EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD0001000159632EGA dataset EGAD00010001596EGA<h4>Background</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.Assessing telomeric DNA content in pediatric cancers using whole-genome sequencing data.Targeting oxidative stress in embryonal rhabdomyosarcoma.Chen Xiang X, Stewart Elizabeth E, Shelat Anang A AA, Qu Chunxu C, Bahrami Armita A, Hatley Mark M, Wu Gang G, Bradley Cori C, McEvoy Justina J, Pappo Alberto A, Spunt Sheri S, Valentine Marcus B MB, Valentine Virginia V, Krafcik Fred F, Lang Walter H WH, Wierdl Monika M, Tsurkan Lyudmila L, Tolleman Viktor V, Federico Sara M SM, Morton Chris C, Lu Charles C, Ding Li L, Easton John J, Rusch Michael M, Nagahawatte Panduka P, Wang Jianmin J, Parker Matthew M, Wei Lei L, Hedlund Erin E, Finkelstein David D, Edmonson Michael M, Shurtleff Sheila S, Boggs Kristy K, Mulder Heather H, Yergeau Donald D, Skapek Steve S, Hawkins Douglas S DS, Ramirez Nilsa N, Potter Philip M PM, Sandoval John A JA, Davidoff Andrew M AM, Mardis Elaine R ER, Wilson Richard K RK, Zhang Jinghui J, Downing James R JR, Dyer Michael A MAParker Matthew M, Chen Xiang X, Bahrami Armita A, Dalton James J, Rusch Michael M, Wu Gang G, Easton John J, Cheung Nai-Kong NK, Dyer Michael M, Mardis Elaine R ER, Wilson Richard K RK, Mullighan Charles C, Gilbertson Richard R, Baker Suzanne J SJ, Zambetti Gerard G, Ellison David W DW, Downing James R JR, Zhang Jinghui JfalseDNA methylation of Rhabdomyosarcoma tumorsDNA methylation data from patient RMS tumor samples from Illumina 450 K arays2019-08-05 17:30:56EGAD0001000159696062323225424332040EGAC00001000044EGAS00001000256