Molecular Detection of Tumor Cells in Bronchoalveolar Lavage Fluid From Patients With Early Stage Lung Cancer

Ahrendt, Steven A.; Chow, John T.; Xu, Lihua; Yang, Stephen C.; Eisenberger, Claus Ferdinand; Esteller, Manel; Herman, James G.; Li, Wu; Decker, P; Jen, Jin; Sidransky, David

doi:10.1093/jnci/91.4.332

Cited by 294 publications

(157 citation statements)

References 18 publications

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“…Clonal loss of heterozygosity (3,4), p53 mutations (5), increased telomerase activity (6), and promoter methylation (7) can occur in large patches of histologically normal epithelial cells of the large airway in current and former smokers with or without lung cancer. The tumor suppressor genes p16 and FHIT are commonly inactivated by promoter methylation in early tumorigenesis of the lung and head and neck, and this methylation is associated with smoking (8)(9)(10). Moreover, methylation of p16 and other genes in sputum or lung samples (11) can persist after smoking cessation and is associated (strongest for p16) with an increased risk of lung cancer (12).…”

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confidence: 99%

The Oral Cavity as a Molecular Mirror of Lung Carcinogenesis

Sidransky

2008

Cancer Prevention Research

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The lung is a great challenge to oncologists and is where lethal human cancers develop more frequently than in any other organ site. Two large, expensive chemoprevention trials, the Alpha-Tocopherol and Beta-Carotene (ATBC) study and Beta-Carotene and Retinol Efficacy Trial (CAR-ET), highlight the intractability of the lung thus far to effective cancer prevention (1, 2). Both of these prevention trials suggested neutral or harmful results (by primary analyses) in a combined population of more than 47,000 smokers who were followed up to 10 years. The large size and long duration of these trials reflect, in part, the limitation of smoking as the primary risk eligibility criterion; their inefficacy may reflect the limitations of the commonly used nontargeted agents (vitamin E, β-carotene, and retinol). These limitations may be overcome by molecular research designed (a) to identify the highest risk subgroups among smokers, which would in turn allow the initiation of smaller, shorter-term prevention trials, and (b) to identify targeted drugs with a strong molecular rationale that will increase their preventive efficacy in the lung.Cigarette smoke creates a field of tissue injury throughout the lungs and head and neck. Clonal loss of heterozygosity (3, 4), p53 mutations (5), increased telomerase activity (6), and promoter methylation (7) can occur in large patches of histologically normal epithelial cells of the large airway in current and former smokers with or without lung cancer. The tumor suppressor genes p16 and FHIT are commonly inactivated by promoter methylation in early tumorigenesis of the lung and head and neck, and this methylation is associated with smoking (8-10). Moreover, methylation of p16 and other genes in sputum or lung samples (11) can persist after smoking cessation and is associated (strongest for p16) with an increased risk of lung cancer (12). Methylation markers including p16 are also a prognostic factor for aggressive disease in patients with stage I non-small-cell lung cancer (13). These molecular markers offer promise for measuring cancer risk and for monitoring trials of potential cancer prevention agents in the lung and head and neck. In the lung, however, these and other molecular markers measured directly in tissues are difficult to monitor, a difficulty that will require creative approaches to overcome.Monitoring molecular activity in the lung currently relies predominantly on bronchoscopy-directed biopsies and sputum specimens. Bronchoscopy requires a physician and is invasive and expensive, making it unfeasible for population-based studies. Sputum analysis is limited by the frequently unpleasant difficulty in producing sputum encountered by people who do not smoke or have no active inflammatory disorder (e.g., chronic bronchitis), by issues related to standardization of the timing of sample collection, and by the complex mixture of airway epithelial cells and other contaminating cells contained in sputum.A relatively noninvasive way to potentially monitor molecular changes in the l...

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confidence: 99%

The Oral Cavity as a Molecular Mirror of Lung Carcinogenesis

Sidransky

2008

Cancer Prevention Research

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“…1,2 Alterations involving specific tetranucleotide microsatellite DNA sequences, termed "elevated microsatellite alterations at selected tetranucleotide repeats," or EMAST, have not been linked to MMR dysfunction. EMAST has been previously observed in non-small-cell lung, 3,4 skin, 5 ovarian, 6 and bladder cancers. 5,7 The etiology for EMAST is not known, but EMAST has been used as a biomarker for some of these tumors.…”

Section: Introductionmentioning

confidence: 84%

“…[3][4][5][6][7][25][26][27] Several studies could find no link between EMAST and DNA MMR deficiency, the cause of MSI. While the etiology of EMAST is still not clear, general clues point toward some epigenetic relaxation of DNA MMR as one possibility for its cause.…”

