DNA Methylation Markers and Early Recurrence in Stage I Lung Cancer

Brock, Malcolm V.; Hooker, Craig M.; Ota-Machida, Emi; Han, Yu; Guo, Mingzhou; Ames, Stephen; Glöckner, Sabine C.; Piantadosi, Steven; Gabrielson, Edward; Pridham, Genevieve; Pelosky, Kristen; Belinsky, Steven A.; Yang, Stephen C.; Baylin, Stephen B.; Herman, James G.

doi:10.1056/nejmoa0706550

Cited by 547 publications

(453 citation statements)

References 26 publications

Supporting

Mentioning

431

Contrasting

Unclassified

Order By: Relevance

“…Deletion or hypermethylation of CDKN2A is a frequent oncogenic event in various types of carcinomas, including for example lung cancer, head and neck squamous cell carcinoma, and salivary duct carcinoma. [37][38][39] Further studies will be needed to confirm the significance of CDKN2A deletions in mucoepidermoid carcinomas with and without CRTC1-MAML2 gene fusion.…”

Section: Discussionmentioning

confidence: 99%

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

et al. 2013

View full text Add to dashboard Cite

Mucoepidermoid carcinoma is the most common salivary gland malignancy, and includes a spectrum of lesions ranging from non-aggressive low-grade tumors to aggressive high-grade tumors. To further characterize this heterogeneous group of tumors we have performed a comprehensive analysis of copy number alterations and CRTC1-MAML2 fusion status in a series of 28 mucoepidermoid carcinomas. The CRTC1-MAML2 fusion was detected by RT-PCR or fluorescence in situ hybridization in 18 of 28 mucoepidermoid carcinomas (64%). All 15 low-grade tumors were fusion-positive whereas only 3 of 13 high-grade tumors were fusion-positive. Highresolution array-based comparative genomic hybridization revealed that fusion-positive tumors had significantly fewer copy number alterations/tumor compared with fusion-negative tumors (1.5 vs 9.5; P ¼ 0.002). Twelve of 18 fusion-positive tumors had normal genomic profiles whereas only 1 out of 10 fusionnegative tumors lacked copy number alterations. The profiles of fusion-positive and fusion-negative tumors were very similar to those of low-and high-grade tumors. Thus, low-grade mucoepidermoid carcinomas had significantly fewer copy number alterations/tumor compared with high-grade mucoepidermoid carcinomas (0.7 vs 8.6; Po0.0001). The most frequent copy number alterations detected were losses of 18q12.2-qter (including the tumor suppressor genes DCC, SMAD4, and GALR1), 9p21.3 (including the tumor suppressor genes CDKN2A/B), 6q22.1-q23.1, and 8pter-p12.1, and gains of 8q24.3 (including the oncogene MAFA), 11q12.3-q13.2, 3q26.1-q28, 19p13.2-p13.11, and 8q11.1-q12.2 (including the oncogenes LYN, MOS, and PLAG1). On the basis of these results we propose that mucoepidermoid carcinoma may be subdivided in (i) low-grade, fusion-positive mucoepidermoid carcinomas with no or few genomic imbalances and favorable prognosis, (ii) high-grade, fusion-positive mucoepidermoid carcinomas with multiple genomic imbalances and unfavorable prognosis, and (iii) a heterogeneous group of high-grade, fusion-negative adenocarcinomas with multiple genomic imbalances and unfavorable outcome. Taken together, our studies indicate that molecular genetic analysis can be a useful adjunct to histologic scoring of mucoepidermoid carcinoma and may lead to development of new clinical guidelines for management of these patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

et al. 2013

View full text Add to dashboard Cite

show abstract

“…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.…”

mentioning

confidence: 99%

The Oral Cavity as a Molecular Mirror of Lung Carcinogenesis

Sidransky

2008

Cancer Prevention Research

View full text Add to dashboard Cite

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...

show abstract

“…As methylation of RASSF1A has been reported in a variety of tumors 24, 26, RASSF1A promoter methylation has been reported to be a useful predictor for clinical outcome in lung cancer, hepatocellular carcinoma, and breast cancer 26, 27, 28. In this study, RASSF1A promoter methylation was found to be associated with shorter duration of progression‐free survival using univariate survival analysis, but this gene was not a prognostic factor in a multivariate Cox model, adjusting for patient's age, chromosome 19q loss, and Ki67 proliferative index.…”

Section: Discussionmentioning

confidence: 99%

Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in oligodendroglial tumors

Kuo

Lee

et al. 2016

Cancer Medicine

View full text Add to dashboard Cite

Aberrant methylation has been associated with transcriptional inactivation of tumor‐related genes in a wide spectrum of human neoplasms. The influence of DNA methylation in oligodendroglial tumors is not fully understood. Genomic DNA was isolated from 61 oligodendroglial tumors for analysis of methylation using methylation‐specific multiplex ligation‐dependent probe amplification assay (MS‐MLPA). We correlated methylation status with clinicopathological findings and outcome. The genes found to be most frequently methylated in oligodendroglial tumors were RASSF1A (80.3%), CASP8 (70.5%), and CDKN2A (52.5%). Kaplan–Meier survival curve analysis demonstrated longer duration of progression‐free survival in patients with 19q loss, aged less than 38 years, and with a proliferative index of less than 5%. Methylation of the ESR1 promoter is significantly associated with shorter duration of overall survival and progression‐free survival, and that methylation of IGSF4 and RASSF1A is significantly associated with shorter duration of progression‐free survival. However, none of the methylation status of ESR1, IGSF4, and RASSF1A was of prognostic value for survival in a multivariate Cox model. A number of novel and interesting epigenetic alterations were identified in this study. The findings highlight the importance of methylation profiles in oligodendroglial tumors and their possible involvement in tumorigenesis.

show abstract

DNA Methylation Markers and Early Recurrence in Stage I Lung Cancer

Abstract: Methylation of the promoter region of the four genes in patients with stage I NSCLC treated with curative intent by means of surgery is associated with early recurrence.

Cited by 547 publications

References 26 publications

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

The Oral Cavity as a Molecular Mirror of Lung Carcinogenesis

Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in oligodendroglial tumors

Contact Info

Product

Resources

About