Abstract 1118: Absence of mouse-specific tumor evolution in patient-derived cancer xenografts

Abstract

Abstract Patient-Derived Xenografts (PDXs) are preclinical models largely used to study tumor biology and drug response. Recent literature highlighted the possibility that growth of human tumors in a mouse microenvironment imposes a selection driving mouse-specific genetic evolution of PDXs, which may compromise their reliability as human cancer models. Conversely, independent studies observed a conservation of the genomic landscape during PDX engraftment and passaging. We noticed that PDX genetic evolution was particularly evident in studies based on copy number aberration (CNA) inferred from gene expression data, while it was negligible when DNA-based CNA profiles were employed. Therefore, in a joint international effort of the EurOPDX and PDXNet consortia, we assembled a dataset of 37 hepatocellular and 54 gastric carcinoma tumor or PDX samples with matched RNA-based and DNA-based CNA profiles. We found that DNA-based CNA profiles invariably yield higher concordance between patient's tumor and derived PDXs than those inferred from RNA. RNA-based profiles displayed poor concordance with matched DNA-based profiles, and much lower resolution, so that they missed many focal copy number events detected by DNA-based methods. These results revealed that CNA measurements cannot be accurately estimated by expression data and that a systematic reassessment of CNA dynamics in PDXs based on DNA data is required. To this aim, we generated CNA profiles by low-pass whole genome sequencing (WGS) of 87 colorectal and 43 breast cancer triplets, each composed of matched patient's tumor (PT) and PDX at early (PDX-early) and later (PDX-late) passage. In this way, for each tumor type, we generated three perfectly matched PT, PDX-early and PDX-late cohorts and performed CNA recurrence analysis by GISTIC in each cohort. The hypothesis was that if the mouse host induces a selective pressure capable of shaping the CNA landscape during PDX engraftment and propagation, GISTIC analysis would highlight systematic and progressive changes, from the PT to the PDX-early cohort, and then to the PDX-late cohort. Notably instead, the CNA profiles of the PT and PDX-early/late cohorts were virtually indistinguishable, with no progressive accumulation or loss of CNA during PDX passage and only minor changes not functionally related or associated to cancer-driver or actionable genes. These results were not consequence of insufficient capture of the CNA repertoire, since the GISTIC profiles recapitulated those generated by TCGA for colorectal and breast cancer. In summary, our analyses highlighted that while RNA-based CNA inferences have inadequate resolution and accuracy to study genomic evolution in PDXs, DNA-based CNA profiles confirm retention of CNAs in PTs and PDXs, excluding a systematic mouse driven selection via copy number changes. Ultimately, these results support the robustness of PDXs as preclinical models for predicting drug response. Citation Format: Jessica Giordano, Xing Yi Woo, Anuj Srivastava, Zi-Ming Zhao, Michael W. Lloyd, Roebi de Bruijn, Yun-Suhk Suh, Francesco Galimi, Andrea Bertotti, Adam Lafferty, Alice C. O'Farrell, Elodie Modave, Diether Lambrechts, Petra ter Brugge, Violeta Serra, Elisabetta Marangoni, Rania El Botty, Jong-Il Kim, Han-Kwang Yang, Charles Lee, Dennis A. Dean, Brandi Davis-Dusenbery, Yvonne A. Evrard, James H. Doroshow, Alana L. Welm, Bryan E. Welm, Michael T. Lewis, Bingliang Fang, Jack Roth, Funda Meric-Bernstam, Meenhard Herlyn, Michael Davies, Li Ding, Shunqiang Li, Ramaswamy Govindan, Jeffrey A. Moscow, Carol J. Bult, Claudio Isella, Livio Trusolino, Annette T. Byrne, Jos Jonkers, Jeffrey H. Chuang, Enzo Medico, EurOPDX consortium & PDXNET consortium. Absence of mouse-specific tumor evolution in patient-derived cancer xenografts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1118.