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Deterministic evolution and stringent selection during preneoplasia.

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Karlsson, Kasper 
Przybilla, Moritz J  ORCID logo
Xu, Hang 


The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention1. Here we model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over 2 years. TP53 loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single-cell sequencing of TP53-deficient gastric organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programmes repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a marked degree of phenotypic convergence in premalignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and show evolutionary constraints and barriers to malignant transformation, with implications for earlier detection and interception of aggressive, genome-instable tumours.


Acknowledgements: We thank Z. Hu, S. Tilk, L. Attardi and A. Bhatt for helpful discussions, the Stanford University Hospital Tissue Procurement Shared Resource facility for specimen procurement and the Stanford Functional Genomics Core for assistance with sequencing. This work was supported by the US Department of Health & Human Services National Institutes of Health Director’s Pioneer Award (no. DP1-CA238296) to C.C. and a National Cancer Institute Cancer Target Discovery and Development Center (no. U01-CA217851) to C.J.K. and C.C. K. Karlsson was supported in part by a Swedish Research Council (Ventenskapsradet) International postdoctoral grant (no. 2018-00454).


Humans, Cell Transformation, Neoplastic, Clonal Evolution, Genomic Instability, Mutation, Stomach Neoplasms, Selection, Genetic, Precancerous Conditions, Organoids, Aneuploidy, DNA Copy Number Variations, Single-Cell Analysis, Tumor Suppressor Protein p53, Disease Progression, Cell Lineage

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Springer Science and Business Media LLC