title: Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases.
abstract: Tumor organoids are 3D cultures of cancer cells. They can be derived from the tumor of each individual patient, thereby providing an attractive ex vivo assay to tailor treatment. Using patient-derived tumor organoids for this purpose requires that organoids derived from biopsies maintain the genetic diversity of the in vivo tumor. In this study tumor biopsies were obtained from 14 patients with metastatic colorectal cancer (i) to test the feasibility of organoid culture from metastatic biopsy specimens and (ii) to compare the genetic diversity of patient-derived tumor organoids and the original tumor biopsy. Genetic analysis was performed using SOLiD sequencing for 1,977 cancer-relevant genes. Copy number profiles were generated from sequencing data using CopywriteR. Here we demonstrate that organoid cultures can be established from tumor biopsies of patients with metastatic colorectal cancer with a success rate of 71%. Genetic analysis showed that organoids reflect the metastasis from which they were derived. Ninety percent of somatic mutations were shared between organoids and biopsies from the same patient, and the DNA copy number profiles of organoids and the corresponding original tumor show a correlation of 0.89. Most importantly, none of the mutations that were found exclusively in either the tumor or organoid culture are in driver genes or genes amenable for drug targeting. These findings support further exploration of patient-derived organoids as an ex vivo platform to personalize anticancer treatment.
authors.affiliation: Department of Molecular Oncology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;
authors.forename: Fleur
authors.initials: F
authors.lastname: Weeber
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, 3584 CT Utrecht, The Netherlands; Cancer Genomics.nl, 3584 CG Utrecht, The Netherlands; Foundation Hubrecht Organoid Technology (HUB), 3584 CT, Utrecht, The Netherlands;
authors.forename: Marc
authors.initials: M
authors.lastname: van de Wetering
authors.affiliation: Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;
authors.forename: Marlous
authors.initials: M
authors.lastname: Hoogstraat
authors.affiliation: Department of Molecular Oncology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;
authors.forename: Krijn K
authors.initials: KK
authors.lastname: Dijkstra
authors.affiliation: Department of Molecular Oncology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;
authors.forename: Oscar
authors.initials: O
authors.lastname: Krijgsman
authors.affiliation: Department of Molecular Oncology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuilman
authors.affiliation: Department of Radiotherapy, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors.forename: Christa G M
authors.initials: CG
authors.lastname: Gadellaa-van Hooijdonk
authors.affiliation: Department of Molecular Oncology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;
authors.forename: Daphne L
authors.initials: DL
authors.lastname: van der Velden
authors.affiliation: Department of Molecular Oncology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Peeper
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, 3584 CT Utrecht, The Netherlands; Cancer Genomics.nl, 3584 CG Utrecht, The Netherlands; Department of Medical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;
authors.forename: Edwin P J G
authors.initials: EP
authors.lastname: Cuppen
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, 3584 CT Utrecht, The Netherlands; Cancer Genomics.nl, 3584 CG Utrecht, The Netherlands; Foundation Hubrecht Organoid Technology (HUB), 3584 CT, Utrecht, The Netherlands;
authors.forename: Robert G
authors.initials: RG
authors.lastname: Vries
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, 3584 CT Utrecht, The Netherlands; Cancer Genomics.nl, 3584 CG Utrecht, The Netherlands; Foundation Hubrecht Organoid Technology (HUB), 3584 CT, Utrecht, The Netherlands; Department of Molecular Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; h.clevers@hubrecht.eu e.voest@nki.nl.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Department of Molecular Oncology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands; Cancer Genomics.nl, 3584 CG Utrecht, The Netherlands; Foundation Hubrecht Organoid Technology (HUB), 3584 CT, Utrecht, The Netherlands; Department of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands h.clevers@hubrecht.eu e.voest@nki.nl.
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
mesh_terms: D024221:Antineoplastic Protocols / Q000592:standards; D001483:Base Sequence; D018929:Cell Culture Techniques / Q000379:methods*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000235:genetics*; D009940:Organoids / Q000737:chemistry / Q000166:cytology* / Q000254:growth & development*; D057285:Precision Medicine / Q000379:methods; D017422:Sequence Analysis, DNA
keywords: DNA sequencing; biopsy-derived tumor organoids; colorectal cancer; copy number analysis; personalized medicine