Abstract
Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs) in 1,451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multiregion samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.
Highlights
IntroductionHuman tumors engrafted into transplant-compliant recipient mice (patient-derived xenografts (PDXs)) have advantages over previous model systems of human cancer (for example, genetically engineered mouse models and cancer cell lines3) for preclinical drug efficacy studies because they allow researchers to directly study human cells and tissues in vivo
Human tumors engrafted into transplant-compliant recipient mice (patient-derived xenografts (PDXs)) have advantages over previous model systems of human cancer for preclinical drug efficacy studies because they allow researchers to directly study human cells and tissues in vivo4–7
We have assembled copy number alterations (CNAs) profiles of 1,451 unique samples (324 patient tumor (PT) samples and 1,127 Patient-derived xenografts (PDXs) samples), corresponding to 509 PDX models contributed by participating centers of the PDXNET, the EurOPDX Consortium and other published datasets11,26
Summary
Human tumors engrafted into transplant-compliant recipient mice (patient-derived xenografts (PDXs)) have advantages over previous model systems of human cancer (for example, genetically engineered mouse models and cancer cell lines3) for preclinical drug efficacy studies because they allow researchers to directly study human cells and tissues in vivo. Ben-David et al. reported extensive PDX copy number divergence from the PT of origin and across passages, based mainly on large-scale assessment of copy number alteration (CNA) profiles inferred from gene expression microarray data They raised concerns about genetic evolution in PDXs as a consequence of mouse-specific selective pressures, which could impact the capacity of PDXs to faithfully model patient treatment response. Such results contrast with reports of observations of genomic fidelity of PDX models with respect to the originating PTs and from early to late passages by direct DNA measurements in several dozen PDX models. This work finely enumerates the copy number profiles in hundreds of publicly available models, which will enable researchers to assess the suitability of each for individualized treatment studies
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