Section: Discussionmentioning

confidence: 99%

973 Relationship of EMAST and Microsatellite Instability Among Patients With Rectal Cancer

Devaraj¹,

Ramamoorthy²,

Sandler³

et al. 2010

Gastroenterology

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Background Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature identified in 60% of sporadic colon cancers and may be linked with heterogeneous expression of the DNA mismatch repair (MMR) protein hMSH3. Unlike microsatellite instability-high (MSI-H) in which hypermethylation of hMLH1 occurs followed by multiple susceptible gene mutations, EMAST may be associated with inflammation and subsequent relaxation of MMR function with the biological consequences not known. We evaluated the prevalence of EMAST and MSI in a populationbased cohort of rectal cancers, as EMAST has not been previously determined in rectal cancers. Methods We analyzed 147 sporadic cases of rectal cancer using five tetranucleotide microsatellite markers and NationalCancer-Institute-recommended MSI (mononucleotide and dinucleotide) markers. EMAST and MSI determinations were made on analysis of DNA sequences of the polymerase chain reaction products and determined positive if at least two loci were found to have frame-shifted repeats upon comparison between normal and cancer samples from the same patient. We correlated EMAST data with race, gender, and tumor stage and examined the samples for lymphocyte infiltration. Results Among this cohort of patients with rectal cancer (mean age 62.2±10.3 years, 36% female, 24% African American), 3/147 (2%) showed MSI (three males, two African American) and 49/147 (33%) demonstrated EMAST. Rectal tumors from African Americans were more likely to show EMAST than Caucasians (18/37, 49% vs. 27/104, 26%, p=0.014) and were associated with advanced stage (18/29, 62% EMAST vs. 18/53, 37%, non-EMAST p=0.02). There was no association between EMAST and gender. EMAST was more prevalent in rectal tumors that showed peri-tumoral infiltration compared to those without (30/49, 60% EMAST vs. 24/98, 25% non-EMAST, p=0.0001). Conclusions EMAST in rectal cancer is common and MSI is rare. EMAST is associated with African-American race and may be more commonly seen with metastatic disease. The etiology and consequences of EMAST are under investigation, but its association with immune cell infiltration suggests that inflammation may play a role for its development.

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“…The advantage of this detection technology is built on the basis of the following: positive PCR signals are not masked by the contamination of normal cells, promoter hypermethylation can occur at an early stage of cancer which allows early diagnosis and all tumours have one or more loci that contain hypermethylated tumour suppressor genes. The development of detection techniques also allowed promoter hypermethylation to be identified using bronchoalveolar lavages [94], lymph nodes [95], stool and sputum [96] to screen methylation of tumour suppressors. The screening of promoter hypermethylation in serum DNA from non-small cell lung cancer also opens the avenue for researchers to further develop this technology for diagnosis [97].…”

Section: Dna Methylation Biomarkers Treatment and Monitoring Of Dismentioning

confidence: 99%

DNA Methylation in Mammalian Cells

Winata¹,

William²,

Keena³

et al. 2018

Gene Expression and Regulation in Mammalian Cells - Transcription Toward the Establishment of Novel Therapeutics

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Epigenetic regulation was first studied in the 1970s and has quickly gained global interest. It is involved at many different stages of mammalian cell development. The broad nature of epigenetic regulation has led to it being referred to as an 'all stage' mechanism of regulation as it is implicated in many developmental stages including embryonic development, ageing and in cancer progression. The term 'epigenetic' refers to the alteration of gene expression without changing the genomic sequence. Epigenetic regulation involves the main subtypes of DNA methylation and histone modification, and microRNA expression. Epigenetic alteration is used by mammalian cells to 'turn-on and -off' the gene expression. During embryonic development this process is used to induce cell apoptosis of genes that are no longer useful. During cancer development, epigenetics works to repress tumour suppressor gene expression and activate oncogene expression. The stability and sustainability for the detection of epigenetic markers make it an attractive area for biomarker and drug discovery. In this book chapter we will discuss the key epigenetic processes involved in mammalian cell development and disease progression, specifically in cancer.

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Molecular Detection of Tumor Cells in Bronchoalveolar Lavage Fluid From Patients With Early Stage Lung Cancer

Abstract: Although still limited by sensitivity, molecular diagnostic strategies can detect the presence of neoplastic cells in the proximal airway of patients with surgically resectable NSCLC.

Cited by 294 publications

References 18 publications

The Oral Cavity as a Molecular Mirror of Lung Carcinogenesis

The Oral Cavity as a Molecular Mirror of Lung Carcinogenesis

973 Relationship of EMAST and Microsatellite Instability Among Patients With Rectal Cancer

DNA Methylation in Mammalian Cells

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