DNA methylation patterns in lung carcinomas |
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| Authors: | Gerd P. Pfeifer Tibor A. Rauch |
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| Affiliation: | 1. Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China;2. Department of Thoracic Surgery Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China;3. Department of Radiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China;4. Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China;1. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L''Hospitalet de Llobregat, Barcelona, Catalonia, Spain and Centro de Investigación Biomédica en Red de Cáncer (CIBERONC);2. Department of Respiratory Medecine, Hôpital Louis-Pradel, Hospices civils de Lyon, 28 avenue du Doyen Lépine, 69677, Lyon cedex, France;3. Instituciò Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Catalonia, Spain;4. Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain;1. Department of Genetics and Postgenomic Technologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia;2. Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk State, Russia;3. Tomsk Cancer Research Institute, National Research Tomsk Polytechnic University, Tomsk, Russia;4. Tomsk Cancer Research Institute, National Research Tomsk State University, Tomsk, Russia;5. Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia;6. Institute of Chemical Biology and Fundamental Medicine SB RAS, Academician E.N. Meshalkin Novosibirsk Research Institute of Circulation Pathology, Novosibirsk, Russia Technical University, Novosibirsk, Russia;1. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands;2. Department of Pulmonology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;3. Department of Pathology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands;4. Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands;5. Fred Hutchinson Cancer Research Center, Seattle, USA;6. Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, USA;7. Department of Pulmonology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands |
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| Abstract: | The genome of epithelial tumors is characterized by numerous chromosomal aberrations, DNA base sequence changes, and epigenetic abnormalities. The epigenome of cancer cells has been most commonly studied at the level of DNA CpG methylation. In squamous cell carcinomas of the lung, CpG methylation patterns undergo substantial changes relative to normal lung epithelium. Using a genome-scale mapping technique for CpG methylation (MIRA-chip), we characterized CpG island methylation and methylation patterns of entire chromosome arms at a level of resolution of ～100 bp. In individual stage I lung carcinomas, several hundred and probably up to a thousand CpG islands become methylated. Interestingly, a large fraction (almost 80%) of the tumor-specifically methylated sequences are targets of the Polycomb complex in embryonic stem cells. Homeobox genes are particularly overrepresented and all four HOX gene loci on chromosomes 2, 7, 12, and 17 are hotspots for tumor-associated methylation because of the presence of multiple methylated CpG islands within these loci. DNA hypomethylation at CpGs in squamous cell tumors preferentially affects repetitive sequence classes including SINEs, LINEs, subtelomeric repeats, and segmental duplications. Since these epigenetic changes are found in early stage tumors, their contribution to tumor etiology as well as their potential usefulness as diagnostic or prognostic biomarkers of the disease should be considered. |
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