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Open Access Research

Assessing telomeric DNA content in pediatric cancers using whole-genome sequencing data

Matthew Parker1, Xiang Chen1, Armita Bahrami2, James Dalton2, Michael Rusch1, Gang Wu1, John Easton3, Nai-Kong Cheung4, Michael Dyer5, Elaine R Mardis67, Richard K Wilson67, Charles Mullighan2, Richard Gilbertson5, Suzanne J Baker5, Gerard Zambetti8, David W Ellison2, James R Downing2, Jinghui Zhang1* and the Pediatric Cancer Genome Project

Author Affiliations

1 Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA

2 Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA

3 The Pediatric Cancer Genome Project, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA

4 Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA

5 Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA

6 The Genome Center at Washington University, Washington University, 4444 Forest Park Ave, St Louis, Missouri 63108, USA

7 Department of Genetics, Washington University, 4444 Forest Park Ave, St Louis, Missouri 63108, USA

8 Department of Biochemistry, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA

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Genome Biology 2012, 13:R113  doi:10.1186/gb-2012-13-12-r113

Published: 11 December 2012

Abstract

Background

Telomeres are the protective arrays of tandem TTAGGG sequence and associated proteins at the termini of chromosomes. Telomeres shorten at each cell division due to the end-replication problem and are maintained above a critical threshold in malignant cancer cells to prevent cellular senescence or apoptosis. With the recent advances in massive parallel sequencing, assessing telomere content in the context of other cancer genomic aberrations becomes an attractive possibility. We present the first comprehensive analysis of telomeric DNA content change in tumors using whole-genome sequencing data from 235 pediatric cancers.

Results

To measure telomeric DNA content, we counted telomeric reads containing TTAGGGx4 or CCCTAAx4 and normalized to the average genomic coverage. Changes in telomeric DNA content in tumor genomes were clustered using a Bayesian Information Criterion to determine loss, no change, or gain. Using this approach, we found that the pattern of telomeric DNA alteration varies dramatically across the landscape of pediatric malignancies: telomere gain was found in 32% of solid tumors, 4% of brain tumors and 0% of hematopoietic malignancies. The results were validated by three independent experimental approaches and reveal significant association of telomere gain with the frequency of somatic sequence mutations and structural variations.

Conclusions

Telomere DNA content measurement using whole-genome sequencing data is a reliable approach that can generate useful insights into the landscape of the cancer genome. Measuring the change in telomeric DNA during malignant progression is likely to be a useful metric when considering telomeres in the context of the whole genome.