Mariscal, I., Chavez, A., Acuna, C., Salazar, A. M., Lizano, M., Duenas-Gonzalez, A.
(2003). Reactivation of Tumor Suppressor Genes by the Cardiovascular Drugs Hydralazine and Procainamide and Their Potential Use in Cancer Therapy. Clin Cancer Res
9: 1596-1603
[Abstract]
[Full Text]
-
PATEL, A., GROOPMAN, J. D., UMAR, A.
(2003). DNA Methylation as a Cancer-Specific Biomarker: From Molecules to Populations. Annals NYAS Online
983: 286-297
[Abstract]
[Full Text]
-
VERMA, M.
(2003). Viral Genes and Methylation. Annals NYAS Online
983: 170-180
[Abstract]
[Full Text]
-
Newman, D., Sakaue, M., Koo, J. S., Kim, K.-S., Baek, S. J., Eling, T., Jetten, A. M.
(2003). Differential Regulation of Nonsteroidal Anti-Inflammatory Drug-Activated Gene in Normal Human Tracheobronchial Epithelial and Lung Carcinoma Cells by Retinoids. Mol Pharmacol
63: 557-564
[Abstract]
[Full Text]
-
Vourlekis, J. S., Szabo, E.
(2003). Predicting Success in Cancer Prevention Trials. J Natl Cancer Inst
95: 178-179
[Full Text]
-
Soria, J.-C., Xu, X., Liu, D. D., Lee, J. J., Kurie, J., Morice, R. C., Khuri, F., Mao, L., Hong, W. K., Lotan, R.
(2003). Retinoic Acid Receptor {beta} and Telomerase Catalytic Subunit Expression in Bronchial Epithelium of Heavy Smokers. J Natl Cancer Inst
95: 165-168
[Abstract]
[Full Text]
-
Chan, E. C., Lam, S. Y., Tsang, K. W., Lam, B., Ho, J. C. M., Fu, K. H., Lam, W. K., Kwong, Y. L.
(2002). Aberrant Promoter Methylation in Chinese Patients with Non-Small Cell Lung Cancer: Patterns in Primary Tumors and Potential Diagnostic Application in Bronchoalevolar Lavage. Clin Cancer Res
8: 3741-3746
[Abstract]
[Full Text]
-
Reid, M. E., Duffield-Lillico, A. J., Garland, L., Turnbull, B. W., Clark, L. C., Marshall, J. R.
(2002). Selenium Supplementation and Lung Cancer Incidence: An Update of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev
11: 1285-1291
[Abstract]
[Full Text]
-
Rathi, A., Virmani, A. K., Schorge, J. O., Elias, K. J., Maruyama, R., Minna, J. D., Mok, S. C., Girard, L., Fishman, D. A., Gazdar, A. F.
(2002). Methylation Profiles of Sporadic Ovarian Tumors and nonmalignant Ovaries from High-Risk Women. Clin Cancer Res
8: 3324-3331
[Abstract]
[Full Text]
-
Zochbauer-Muller, S., Minna, J. D., Gazdar, A. F.
(2002). Aberrant DNA Methylation in Lung Cancer: Biological and Clinical Implications. Oncologist
7: 451-457
[Abstract]
[Full Text]
-
Esteller, M., Guo, M., Moreno, V., Peinado, M. A., Capella, G., Galm, O., Baylin, S. B., Herman, J. G.
(2002). Hypermethylation-associated Inactivation of the Cellular Retinol-Binding-Protein 1 Gene in Human Cancer. Cancer Res
62: 5902-5905
[Abstract]
[Full Text]
-
Chen, L. I., Sommer, K. M., Swisshelm, K.
(2002). Downstream Codons in the Retinoic Acid Receptor beta -2 and beta -4 mRNAs Initiate Translation of a Protein Isoform That Disrupts Retinoid-activated Transcription. J. Biol. Chem.
277: 35411-35421
[Abstract]
[Full Text]
-
Farias, E. F., Arapshian, A., Bleiweiss, I. J., Waxman, S., Zelent, A., Mira-y-Lopez, R.
(2002). Retinoic Acid Receptor {alpha}2 Is a Growth Suppressor Epigenetically Silenced In MCF-7 Human Breast Cancer Cells. Cell Growth Differ
13: 335-341
[Abstract]
[Full Text]
-
McGregor, F., Muntoni, A., Fleming, J., Brown, J., Felix, D. H., MacDonald, D. G., Parkinson, E. K., Harrison, P. R.
