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Bioinformatics Advance Access published online on June 19, 2009
Bioinformatics, doi:10.1093/bioinformatics/btp364
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© The Author (2009). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Copy number variation has little impact on bead-array-based measures of DNA methylation

E. Andrés Houseman 1,2,*, Brock C. Christensen 3, Margaret R. Karagas 4, Margaret R. Wrensch 5,6, Heather H. Nelson 7, Joseph L. Wiemels 5,6, Shichun Zheng 5, John K. Wiencke 5, Karl T. Kelsey 1,3 and Carmen J. Marsit 3

1Department of Community Health Center for Environmental Health and Technology, Brown University, Providence, RI, 02912.
2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115
3Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, 02912
4Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH, 03756
5Department of Neurological Surgery, University of California - San Francisco, San Francisco, CA, 94143
6Department of Epidemiology and Biostatistics, University of California - San Francisco, San Francisco, CA, 94143
7Division of Epidemiology and Community Health, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, 55455.

*To whom correspondence should be addressed. Dr. Eugene Houseman, E-mail: E_Andres_Houseman{at}brown.edu, ahousema{at}hsph.harvard.edu


  Abstract

Motivation: Integration of various genome-scale measures of molecular alterations is of great interest to researchers aiming to better define disease processes or identify novel targets with clinical utility. Particularly important in cancer are measures of gene copy number DNA methylation. However, copy number variation may bias the measurement of DNA methylation. To investigate possible bias, we analyzed integrated data obtained from 19 head and neck squamous cell carcinoma (HNSCC) tumors and 23 mesothelioma tumors.

Results: Statistical analysis of observational data produced results consistent with those anticipated from theoretical mathematical properties. Average beta value reported by Illumina GoldenGate (a bead-array platform) was significantly smaller than a similar measure constructed from the ratio of average dye intensities. Among CpGs that had only small variations in measured methylation across tumors (filtering out clearly biological methylation signatures), there were no systematic copy number effects on methylation for 3 and 4+ copies; however, 1 copy led to small systematic negative effects, and 0 copies led to substantial significant negative effects.

Conclusions: Since mathematical considerations suggest little bias in methylation assayed using bead-arrays, the consistency of observational data with anticipated properties suggests little bias.However, further analysis of systematic copy number effects across CpGs suggest that though there may be little bias when there are copy number gains, small biases may result when 1 allele is lost, and substantial biases when both alleles are lost. These results suggest that further integration of these measures can be useful for characterizing the biological relationships between these somatic events.

Associate Editor: Dr. Alex Bateman

Received on February 19, 2009; revised on June 4, 2009; accepted on June 9, 2009

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