1. Next-generation sequencing analysis and algorithms for PDX and CDX models
- Author
-
Richard Marais, Christopher Wirth, Kristopher K. Frese, Garima Khandelwal, Maria Romina Girotti, Caroline Dive, Marek Dynowski, Crispin J. Miller, Ged Brady, Christopher Smowton, and Samuel J. Taylor
- Subjects
0301 basic medicine ,Cancer Research ,CIENCIAS MÉDICAS Y DE LA SALUD ,MELANOMA ,Biology ,medicine.disease_cause ,DNA sequencing ,Deep sequencing ,purl.org/becyt/ford/1 [https] ,SEQUENCING ,Ciencias Biológicas ,03 medical and health sciences ,Neoplasms ,medicine ,Animals ,Humans ,Exome ,Epigenetics ,purl.org/becyt/ford/1.6 [https] ,Molecular Biology ,Mutation ,Gene Expression Profiling ,Cancer ,High-Throughput Nucleotide Sequencing ,Patología ,purl.org/becyt/ford/3.1 [https] ,Bioquímica y Biología Molecular ,medicine.disease ,Neoplastic Cells, Circulating ,Xenograft Model Antitumor Assays ,PDXs ,Gene expression profiling ,Disease Models, Animal ,Medicina Básica ,030104 developmental biology ,Oncology ,CDXs ,Cancer research ,purl.org/becyt/ford/3 [https] ,Carcinogenesis ,Algorithm ,Algorithms ,Software ,CIENCIAS NATURALES Y EXACTAS - Abstract
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. Fil: Khandelwal, Garima. University of Manchester; Reino Unido Fil: Girotti, Maria Romina. University of Manchester; Reino Unido. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Smowton, Christopher. University of Manchester; Reino Unido Fil: Taylor, Sam. University of Manchester; Reino Unido Fil: Wirth, Christopher. University of Manchester; Reino Unido Fil: Dynowski, Marek. University of Manchester; Reino Unido Fil: Frese, Kristopher K.. University of Manchester; Reino Unido Fil: Brady, Ged. University of Manchester; Reino Unido Fil: Dive, Caroline. University of Manchester; Reino Unido Fil: Marais, Richard. University of Manchester; Reino Unido Fil: Miller, Crispin. University of Manchester; Reino Unido
- Published
- 2017