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An Integrated Framework for Genome Analysis Reveals Numerous Previously Unrecognizable Structural Variants in Leukemia Patients’ Samples

Jie Xu, Fan Song, Emily Schleicher, Christopher Pool, Darrin Bann, Max Hennessy, Kathryn Sheldon, Emma Batchelder, Charyguly Annageldiyev, Arati Sharma, Yuanyuan Chang, Alex Hastie, Barbara Miller, David Goldenberg, Shin Mineishi, David Claxton, George-Lucian Moldovan, Feng Yue, James R. Broach
doi: https://doi.org/10.1101/563270
Jie Xu
1Department of Biochemistry, Penn State College of Medicine, Hershey, PA 17033
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Fan Song
1Department of Biochemistry, Penn State College of Medicine, Hershey, PA 17033
6Huck Institute of Life Sciences, Penn State University, State College, PA 16802
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Emily Schleicher
1Department of Biochemistry, Penn State College of Medicine, Hershey, PA 17033
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Christopher Pool
3Department of Otolaryngology, PennState Health, Hershey Medical Center, Hershey, PA 17033
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Darrin Bann
3Department of Otolaryngology, PennState Health, Hershey Medical Center, Hershey, PA 17033
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Max Hennessy
3Department of Otolaryngology, PennState Health, Hershey Medical Center, Hershey, PA 17033
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Kathryn Sheldon
2Institute for Personalized Medicine Penn State College of Medicine, Hershey, PA 17033
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Emma Batchelder
2Institute for Personalized Medicine Penn State College of Medicine, Hershey, PA 17033
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Charyguly Annageldiyev
4Department of Hematology Oncology, PennState Health, Hershey Medical Center, Hershey, PA 17033
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Arati Sharma
4Department of Hematology Oncology, PennState Health, Hershey Medical Center, Hershey, PA 17033
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Yuanyuan Chang
7Bionano Genomics, 9540 Towne Centre Drive, Suite 100, San Diego, CA 92121
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Alex Hastie
7Bionano Genomics, 9540 Towne Centre Drive, Suite 100, San Diego, CA 92121
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Barbara Miller
5Departments of Pediatrics and Medicine, PennState Health, Hershey Medical Center, Hershey, PA 17033
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David Goldenberg
3Department of Otolaryngology, PennState Health, Hershey Medical Center, Hershey, PA 17033
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Shin Mineishi
5Departments of Pediatrics and Medicine, PennState Health, Hershey Medical Center, Hershey, PA 17033
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David Claxton
4Department of Hematology Oncology, PennState Health, Hershey Medical Center, Hershey, PA 17033
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George-Lucian Moldovan
1Department of Biochemistry, Penn State College of Medicine, Hershey, PA 17033
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Feng Yue
1Department of Biochemistry, Penn State College of Medicine, Hershey, PA 17033
2Institute for Personalized Medicine Penn State College of Medicine, Hershey, PA 17033
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James R. Broach
1Department of Biochemistry, Penn State College of Medicine, Hershey, PA 17033
2Institute for Personalized Medicine Penn State College of Medicine, Hershey, PA 17033
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  • For correspondence: jbroach@pennstatehealth.psu.edu
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Abstract

While genomic analysis of tumors has stimulated major advances in cancer diagnosis, prognosis and treatment, current methods fail to identify a large fraction of somatic structural variants in tumors. We have applied a combination of whole genome sequencing and optical genome mapping to a number of adult and pediatric leukemia samples, which revealed in each of these samples a large number of structural variants not recognizable by current tools of genomic analyses. We developed computational methods to determine which of those variants likely arose as somatic mutations. The method identified 97% of the structural variants previously reported by karyotype analysis of these samples and revealed an additional fivefold more such somatic rearrangements. The method identified on average tens of previously unrecognizable inversions and duplications and hundreds of previously unrecognizable insertions and deletions. These structural variants recurrently affected a number of leukemia associated genes as well as cancer driver genes not previously associated with leukemia and genes not previously associated with cancer. A number of variants only affected intergenic regions but caused cis-acting alterations in expression of neighboring genes. Analysis of TCGA data indicates that the status of several of the recurrently mutated genes identified in this study significantly affect survival of AML patients. Our results suggest that current genomic analysis methods fail to identify a majority of structural variants in leukemia samples and this lacunae may hamper diagnostic and prognostic efforts.

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Posted February 28, 2019.
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An Integrated Framework for Genome Analysis Reveals Numerous Previously Unrecognizable Structural Variants in Leukemia Patients’ Samples
Jie Xu, Fan Song, Emily Schleicher, Christopher Pool, Darrin Bann, Max Hennessy, Kathryn Sheldon, Emma Batchelder, Charyguly Annageldiyev, Arati Sharma, Yuanyuan Chang, Alex Hastie, Barbara Miller, David Goldenberg, Shin Mineishi, David Claxton, George-Lucian Moldovan, Feng Yue, James R. Broach
bioRxiv 563270; doi: https://doi.org/10.1101/563270
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An Integrated Framework for Genome Analysis Reveals Numerous Previously Unrecognizable Structural Variants in Leukemia Patients’ Samples
Jie Xu, Fan Song, Emily Schleicher, Christopher Pool, Darrin Bann, Max Hennessy, Kathryn Sheldon, Emma Batchelder, Charyguly Annageldiyev, Arati Sharma, Yuanyuan Chang, Alex Hastie, Barbara Miller, David Goldenberg, Shin Mineishi, David Claxton, George-Lucian Moldovan, Feng Yue, James R. Broach
bioRxiv 563270; doi: https://doi.org/10.1101/563270

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