Establishment and Characterization of 21 Human Colorectal Cancer Patient-Derived Organoids

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Abstract Purpose Colorectal cancer (CRC) is the third leading cause of cancer-related mortalities in Korea. It is also the third most frequently diagnosed malignancy worldwide. To significantly improve its oncologic outcome, there is a need to study the diagnosis and treatment strategies further. Methods We established 21 patients-derived organoids from 20 patients with CRC, and characterized their cellular and molecular features. Whole exome sequencing (WES) was performed for these organoids to obtain mutational profiles. It generally took 3 ~ 4 weeks for organoids to grow enough for DNA/RNA extraction and drug screening. The research protocol was reviewed and approved by the institutional review board of the Seoul National University Hospital (IRB No. 1102-098-357). Results Single nucleotide variations, in-frame deletions and insertions, and splice site mutations of CRC related genes were found and classified based on their existing pathogenicity reports from National Center for Biotechnology Information (NCBI). Heterogeneity was confirmed by comparing the expression of each organoid in the major cancer pathway through RNA sequencing. Also, drug sensitivity assay was performed to measure cell viability after treatment with 24 anti-cancer drugs approved by FDA. Conclusion We used the organoid model to identify tumor heterogeneity through various screening. By integrating mutational profiles of WES, RNA-seq, and drug screening results, we could elucidate which mechanism went wrong. Results suggested that tumor heterogeneity should be considered when using organoids as a preclinical model and that organoids are a suitable platform for use in precision medicine. Organoid model is meaningful because we can figure out what therapy will be good for a patient in vitro in a few weeks so that clinical application can be suggested.

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