(2002). Molecular Changes Associated with Oral Dysplasia Progression and Acquisition of Immortality: Potential for Its Reversal by 5-Azacytidine. Cancer Res
62: 4757-4766
[Abstract]
[Full Text]
-
Suh, Y.-A., Lee, H.-Y., Virmani, A., Wong, J., Mann, K. K., Miller, W. H. Jr., Gazdar, A., Kurie, J. M.
(2002). Loss of Retinoic Acid Receptor {beta} Gene Expression Is Linked to Aberrant Histone H3 Acetylation in Lung Cancer Cell Lines. Cancer Res
62: 3945-3949
[Abstract]
[Full Text]
-
Tomizawa, Y., Kohno, T., Kondo, H., Otsuka, A., Nishioka, M., Niki, T., Yamada, T., Maeshima, A., Yoshimura, K., Saito, R., Minna, J. D., Yokota, J.
(2002). Clinicopathological Significance of Epigenetic Inactivation of RASSF1A at 3p21.3 in Stage I Lung Adenocarcinoma. Clin Cancer Res
8: 2362-2368
[Abstract]
[Full Text]
-
Virmani, A. K., Tsou, J. A., Siegmund, K. D., Shen, L. Y. C., Long, T. I., Laird, P. W., Gazdar, A. F., Laird-Offringa, I. A.
(2002). Hierarchical Clustering of Lung Cancer Cell Lines Using DNA Methylation Markers. Cancer Epidemiol Biomarkers Prev
11: 291-297
[Abstract]
[Full Text]
-
Maruyama, R., Toyooka, S., Toyooka, K. O., Virmani, A. K., Zochbauer-Muller, S., Farinas, A. J., Minna, J. D., McConnell, J., Frenkel, E. P., Gazdar, A. F.
(2002). Aberrant Promoter Methylation Profile of Prostate Cancers and Its Relationship to Clinicopathological Features. Clin Cancer Res
8: 514-519
[Abstract]
[Full Text]
-
Chan, M. W. Y., Chan, L. W., Tang, N. L. S., Tong, J. H. M., Lo, K. W., Lee, T. L., Cheung, H. Y., Wong, W. S., Chan, P. S. F., Lai, F. M. M., To, K. F.
(2002). Hypermethylation of Multiple Genes in Tumor Tissues and Voided Urine in Urinary Bladder Cancer Patients. Clin Cancer Res
8: 464-470
[Abstract]
[Full Text]
-
Brabender, J., Danenberg, K. D., Metzger, R., Schneider, P. M., Lord, R. V., Groshen, S., Tsao-Wei, D. D., Park, J., Salonga, D., Holscher, A. H., Danenberg, P. V.
(2002). The Role of Retinoid X Receptor Messenger RNA Expression in Curatively Resected Non-Small Cell Lung Cancer. Clin Cancer Res
8: 438-443
[Abstract]
[Full Text]
-
Kwong, J., Lo, K.-W., To, K.-F., Teo, P. M. L., Johnson, P. J., Huang, D. P.
(2002). Promoter Hypermethylation of Multiple Genes in Nasopharyngeal Carcinoma. Clin Cancer Res
8: 131-137
[Abstract]
[Full Text]
-
Ping Siu, L. L., Cheung Chan, J. K., Wong, K.-F., Kwong, Y.-L.
(2002). Specific Patterns of Gene Methylation in Natural Killer Cell Lymphomas : p73 Is Consistently Involved. Am J Pathol
160: 59-66
[Abstract]
[Full Text]
-
Maruyama, R., Toyooka, S., Toyooka, K. O., Harada, K., Virmani, A. K., Zochbauer-Muller, S., Farinas, A. J., Vakar-Lopez, F., Minna, J. D., Sagalowsky, A., Czerniak, B., Gazdar, A. F.
(2001). Aberrant Promoter Methylation Profile of Bladder Cancer and Its Relationship to Clinicopathological Features. Cancer Res
61: 8659-8663
[Abstract]
[Full Text]
-
Toyooka, S., Toyooka, K. O., Maruyama, R., Virmani, A. K., Girard, L., Miyajima, K., Harada, K., Ariyoshi, Y., Takahashi, T., Sugio, K., Brambilla, E., Gilcrease, M., Minna, J. D., Gazdar, A. F.
(2001). DNA Methylation Profiles of Lung Tumors. Mol Cancer Ther
1: 61-67
[Abstract]
[Full Text]
-
Lippman, S. M., Spitz, M. R.
