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Nucleic Acids Research Advance Access originally published online on June 3, 2009
Nucleic Acids Research 2009 37(14):4603-4612; doi:10.1093/nar/gkp457
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Nucleic Acids Research, 2009, Vol. 37, No. 14 4603-4612
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gene Regulation, Chromatin and Epigenetics

Intra-tumor heterogeneity of MLH1 promoter methylation revealed by deep single molecule bisulfite sequencing

Katherine E. Varley1, David G. Mutch2, Tina B. Edmonston3, Paul J. Goodfellow4 and Robi D. Mitra1,*

1Department of Genetics, Center for Genome Sciences, Washington University School of Medicine, 2Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, Missouri, 3Thomas Jefferson University, Department of Pathology, Anatomy and Cell Biology, Philadelphia, PA and 4Department of Surgery, Washington University School of Medicine, St Louis, MO, USA

*To whom correspondence should be addressed. Tel: +314 362 2751; Fax: +314 362 2157; Email: rmitra{at}genetics.wustl.edu

Received November 13, 2008. Revised May 11, 2009. Accepted May 14, 2009.

A single tumor may contain cells with different somatic mutations. By characterizing this genetic heterogeneity within tumors, advances have been made in the prognosis, treatment and understanding of tumorigenesis. In contrast, the extent of epigenetic intra-tumor heterogeneity and how it influences tumor biology is under-explored. We have characterized epigenetic heterogeneity within individual tumors using next-generation sequencing. We used deep single molecule bisulfite sequencing and sample-specific DNA barcodes to determine the spectrum of MLH1 promoter methylation across an average of 1000 molecules in each of 33 individual samples in parallel, including endometrial cancer, matched blood and normal endometrium. This first glimpse, deep into each tumor, revealed unexpectedly heterogeneous patterns of methylation at the MLH1 promoter within a subset of endometrial tumors. This high-resolution analysis allowed us to measure the clonality of methylation in individual tumors and gain insight into the accumulation of aberrant promoter methylation on both alleles during tumorigenesis.


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