Pan-cancer analysis reveals genomic fidelity and evolution of patient-derived organoids

Abstract Patient-derived organoids (PDOs) are gaining recognition as a promising ex vivo model for cancer research, offering advantages over traditional 2D cell lines by better recapitulating tumor biology. In this study, we assess the genomic stability and evolution of PDOs by analyzing copy-number alterations (CNAs) in 261 PDO samples across 15 cancer types. These results are compared with data from previously analyzed patient-derived xenografts (PDXs). We observe that PDOs exhibit genomic evolution over passaging, with an increasing divergence from the original tumor genome over time. Importantly, across cancer types, PDOs maintain higher genomic fidelity and are more genetically similar to their tumors of origin than PDX models. Moreover, PDOs show greater genomic stability during culture passaging compared to PDXs. These findings position PDOs as a potentially more reliable and representative model for cancer research, offering an alternative with better genomic stability for translational studies and drug testing.