Abstract
BackgroundThe use of tumour xenografts is a well-established research tool in cancer genomics but has not yet been comprehensively evaluated for cancer epigenomics.MethodsIn this study, we assessed the suitability of patient-derived tumour xenografts (PDXs) for methylome analysis using Infinium 450 K Beadchips and MeDIP-seq.ResultsControlled for confounding host (mouse) sequences, comparison of primary PDXs and matching patient tumours in a rare (osteosarcoma) and common (colon) cancer revealed that an average 2.7% of the assayed CpG sites undergo major (Δβ ≥ 0.51) methylation changes in a cancer-specific manner as a result of the xenografting procedure. No significant subsequent methylation changes were observed after a second round of xenografting between primary and secondary PDXs. Based on computational simulation using publically available methylation data, we additionally show that future studies comparing two groups of PDXs should use 15 or more samples in each group to minimise the impact of xenografting-associated changes in methylation on comparison results.ConclusionsOur results from rare and common cancers indicate that PDXs are a suitable discovery tool for cancer epigenomics and we provide guidance on how to overcome the observed limitations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-014-0116-0) contains supplementary material, which is available to authorized users.
Highlights
The use of tumour xenografts is a well-established research tool in cancer genomics but has not yet been comprehensively evaluated for cancer epigenomics
Xenografting of human tumours into mice or rats has been performed since the late 1960s [1], but it was not until the advent of immunodeficient mouse strains (for example, severe combined immunodeficiency (SCID) mice) in the mid-1980s that the practice became widespread in basic research and preclinical studies [2]
A final sample set consisting of two patient tumours (T1P and T2P), four first generation patient-derived tumour xenograft (PDX), and three second generation PDXs were available for methylation analysis on the Illumina Infinium 450 K Beadchips [19]
Summary
The use of tumour xenografts is a well-established research tool in cancer genomics but has not yet been comprehensively evaluated for cancer epigenomics. Xenografting of human tumours into mice or rats has been performed since the late 1960s [1], but it was not until the advent of immunodeficient mouse strains (for example, severe combined immunodeficiency (SCID) mice) in the mid-1980s that the practice became widespread in basic research and preclinical studies [2] These new models of disease brought with them new hopes of therapeutic advances but have displayed a number of noteworthy limitations [2]. Because OS presents most often in adolescents and young adults, who are less likely to enrol into clinical trials [7], patient recruitment can often take several years, enhancing the inherent jeopardy in drug selection for these trials With this in mind, in vivo tumour models that most accurately replicate the patient’s condition are a crucial factor in experimental pharmacology
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