(2001). Lung Cancer Chemoprevention: An Integrated Approach. J Clin Oncol
19: 74s-82
[Abstract]
[Full Text]
-
Toyooka, S., Pass, H. I., Shivapurkar, N., Fukuyama, Y., Maruyama, R., Toyooka, K. O., Gilcrease, M., Farinas, A., Minna, J. D., Gazdar, A. F.
(2001). Aberrant Methylation and Simian Virus 40 Tag Sequences in Malignant Mesothelioma. Cancer Res
61: 5727-5730
[Abstract]
[Full Text]
-
Virmani, A. K., Rathi, A., Sathyanarayana, U. G., Padar, A., Huang, C. X., Cunnigham, H. T., Farinas, A. J., Milchgrub, S., Euhus, D. M., Gilcrease, M., Herman, J., Minna, J. D., Gazdar, A. F.
(2001). Aberrant Methylation of the Adenomatous Polyposis Coli (APC) Gene Promoter 1A in Breast and Lung Carcinomas. Clin Cancer Res
7: 1998-2004
[Abstract]
[Full Text]
-
Maitra, A., Wistuba, I. I., Washington, C., Virmani, A. K., Ashfaq, R., Milchgrub, S., Gazdar, A. F., Minna, J. D.
(2001). High-Resolution Chromosome 3p Allelotyping of Breast Carcinomas and Precursor Lesions Demonstrates Frequent Loss of Heterozygosity and a Discontinuous Pattern of Allele Loss. Am J Pathol
159: 119-130
[Abstract]
[Full Text]
-
Toyooka, K. O., Toyooka, S., Virmani, A. K., Sathyanarayana, U. G., Euhus, D. M., Gilcrease, M., Minna, J. D., Gazdar, A. F.
(2001). Loss of Expression and Aberrant Methylation of the CDH13 (H-Cadherin) Gene in Breast and Lung Carcinomas. Cancer Res
61: 4556-4560
[Abstract]
[Full Text]
-
Costello, J. F, Plass, C.
(2001). Methylation matters. J. Med. Genet.
38: 285-303
[Abstract]
[Full Text]
-
Zöchbauer-Müller, S., Fong, K. M., Maitra, A., Lam, S., Geradts, J., Ashfaq, R., Virmani, A. K., Milchgrub, S., Gazdar, A. F., Minna, J. D.
(2001). 5' CpG Island Methylation of the FHIT Gene Is Correlated with Loss of Gene Expression in Lung and Breast Cancer. Cancer Res
61: 3581-3585
[Abstract]
[Full Text]
-
Lippman, S. M., Lee, J. J., Karp, D. D., Vokes, E. E., Benner, S. E., Goodman, G. E., Khuri, F. R., Marks, R., Winn, R. J., Fry, W., Graziano, S. L., Gandara, D. R., Okawara, G., Woodhouse, C. L., Williams, B., Perez, C., Kim, H. W., Lotan, R., Roth, J. A., Hong, W. K.
(2001). Randomized Phase III Intergroup Trial of Isotretinoin to Prevent Second Primary Tumors in Stage I Non-Small-Cell Lung Cancer. J Natl Cancer Inst
93: 605-618
[Abstract]
[Full Text]
-
Virmani, A. K., Muller, C., Rathi, A., Zoechbauer-Mueller, S., Mathis, M., Gazdar, A. F.
(2001). Aberrant Methylation during Cervical Carcinogenesis. Clin Cancer Res
7: 584-589
[Abstract]
[Full Text]
-
Zöchbauer-Müller, S., Fong, K. M., Virmani, A. K., Geradts, J., Gazdar, A. F., Minna, J. D.
(2001). Aberrant Promoter Methylation of Multiple Genes in Non-Small Cell Lung Cancers. Cancer Res
61: 249-255
[Abstract]
[Full Text]
-
Lamy, A., Métayer, J., Thiberville, L., Frébourg, T., Sesboüé, R.
(2001). Re: Promoter Methylation and Silencing of the Retinoic Acid Receptor-{{beta}} Gene in Lung Carcinomas. J Natl Cancer Inst
93: 66-67
[Full Text]
-
Gazdar, A. F., Zöchbauer-Möller, S., Virmani, A., Kurie, J., Minna, J. D., Lam, S.
(2001). RESPONSE: Re: Promoter Methylation and Silencing of the Retinoic Acid Receptor-{{beta}} Gene in Lung Carcinomas. J Natl Cancer Inst
93: 67-68
[Full Text]
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