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DNA methylation biomarkers for lung cancer

  • Research Article
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Tumor Biology

Abstract

Changes in DNA methylation patterns are an important characteristic of human cancer including lung cancer. In particular, hypermethylation of CpG islands is a signature of malignant progression. Methylated CpG islands are promising diagnostic markers for the early detection of cancer. However, the full extent and sequence context of DNA hypermethylation in lung cancer has remained unknown. We have used the methylated CpG island recovery assay and high-resolution microarray analysis to find hypermethylated CpG islands in squamous cell carcinomas (SCC) and adenocarcinomas of the lung. Each tumor contained several hundred hypermethylated CpG islands. In an initial microarray screen, 36 CpG islands were methylated in five of five (=100%) of the SCC tumors tested and 52 CpG islands were methylated in at least 75% of the adenocarcinomas tested (n = 8). Using sodium-bisulfite-based approaches, 12 CpG islands (associated with the BARHL2, EVX2, IRX2, MEIS1, MSX1, NR2E1, OC2, OSR1, OTX1, PAX6, TFAP2A, and ZNF577 genes) were confirmed to be methylated in 85% to 100% of the squamous cell carcinomas and 11 CpG islands (associated with the CHAD, DLX4, GRIK2, KCNG3, NR2E1, OSR1, OTX1, OTX2, PROX1, RUNX1, and VAX1 genes) were methylated in >80% of the adenocarcinomas. From the list of genes that were methylated in lung adenocarcinomas, we identified the gene FAT4 and found that this gene was methylated in 39% of the tumors. FAT4 is the closest mammalian homologue of the Drosophila tumor suppressor Fat which is an important component of the Hippo growth control pathway. Many of these newly discovered methylated CpG islands hold promise for becoming biomarkers for the early detection of lung cancer.

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Acknowledgments

This work was supported by NIH grant CA084469 and a grant from the University of California Tobacco Related Disease Research Program (TRDRP) (to G.P.P.)

Conflicts of interest

Under a licensing agreement between City of Hope and Active Motif (Carlsbad, CA), the methylated CpG island recovery assay (MIRA) technique was licensed to Active Motif, and the authors T.A.R. and G.P.P. are entitled to a share of the royalties received by City of Hope from sales of the licensed technology.

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  1. Tibor A. Rauch

    Present address: Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, 60612, USA

Authors and Affiliations

  1. Division of Biology, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA

    Tibor A. Rauch, Zunde Wang, Arthur D. Riggs & Gerd P. Pfeifer

  2. Department of Information Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA

    Xiwei Wu

  3. Division of Thoracic Surgery, University of Texas, Southwestern Medical Center, Dallas, TX, 75390, USA

    Kemp H. Kernstine

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  1. Tibor A. Rauch
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Correspondence to Gerd P. Pfeifer.

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Tibor A. Rauch and Zunde Wang contributed equally to this work.

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Rauch, T.A., Wang, Z., Wu, X. et al. DNA methylation biomarkers for lung cancer. Tumor Biol. 33, 287–296 (2012). https://doi.org/10.1007/s13277-011-0282-2

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