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

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.

A breast cancer patient-derived xenograft and organoid platform for drug discovery and precision oncology

“…Overall, we observed a high correlation between patient samples and their derived models compared to models from different patients (p=9.14e-42, 95% CI = 0.57 to 0.63, Mann-Whitney U of Spearman correlation values; Figure 4b and Figure S57 ). This result supports the recent PDXNet finding of gross CNV conservation from patient samples to their derived models 1 . At the gene level, we only observed a few genes that transitioned from amplification to deletion following model passaging.…”

“…As we and others have reported 1, 34, 37, 42, 43 , the molecular and pathophysiological features of breast PDX are representative of the human breast cancers from which they arise. Growth of ER+ breast cancers is very challenging, due in part to their relatively slow growth rate and to their dependence on estrogen, which is present at lower levels in mice than in humans 44 .…”

“…To model solid tumors from cancer patients more accurately, our group and others have developed and exploited patient-derived xenografts (PDX), whereby fragments of human tumors are implanted directly into immune-deficient mice and grown in a serially-transplantable manner. PDX models recapitulate human tumors with relatively high fidelity 1 and exhibit treatment responses that are concordant with those observed in the patients from which they are derived (recently reviewed 2 ). While imperfect, PDX models are currently the most robust way to model diverse human tumors in the laboratory in vivo .…”

“…Systematic, engraftment-specific copy number changes have been reported to occur in PDX models 51 ; however, a recent comprehensive study found that copy number changes are minimal and largely attributed to spatial heterogeneity of samples, rather than evolution upon PDX engraftment 1 . To examine whether gross copy number changes occurred in our models following in vivo and ex vivo passaging, we assessed copy number differences in the early- and late-passage models versus their matching patient tumors using SNP arrays.…”

“…Although no sequencing data was reported in our previous manuscript with the 12 initial PDX lines, we had reported CNV data 37 . Those CNV data were not analyzed using the new PDXNet standards 1 and reflect older technology. We have therefore repeated CNV analysis using newer technology.…”