Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts

Abstract

41 a PDXNET consortium 42 b EurOPDX consortium 43 # These authors contributed equally to this work.44 § These authors jointly supervised this work. ABSTRACT 107Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical 108 studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution 109 during PDX engraftment and propagation, impacting the accuracy of PDX modeling of human 110 cancer. Here we exhaustively analyze copy number alterations (CNAs) in 1451 PDX and matched 111 patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing 112 and microarray data displayed substantially higher resolution and dynamic range than gene 113 expression-based inferences, and they also showed strong CNA conservation from PTs through 114 late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-115 late trios confirmed high-resolution CNA retention. We observed no significant enrichment of 116 cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between 117 patient and PDX tumors were comparable to variations in multi-region samples within patients. 118Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse 119 host. 121 MAIN 122A variety of models of human cancer have been used to study basic biological processes and 123 predict responses to treatment. For example, mouse models with genetically engineered 124 mutations in oncogenes and tumor suppressor genes have clarified the genetic and molecular 125 basis of tumor initiation and progression 1,2 , though responses sometimes differ between human 126 and mouse 3 . Cell lines have also been widely used to study cancer cells, but they lack the 127 heterogeneity and microenvironment of in vivo tumors and have shown limitations for predicting 128 clinical response 4 . Human tumors engrafted into transplant-compliant recipient mice (patient-129 derived xenografts, PDX) have advantages over prior systems for preclinical drug efficacy studies 130 because they allow researchers to directly study human cells and tissues in vivo 5-8 . Comparisons131 of genome characteristics and histopathology of primary tumors and xenografts of human breast 132 cancer 9-13 , ovarian cancer 14 , colorectal cancer 15 and lung cancer 16-18 , have demonstrated that the 133 biological properties of patient-derived tumors are largely preserved in xenografts. A growing body 134 of literature supports their use in cancer drug discovery and development 19-21 . 135A caveat to PDX models is that intratumoral evolution can occur during engraftment and 136 passaging 11,22-25 . Such evolution could potentially modify treatment response of PDXs with 137 respect to the patient tumors 23,26,27 , particularly if the evolution were to systematically alter cancer-138 related genes. This issue is related to multi-region comparisons of patient tumors 28-31 , for which 139 local mutational and immune infiltration variations have sugg...

DNA-based copy number analysis confirms genomic evolution of PDX models

“…Using both approaches, the fraction of the genome discordant between two samples was defined for each PDX model. Woo et al reported that most discordant CNAs corresponded to small focal events (average size: 1.53 Mb) 2 , in contrast to our previous findings that CN evolution often involved entire chromosome arms and whole chromosomes. We therefore also evaluated the number of discordant chromosomearm CNAs in Woo et al's dataset.…”

Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

“…The difference in results may be related to the subcutaneous transplantation, which may lead to a different tumor evolution than in the brain. Alternatively, it may be due to differences in data analysis, since array-CGH based CNA determination, employed by us, is known to be more accurate than CNAs inferred from gene expression profiles [115]. We further observed extensive preservation of genetic intratumoral heterogeneity, although some fluctuations in subclonal architecture were detected.…”

Patient-Derived Xenograft and Organoid Models for Precision Medicine Targeting of the Tumour Microenvironment in Head and Neck Cancer

“…However, an analysis of CNA in 1451 PDX models including HNSCC models, using five separate RNA- and DNA-based approaches to estimate copy number, rather than inferring CNA from gene expression microarray data, has contested these claims. Strong conservation of CNA from primary tumours through late-passage PDXs was observed with any differences in CNA comparable to spatial variation within patient tumours, and no systematic selection for CNA in cancer or treatment-related genes on engraftment or with passaging [ 117 ]. These findings do not argue against spontaneous tumour evolution [ 112 , 113 ], but rather suggest that the PDX mouse host does not drive systematic tumour evolution.…”