DNA methylation analysis: a powerful new tool for lung cancer diagnosis

Abstract

Carcinoma of the lung is the most common cause of cancer death worldwide. The estimated 5-year survival ranges from 6 -16%, depending on the cell type. The best opportunity for improving survival of lung cancer patients is through early detection, when curative surgical resection is possible. Although the subjects at increased risk for developing carcinoma of the lung (long-term smokers) can be identified, only 10 -20% of this group will ultimately develop the disease. Screening tests of long-term smokers employed to date (radiography and sputum cytology) have not been successful in reducing lung cancer mortality. The application of molecular markers specific for lung cancer offers new possibilities for early detection. Hypermethylation of CpG islands in the promoter regions of genes is a common phenomenon in lung cancer, as demonstrated by the analysis of the methylation status of over 40 genes from lung cancer tumors, cell lines, patient sputum and/ or serum. Determination of the methylation patterns of multiple genes to obtain complex DNA methylation signatures promises to provide a highly sensitive and specific tool for lung cancer diagnosis. When combined with the development of non-invasive methods to detect such signatures, this may provide a viable method to screen subjects at risk for lung cancer.

DNA hypermethylation in lung cancer is targeted at differentiation-associated genes

“…Methylation-based silencing of tumor suppressors is thought to be an important mechanism for gene inactivation and an early event in tumorigenesis (Belinsky et al, 1998;Nuovo et al, 1999;Baylin and Herman, 2000;Nephew, 2003). Consequently, genepromoter hypermethylation has become central to developing strategies for molecular screening, treatment and prognosis in a variety of cancers types (Tsou et al, 2002;Laird, 2003;Belinsky, 2004;Safar et al, 2005;Ushijima, 2005).…”

“…In lung cancer, the hypermethylation of CpG islands in promoter regions appears to be a common occurrence, as demonstrated by the analysis of genes from primary tumors, cell lines, patient sputum and serum (Rauch et al, 2008;Pfeifer and Rauch, 2009). Methylation 'signatures' with promising diagnostic and prognostic ability have emerged as potential biomarkers for lung cancer progression (Tsou et al, 2002;Belinsky, 2004;Safar et al, 2005). Safar et al (2005) identified the methylation of three genes as determinant of prognostic groups with varying 1-and 2-year survival rates (Safar et al, 2005).…”

Reduced expression of class II histone deacetylase genes is associated with poor prognosis in lung cancer patients

“…3 Histone deacetylation catalyzed by HDACs is the main histone modification in silenced gene promoters. 4 In cancer cells, several genes are silenced by alteration of the chromatin structure with or without DNA methylation, [5][6][7] suggesting the involvement of abnormal HDAC gene activity. 8,9 Mammalian HDACs consist of 2 groups, classical HDAC genes and the recently identified NAD-dependent SIRT family.…”

Meth-DOP-PCR: an assay for the methylation profiling of trace amounts of DNA extracted from bodily fluids

“…In this respect, an enormous interest has been recently raised by the discovery that cancer cells release their DNA into the patient's bodily fluids and that cancer-specific signatures, like point mutations and DNA methylation errors, can be recognized in the circulating DNA by PCR-based technologies that are the core for the development of fast and accurate assay for the early detection of primary cancer or of their recurrence. [1][2][3][4][5] Furthermore, although the identification of DNA methylation markers predictive of the response to chemotherapy is just beginning, several studies have shown the association between specific methylation aberrations and the efficacy of chemotherapy in cancer patients. [6][7][8] Alteration of the methylation status of selected CpG-rich promoter sequences is an early event of cell transformation that influences gene expression and thus is a particularly promising cancer biomarker for early diagnosis (reviewed in Baylin and Herman, 9 Verma and Srivatsava, 10 and Esteller 11 ).…”