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Yan, Helen H N; Siu, Hoi Cheong; Ho, Siu Lun; Yue, Sarah S K; Gao, Yang; Tsui, Wai Yin; Chan, Dessy; Chan, April S; Wong, Jason W H; Man, Alice H Y; Lee, Bernard C H; Chan, Annie S Y; Chan, Anthony K W; Hui, Ho Sang; Cheung, Arthur K L; Law, Wai Lun; Lo, Oswens S H; Yuen, Siu Tsan; Clevers, Hans; Leung, Suet Yi
Gut, 12/2020, Letnik: 69, Številka: 12Journal Article
Sporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs. We established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed. We observed a striking diversity of molecular phenotypes, including fusions. Transcriptionally, fusion organoids resembled normal colon organoids and were distinct from mutant organoids, with high and low expression. Single cell transcriptome analysis confirmed the similarity between fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of in normal human colon organoids led to upregulation of PTK7 protein and suppression of , but less so with an engineered mutation. The frequent co-occurrence of fusions with or mutation was confirmed in TCGA database searches. mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time. These organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.
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Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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