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Mutational order shapes cell state and chromatin accessibility during early colorectal cancer evolution

Using CRISPR mediated gene editing in patient-derived human colon organoids, we investigate how mutational order shapes cell state and downstream phenotype. We find that loss of FBXW7 on a wild-type background produces minimal phenotypic or transcriptomic change but induces a subtle shift towards a foetal-like, regenerative stem cell identity. Strikingly, the order of mutation acquisition produces markedly different outcomes. 'FA' organoids (i.e. FBXW7 loss preceding APC mutation) retain a near-normal morphology and transcriptional profile. In contrast, 'AF' organoids adopt a proliferative stem cell state and a more transformed phenotype, despite identical final genotype. These differences were associated with distinct chromatin accessibility landscapes, and reflect a cell state-dependent constraint on the transcriptional consequences of subsequent mutations.

Type: Cancer Genomics
Archive: European Genome-phenome Archive (EGA)

3 Datasets

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD50000002824	Includes 10 unique sample types: wild-type ('WT'), CRISPR-edited: 'F', 'A', 'FA', 'AF', 'AT', 'ATF' and AAVS1, and co-cultured samples: 'F_CoCult' and 'WT_CoCult'. Each sample has 3 replicates. So in total 30 samples	NextSeq 500	30
EGAD50000002825	ATAC-seq carried out in two batches, each with its own matched wild-type ('WT') Batch 1 - 'FA' (FBXW7 followed by APC mut.), 'AF' and 'WT' [3x replicates each] Batch 2 - 'F' and 'A' [3x replicates each], and 'WT', pcw17 and pcw21 foetal [2x replicates each]	NextSeq 2000	30
EGAD50000002826	Single-cell sorted 10xGenomics libraries were sequenced using the 5'-end chemistry. 'F' mutant and 'WT' organoids had 2x replicates each.	NextSeq 2000	4