File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)

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

TitleOrganoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles
Authors
Keywordscolon carcinogenesis
colorectal cancer
colorectal cancer genes
Early-onset colon cancer
gene expression
Issue Date2020
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
Citation
Gut, 2020, Epub on 2020-03-26 How to Cite?
AbstractObjective: 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.
Persistent Identifierhttp://hdl.handle.net/10722/282491
ISSN
2019 Impact Factor: 19.819
2015 SCImago Journal Rankings: 6.474

 

DC FieldValueLanguage
dc.contributor.authorYan, HHN-
dc.contributor.authorSiu, HC-
dc.contributor.authorHo, SL-
dc.contributor.authorYue, SKS-
dc.contributor.authorGao, Y-
dc.contributor.authorTsui, WY-
dc.contributor.authorChan, D-
dc.contributor.authorChan, AS-
dc.contributor.authorWong, JWH-
dc.contributor.authorMan, AHY-
dc.contributor.authorLee, BCH-
dc.contributor.authorChan, ASY-
dc.contributor.authorChan, AKW-
dc.contributor.authorHui, HS-
dc.contributor.authorCheung, AKL-
dc.contributor.authorLaw, WL-
dc.contributor.authorLo, OSH-
dc.contributor.authorYuen, ST-
dc.contributor.authorClevers, H-
dc.contributor.authorLeung, SY-
dc.date.accessioned2020-05-15T05:28:48Z-
dc.date.available2020-05-15T05:28:48Z-
dc.date.issued2020-
dc.identifier.citationGut, 2020, Epub on 2020-03-26-
dc.identifier.issn0017-5749-
dc.identifier.urihttp://hdl.handle.net/10722/282491-
dc.description.abstractObjective: 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.-
dc.languageeng-
dc.publisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/-
dc.relation.ispartofGut-
dc.rightsGut. Copyright © BMJ Publishing Group.-
dc.rightsThis article has been accepted for publication in [Journal, Year] following peer review, and the Version of Record can be accessed online at [insert full DOI eg. http://dx.doi.org/10.1136/xxxxx]. [© Authors (or their employer(s)) OR © BMJ Publishing Group Ltd ( for assignments of BMJ Case Reports)] <year>-
dc.subjectcolon carcinogenesis-
dc.subjectcolorectal cancer-
dc.subjectcolorectal cancer genes-
dc.subjectEarly-onset colon cancer-
dc.subjectgene expression-
dc.titleOrganoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles-
dc.typeArticle-
dc.identifier.emailYan, HHN: yanhelen@hkucc.hku.hk-
dc.identifier.emailSiu, HC: hcsiu@hku.hk-
dc.identifier.emailGao, Y: ygao0218@HKUCC-COM.hku.hk-
dc.identifier.emailTsui, WY: wtsui112@hkucc.hku.hk-
dc.identifier.emailChan, D: dessyc@hku.hk-
dc.identifier.emailChan, AS: aschan@hku.hk-
dc.identifier.emailWong, JWH: jwhwong@hku.hk-
dc.identifier.emailMan, AHY: alicemhy@hku.hk-
dc.identifier.emailChan, AKW: kwchan@pathology.hku.hk-
dc.identifier.emailHui, HS: hshui@hku.hk-
dc.identifier.emailCheung, AKL: arthurhk@hku.hk-
dc.identifier.emailLaw, WL: lawwl@hkucc.hku.hk-
dc.identifier.emailLo, OSH: oswens@hku.hk-
dc.identifier.emailYuen, ST: styuen@hkucc.hku.hk-
dc.identifier.emailLeung, SY: suetyi@hku.hk-
dc.identifier.authorityYan, HHN=rp01994-
dc.identifier.authorityWong, JWH=rp02363-
dc.identifier.authorityChan, AKW=rp00330-
dc.identifier.authorityCheung, AKL=rp01769-
dc.identifier.authorityLaw, WL=rp00436-
dc.identifier.authorityLeung, SY=rp00359-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1136/gutjnl-2019-320019-
dc.identifier.pmid32217638-
dc.identifier.scopuseid_2-s2.0-85082517481-
dc.identifier.hkuros309947-
dc.identifier.volumeEpub on 2020-03-26-
dc.publisher.placeUnited Kingdom-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats