Abstract
Patient derived xenografts (PDXs) have become a vital, frequently used, component of anti-cancer drug development. PDXs can be serially passaged in vivo for years, and shared across laboratories. As a consequence, the potential for mis-identification and cross-contamination is possible, yet authentication of PDXs appears limited. We present a PDX Authentication System (PAS), by combining a commercially available OpenArray assay of single nucleotide polymorphisms (SNPs) with in-house R studio programs, to validate PDXs established in individual mice from acute lymphoblastic leukemia biopsies. The PAS is sufficiently robust to identify contamination at levels as low as 3%, similar to the gold standard of short tandem repeat (STR) profiling. We have surveyed a panel of PDXs established from 73 individual leukemia patients, and found that the PAS provided sufficient discriminatory power to identify each xenograft. The identified SNP-discrepant PDXs demonstrated distinct gene expression profiles, indicating a risk of contamination for PDXs at high passage number. The PAS also allows for the authentication of tumor cells with complex karyotypes from solid tumors including prostate cancer and Ewing's sarcoma. This study highlights the demands of authenticating PDXs for cancer research, and evaluates a reliable authentication platform that utilizes a commercially available and cost-effective system.
Highlights
Patient derived xenografts (PDXs) are a vital tool for the pre-clinical evaluation of new drugs [1,2,3,4,5,6]
We present a PDX Authentication System (PAS), by combining a commercially available OpenArray assay of single nucleotide polymorphisms (SNPs) with in-house R studio programs, to validate PDXs established in individual mice from acute lymphoblastic leukemia biopsies
If a sample is contaminated with two PDXs, both samples will compete in the mouse and one sample may eventually dominate the other
Summary
Patient derived xenografts (PDXs) are a vital tool for the pre-clinical evaluation of new drugs [1,2,3,4,5,6]. With the increasing use of PDXs in cancer research, implementation of a rapid, accurate and cost-effective genotyping system for PDX authentication would improve the integrity of data produced from PDXs. Short tandem repeats (STRs) are repetitive sequences of DNA that are distributed throughout the human genome [14,15,16]. STRs have a high mutation rate that results in a large diversity of repetitive sequences across the human population. The ability to quantify repetitive elements and their diversity in the population has resulted in the implementation of STRs for the purpose of human identification across www.impactjournals.com/oncotarget forensic science, cell line authentication, and in limited instances authentication of PDXs [17]. The high demand for this technology and its widespread use has resulted in commercially available kits for profiling and authentication, and is a requirement for publication of cell lines in many journals
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