Details

Autor(en) / Beteiligte

• Teschendorff, Andrew E
• Yang, Zhen
• Wong, Andrew
• Pipinikas, Christodoulos P
• Jiao, Yinming
• Jones, Allison
• Anjum, Shahzia
• Hardy, Rebecca
• Salvesen, Helga B
• Thirlwell, Christina
• Janes, Samuel M
• Kuh, Diana
• Widschwendter, Martin

Titel

Correlation of Smoking-Associated DNA Methylation Changes in Buccal Cells With DNA Methylation Changes in Epithelial Cancer

Ist Teil von

• JAMA oncology, 2015-07, Vol.1 (4), p.476

Ort / Verlag

United States

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• The utility of buccal cells as an epithelial source tissue for epigenome-wide association studies (EWASs) remains to be demonstrated. Given the direct exposure of buccal cells to potent carcinogens such as smoke, epigenetic changes in these cells may provide insights into the development of smoke-related cancers. To perform an EWAS in buccal and blood cells to assess the relative effect of smoking on the DNA methylation (DNAme) patterns in these cell types and to test whether these DNAme changes are also seen in epithelial cancer. In 2013, we measured DNAme at more than 480,000 CpG sites in buccal samples provided in 1999 by 790 women (all aged 53 years in 1999) from the United Kingdom Medical Research Council National Survey of Health and Development. This included matched blood samples from 152 women. We constructed a DNAme-based smoking index and tested its sensitivity and specificity to discriminate normal from cancer tissue in more than 5000 samples. CpG sites whose DNAme level correlates with smoking pack-years, and construction of an associated sample-specific smoking index, which measures the mean deviation of DNAme at smoking-associated CpG sites from a normal reference. In a discovery set of 400 women, we identified 1501 smoking-associated CpG sites at a genome-wide significance level of P < 10-7, which were validated in an independent set of 390 women. This represented a 40-fold increase of differentially methylated sites in buccal cells compared with matched blood samples. Hypermethylated sites were enriched for bivalently marked genes and binding sites of transcription factors implicated in DNA repair and chromatin architecture (P < 10-10). A smoking index constructed from the DNAme changes in buccal cells was able to discriminate normal tissue from cancer tissue with a mean receiver operating characteristic area under the curve of 0.99 (range, 0.99-1.00) for lung cancers and of 0.91 (range, 0.71-1.00) for 13 other organs. The corresponding area under the curve of a smoking signature derived from blood cells was lower than that derived from buccal cells in 14 of 15 cancer types (Wilcoxon signed rank test, P = .001). These data point toward buccal cells as being a more appropriate source of tissue than blood to conduct EWASs for smoking-related epithelial cancers.