Promoter Methylation and Silencing of the Retinoic Acid Receptor-  Gene in Lung Carcinomas

Virmani, Arvind K.; Rathi, Asha; Zöchbauer‐Müller, Sabine; Sacchi, Nicoletta; Fukuyama, Yasuro; Bryant, David; Maitra, Anirban; Heda, Shashank; Fong, Kwun M.; Thunnissen, Erik; Minna, John D.; Gazdar, Adi F.

doi:10.1093/jnci/92.16.1303

Cited by 329 publications

(214 citation statements)

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“…13 In the present study, we determined the methylation status profile of 19 TSGs including RUNX3, 3OST2 and SOCS1 genes in nonmalignant colonic epithelia (NME), CAs and CRCs. The 19 genes were chosen for study because of their presumed or known roles in various cellular functions related to cancer development, including cell cycle regulation, tissue invasion and metastasis, JAK-STAT and TGF-b signal pathways, key components of retinoid activity, signal transduction, apoptosis, angiogenesis, putative cytokine, mitotic stress checkpoint, methyltransferase superfamily and O-sulfotransferase [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] and were selected from the 6 ''hallmarks of cancer'' 32,33 (Table I). The aims of our study were as follows: (i) to clarify the methylation status of TSGs not previously studied in detail in CRC and correlate methylation with gene expression; and (ii) to investigate the role of methylation during the multistage pathogenesis of CRC, comparing the tumor profile with that of CAs and NME.…”

Section: Introductionmentioning

confidence: 99%

Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers

Takahashi

Shigematsu

Shivapurkar

et al. 2005

Intl Journal of Cancer

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Aberrant methylation of 5 0 gene promoter regions associated with gene silencing is an epigenetic phenomenon responsible for silencing of tumor suppressor genes in many cancer types. The aims of our study were to study the role of methylation of a large panel of genes during multistage pathogenesis and to correlate our findings with patient age and other clinico-pathological features. We investigated the aberrant promoter methylation profile of 19 genes in 92 colorectal cancers (CRCs) and corresponding nonmalignant epithelia (NME) (n 5 57), and selected 15 genes for studying 26 colorectal adenomas (CAs). On the Basis of our results, the genes could be divided into 3 groups. Group 1 consisted of 13 genes whose methylation was tumor-specific. For 8 of these genes, the methylation frequencies in CAs were similar to those of CRCs, but significantly different from the frequencies in NME. Group 2, consisting of 2 genes demonstrating little or no methylation, were present in any sample type. In Group 3, consisting of 4 genes, relatively frequent methylation was present in both CRCs and NME, and the differences between these specimen types were not significant. Methylation of Group 1 genes were tightly correlated with each other, and these genes demonstrated increased methylation frequencies in CRCs with increasing age. Methylation was not correlated with other clinico-pathological features. In general, methylation frequencies of CAs were intermediate between CRCs and NME. Our study constitutes the most comprehensive methylation profile of CRCs, demonstrates that methylation commences early during CRC pathogenesis and is an age-related phenomenon. ' 2005 Wiley-Liss, Inc.

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Section: Introductionmentioning

confidence: 99%

Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers

Takahashi

Shigematsu

Shivapurkar

et al. 2005

Intl Journal of Cancer

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“…The frequencies of promoter methylation reported in our study are in fact similar to those reported in clinically-detected NSCLC patients. Depending on the different methodology used for methylation detection, the frequencies of promoter methylation reported in primary non CT-detected lung cancers, were around 43% for RARb2, 19 ranged from 30 to 40%, for RASSF1A 20,21 and from 25 to 41% for p16 INK4A . 22,23 We have validated our MSP assays in terms of analytical sensitivity and specificity by using appropriate positive and negative controls.…”

Section: Discussionmentioning

confidence: 99%

Methylation profile in tumor and sputum samples of lung cancer patients detected by spiral computed tomography: A nested case–control study

