Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles

类有机物 生物 转录组 结直肠癌 Wnt信号通路 癌症研究 微卫星不稳定性 癌症 遗传学 基因 等位基因 微卫星 基因表达
作者
Helen H.N. Yan,Hoi Cheong Siu,Siu Lun Ho,Sarah S K Yue,Yang Gao,Wai Yin Tsui,Dessy Chan,April Chan,Jason W.H. Wong,Alice H Y Man,Bernard C. H. Lee,Annie S Y Chan,Anthony K W Chan,Ho Sang Hui,Arthur Cheung,Wai Lun Law,Oswens Siu‐Hung Lo,Siu Tsan Yuen,Hans Clevers,Suet Yi Leung
出处
期刊:Gut [BMJ]
卷期号:69 (12): 2165-2179 被引量:67
标识
DOI:10.1136/gutjnl-2019-320019
摘要

Objective 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. Design 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. Results We observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2 , but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 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. Conclusions 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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