Multiregion Genomic Analysis of Serially Transplanted Patient-derived Xenograft Tumors

Abstract

Background: Intratumoral heterogeneity (ITH) is a major cause underlying therapeutic difficulty of cancer. Although an understanding of ITH is critically important in order to develop novel therapeutic strategies, experimental models that enable the examination of ITH in a time series are lacking.

Materials and methods: We developed an experimental approach based on patient-derived xenograft (PDX) mice and a multiregional sequencing approach (MRA). The multiple regions of primary colorectal cancer (CRC) and serially transplanted PDX tumors were analyzed via whole-exome sequencing and bioinformatic analyses.

Results: Our PDX-MRA of CRC indicated the spatiotemporal genetic transition of ITH. It was found that the subclonal architecture of CRC dynamically changes during serial transplantation. Furthermore, our data suggest that environmental selective pressures drive the development of minor pre-existing subclones in PDX-MRA.

Conclusion: PDX-MRA is a useful tool for understanding the spatiotemporal dynamics of ITH.

Keywords: Colorectal cancer; intratumor heterogeneity; patient-derived xenograft; whole exome sequencing.