Cirincione

Lintas

Conte

et al. 2005

Intl Journal of Cancer

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We evaluated the aberrant promoter methylation profile of a panel of 3 genes in DNA from tumor and sputum samples, in view of a complementary approach to spiral computed tomography (CT) for early diagnosis of lung cancer. The aberrant promoter methylation of RARb2, p16 INK4A and RASSF1A genes was evaluated by methylation-specific PCR in tumor samples of 29 CTdetected lung cancer patients, of which 18 had tumor-sputum pairs available for the analysis, and in the sputum samples from 112 cancer-free heavy smokers enrolled in a spiral CT trial. In tumor samples from 29 spiral CT-detected patients, promoter hypermethylation was identified in 19/29 (65.5%) cases for RARb2, 12/29 (41.4%) for p16 INK4A and 15/29 (51.7%) for RASSF1A. Twenty-three of twenty-nine (79.3%) samples of the tumors exhibited methylation in at least 1 gene. In the sputum samples of 18 patients, methylation was detected in 8/18 (44.4%) for RARb2 and 1/18 (5%) for both RASSF1A and p16 INK4A . At least 1 gene was methylated in 9/18 (50%) sputum samples. Promoter hypermethylation in sputum from 112 cancer-free smokers was observed in 58/112 (51.7%) for RARb2 and 20/112 (17.8%) for p16, whereas methylation of the RASSF1A gene was found in only 1/112 (0.9%) sputum sample. Our study indicates that a high frequency of hypermethylation for RARb2, p16 INK4A and RASSF1A promoters is present in spiral CT-detected tumors, whereas promoter hypermethylation of this panel of genes in uninduced sputum has a limited diagnostic value in early lung cancer detection. ' 2005 Wiley-Liss, Inc.Key words: lung cancer; methylation; sputum; spiral CT Lung cancer is the leading cause of cancer deaths in the world. Although surgical resection still represents the best curative approach for this neoplasm, its efficacy strictly depends on the stage of disease presentation. Earlier diagnosis of patients with lung cancer is expected to increase the number of potentially resectable tumors. 1 Several large prospective randomized trials have demonstrated that conventional sputum cytology and chest radiography are not effective in detecting early lung cancer and reducing lung cancer mortality. 2 In this respect, over the last decade, spiral computed tomography (CT) has been tested as a powerful and fast imaging technique to detect tumors of less than 1 cm in diameter, with a proportion of detection of Stage I tumors greater than 80%, opening new possibilities for the early detection of lung cancer. 3,4 However, because of the complex algorithm of high-resolution CT employed in order to achieve the maximal performance of this approach 3 and to achieve the background noise created by the high detection rate of noncalcified nodules, 5 questions have been raised about the challenge of differential diagnosis, efficacy and costs of spiral CT screening. 6 In 2000, a prospective trial of early lung cancer detection was launched in Milan, using repeated yearly low-dose spiral CT, selective use of positron emission tomography and analysis of molecular markers in a large cohort of 1,035 high-...

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“…1,2 Nonsmall cell lung carcinomas (NSCLCs) are no exception to this, with a plethora of TSG promoters affected, including RASSF1, 3 CDKN2A, 4 CYGB, 5 , EDNRB, 6 RARbeta, 7,8 MGMT, 8 and CDH13. 9 DNMTs (DNA methyltransferases) are the key enzymes responsible for the establishment and maintenance of DNA methylation profiles.…”

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confidence: 99%

UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

Daskalos

Oleksiewicz

Filia

et al. 2010

Cancer

108

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BACKGROUND:The UHRF1 gene possesses an essential role in DNA methylation maintenance, but its contribution to tumor suppressor gene hypermethylation in primary human cancers currently remains unclear. METHODS: mRNA expression levels of UHRF1, DNMT1, DNMT3A, DNMT3B, and E2F1 were evaluated in 105 primary nonsmall cell lung carcinomas by quantitative polymerase chain reaction. The methylation status of CDKN2A and RASSF1 promoters was examined by pyrosequencing. UHRF1 was knocked down by short hairpin RNA in A549 lung adenocarcinoma cells. RESULTS: All 4 genes were overexpressed in a coordinated manner in the lung tumor tissues, and their expression correlated with that of E2F1. Higher UHRF1 expression in tumor tissues correlated with the hypermethylation of CDKN2A (P ¼ .005) and RASSF1 promoters (P ¼ .034), and the relationship with a combined epigenotype was even stronger (P ¼ 2.3 Â 10 À4 ). When UHRF1 was knocked down in A549 lung adenocarcinoma cells, lower methylation levels of RASSF1, CYGB, and CDH13 promoters were observed. Also, UHRF1 knockdown clones demonstrated reduced proliferation and decreased cell migration properties. CONCLUSIONS: Our data demonstrate that UHRF1 is a key epigenetic switch, which controls cell cycle in nonsmall cell lung carcinoma through its ability to sustain the transcriptional silencing of tumor suppressor genes by maintaining their promoters in a hypermethylated status. Thus, UHRF1 should be considered, along with DNMTs, among the potential targets for cancer treatment and/or therapeutic stratification.

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Promoter Methylation and Silencing of the Retinoic Acid Receptor- Gene in Lung Carcinomas

Cited by 329 publications

References 30 publications

Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers

Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers

Methylation profile in tumor and sputum samples of lung cancer patients detected by spiral computed tomography: A nested case–control study

UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

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