Next-gen sequencing analysis and algorithms for PDX and CDX models.
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Authors
Khandelwal, GarimaGirotti, Maria Romina
Smowton, Christopher
Taylor, Sam
Wirth, Chris
Dynowski, Marek
Frese, Kristopher K
Brady, Ged
Dive, Caroline
Marais, Richard
Miller, Crispin J
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RNA Biology Group, Cancer Research UK Manchester InstituteIssue Date
2017-04-25
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Patient-derived xenograft (PDX) and CTC-derived explant (CDX) models are powerful methods for the study of human disease. In cancer research, these methods have been applied to multiple questions including the study of metastatic progression, genetic evolution and therapeutic drug responses. Since PDX and CDX models can recapitulate the highly heterogeneous characteristics of a patient tumor, as well as their response to chemotherapy, there is considerable interest in combining them with next-generation sequencing (NGS) in order to monitor the genomic, transcriptional, and epigenetic changes that accompany oncogenesis. When used for this purpose, their reliability is highly dependent on being able to accurately distinguish between sequencing reads that originate from the host, and those that arise from the xenograft itself. Here we demonstrate that failure to correctly identify contaminating host reads, when analyzing DNA- and RNA-sequencing (DNA-Seq and RNA-Seq) data from PDX and CDX models is a major confounding factor that can lead to incorrect mutation calls and a failure to identify canonical mutation signatures associated with tumorigenicity. In addition, a highly sensitive algorithm and open source software tool for identifying and removing contaminating host sequences is described. Importantly, when applied to PDX and CDX models of melanoma, these data demonstrate its utility as a sensitive and selective tool for the correction of PDX- and CDX-derived whole exome and RNA-Seq data.Citation
Next-gen sequencing analysis and algorithms for PDX and CDX models. 2017 Mol. Cancer Res.Journal
Molecular cancer research : MCRDOI
10.1158/1541-7786.MCR-16-0431PubMed ID
28442585Type
ArticleLanguage
enISSN
1557-3125ae974a485f413a2113503eed53cd6c53
10.1158/1541-7786.MCR-16-0431
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