Tumor-Specific Methylation in Bronchial Lavage for the Early Detection of Non-Small-Cell Lung Cancer

Kim, Hojoong; Kwon, Young Mi; Kim, Jin Seuk; Lee, Haengbyoung; Park, Jung Ho; Shim, Young Mog; Han, Joungho; Park, Joobae; Kim, Duk-Hwan

doi:10.1200/jco.2004.10.077

Cited by 139 publications

(100 citation statements)

References 26 publications

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“…These observations are in agreement with those already reported of elevated rate of RARb2 methylation in sputum, bronchial biopsies and bronchial lavage of smokers without cancer. 25,26 On the contrary, methylation of RASSF1A was detected in a high frequency of tumor samples from the CT-detected patients, but appeared in only one sputum sample from the 112 heavy smokers. These data suggest RASSF1A could more likely behave as a true tumor-associated marker.…”

Section: Discussionmentioning

confidence: 92%

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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Section: Discussionmentioning

confidence: 92%

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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“…''False positives'' can reflect patient age and environmental factors such as smoking. Kim et al 4 reported that age-related methylation of the FHIT gene in normal bronchial epithelium is related to tobacco smoke exposure. We presently found methylation of DAPK in pleural fluid DNA to be associated significantly with smoking history but with not age.…”

Section: Discussionmentioning

confidence: 99%

“…1-3 Aberrant hypermethylation of many tumor suppressor genes has been observed in various specimens from lung cancer patients, including serum, plasma, sputum, lavage fluid, and epithelial brushing. 4,5 Recent studies have demonstrated the presence of promoter hypermethylation of various genes in fluids including bronchoalveolar lavage fluid (BALF), pleural fluid, 6 and peritoneal fluid. 7 These findings raise the possibility that methylation analysis in such materials may be a useful diagnostic tool for cancer detection.…”

mentioning

confidence: 99%

Aberrant promoter methylation in pleural fluid DNA for diagnosis of malignant pleural effusion

Katayama

Hiraki

Aoe

et al. 2007

Intl Journal of Cancer

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Accumulating evidence implicates epigenetic changes such as hypermethylation in carcinogenesis. We investigated whether DNA methylation of 5 tumor suppressor genes in pleural fluid samples could aid in diagnosis of malignant effusion. In samples from 47 patients with malignant pleural effusions and 34 with nonmalignant effusions, we used a methylation-specific polymerase chain reaction to detect aberrant hypermethylation of the promoters of the DNA repair gene O 6 -methylguanine-DNA methyltransferase (MGMT), p16 INK4a , ras association domain family 1A (RASSF1A), apoptosis-related genes, death-associated protein kinase (DAPK), and retinoic acid receptor b (RARb). Promoter hypermethylation was associated with malignant effusion for MGMT (Odds ratio (OR) 5 '), p16 INK4a (OR 5 '), RASSF1A (OR 5 13.8; CI, 1.71-112), and RARb (OR 5 3.17; CI, 1.10-9.11), but not for DAPK. Instead, DAPK methylation was associated with the length of smoking (p < 0.05). Patients with hypermethylation of MGMT, p16 INK4a , RASSF1A or RARb were 5.68 times more likely to have malignant effusions than patients without methylation (p 5 0.008). Methylations per patient were more numerous for lung cancer than nonmalignant pulmonary disease (0.915 vs. 0.206, p < 0.001). Sensitivity, specificity, and positive predictive value of methylation in one or more genes for diagnosis of malignant effusion were 59.6%, 79.4%, and 80.0% respectively. In conclusion, aberrant promoter methylation of tumor suppressor genes in pleural fluid DNA could be a valuable diagnostic marker for malignant pleural effusion. ' 2007 Wiley-Liss, Inc.Key words: MGMT; p16 INK4a ; RASSF1A; DAPK; RARb; malignant pleural effusion Epigenetic changes such as hypermethylation increasingly appear to play a role in carcinogenesis. DNA methylation is one form of epigenetic variability in mammalian cells. [1][2][3] As aberrant hypermethylation in CpG-rich promoter regions of many tumor suppressor genes interferes with gene transcription, hypermethylation can contribute to development and progression of various cancers by abolishing tumor suppressor gene function. 1-3 Aberrant hypermethylation of many tumor suppressor genes has been observed in various specimens from lung cancer patients, including serum, plasma, sputum, lavage fluid, and epithelial brushing. 4,5 Recent studies have demonstrated the presence of promoter hypermethylation of various genes in fluids including bronchoalveolar lavage fluid (BALF), pleural fluid, 6 and peritoneal fluid. 7 These findings raise the possibility that methylation analysis in such materials may be a useful diagnostic tool for cancer detection.A number of studies have demonstrated frequent methylation in lung cancer cells of several tumor suppressor genes including the DNA repair gene O 6 -methylguanine-DNA methyltransferase (MGMT), 8,9 p16 INK4a , 10,11 ras association domain family 1A (RASSF1A), 12,13 apoptosis-associated genes such as death-associated protein kinase (DAPK), 14 and retinoic acid receptor b (RARb) 15 ; in contrast, methylation of thes...

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“…In lung adenocarcinomas/squamous cell carcinomas, the frequency of p16, MGMT, RASSF1, MTHFR, and FHIT promoter methylation was significantly higher among smokers than never-smokers. [98][99][100][101] On the other hand, methylation in certain genes, such as RASSF2, TNFRSF10C, BHLHB5, and BOLL, 102,103 was higher in lung cancers from never-smokers than those from smokers, suggesting smoking may target specific genes for methylation.…”

Section: Methylationmentioning

confidence: 99%

Genetic and epigenetic changes in lung carcinoma and their clinical implications

Wen

Zhang

et al. 2011

Modern Pathology

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Lung cancer is the leading cause of cancer deaths worldwide. Recent advance in targeted therapy for lung cancer patients with epidermal growth factor receptor (EGFR) mutations has demonstrated a promising development toward personalized therapy for lung cancer patients. The development of lung cancer is a complex process, involving a series of genetic and epigenetic changes. Tobacco smoke is the predominant etiologic risk factor for lung cancer. However, some lung cancers, especially adenocarcinomas, arise in patients who have never smoked, suggesting the importance of host genetic/epigenetic susceptibility in the occurrence and development of lung cancer. Understanding of these genetic and epigenetic changes will further aid in the biomarker-driven personalized therapy for lung cancer patients. In this review, we summarize the genetic and epigenetic alterations observed in lung cancers, including chromosomal loss of heterozygosity, tumor-suppressor gene mutation, gene methylation, histone modification, and microRNA expression changes. Clinical and preclinical studies have implied specific genetic/epigenetic changes for clinical application in lung cancer patients. However, more efforts are required in validation of the identified molecular markers in lung cancer patients for early detections, assessment for treatment response, and survival predictions.

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Tumor-Specific Methylation in Bronchial Lavage for the Early Detection of Non-Small-Cell Lung Cancer

Cited by 139 publications

References 26 publications

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

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

Aberrant promoter methylation in pleural fluid DNA for diagnosis of malignant pleural effusion

Genetic and epigenetic changes in lung carcinoma and their clinical implications

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