Show simple item record

dc.contributor.authorSundar, Raghav
dc.contributor.authorLiu, Drolaiz Hw
dc.contributor.authorHutchins, Gordon Ga
dc.contributor.authorSlaney, Hayley L
dc.contributor.authorSilva, Arnaldo Ns
dc.contributor.authorOosting, Jan
dc.contributor.authorHayden, Jeremy D
dc.contributor.authorHewitt, Lindsay C
dc.contributor.authorNg, Cedric Cy
dc.contributor.authorMangalvedhekar, Amrita
dc.contributor.authorNg, Sarah B
dc.contributor.authorTan, Iain Bh
dc.contributor.authorTan, Patrick
dc.contributor.authorGrabsch, Heike I
dc.date.accessioned2021-10-18T15:28:04Z
dc.date.available2021-10-18T15:28:04Z
dc.date.issued2021-10
dc.date.submitted2020-02-01
dc.identifier.issn0017-5749
dc.identifier.othergutjnl-2020-320805
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/329571
dc.description.abstractOBJECTIVE: Endoscopic mucosal biopsies of primary gastric cancers (GCs) are used to guide diagnosis, biomarker testing and treatment. Spatial intratumoural heterogeneity (ITH) may influence biopsy-derived information. We aimed to study ITH of primary GCs and matched lymph node metastasis (LNmet). DESIGN: GC resection samples were annotated to identify primary tumour superficial (PTsup), primary tumour deep (PTdeep) and LNmet subregions. For each subregion, we determined (1) transcriptomic profiles (NanoString 'PanCancer Progression Panel', 770 genes); (2) next-generation sequencing (NGS, 225 gastrointestinal cancer-related genes); (3) DNA copy number profiles by multiplex ligation-dependent probe amplification (MLPA, 16 genes); and (4) histomorphological phenotypes. RESULTS: NanoString profiling of 64 GCs revealed no differences between PTsup1 and PTsup2, while 43% of genes were differentially expressed between PTsup versus PTdeep and 38% in PTsup versus LNmet. Only 16% of genes were differently expressed between PTdeep and LNmet. Several genes with therapeutic potential (eg IGF1, PIK3CD and TGFB1) were overexpressed in LNmet and PTdeep compared with PTsup. NGS data revealed orthogonal support of NanoString results with 40% mutations present in PTdeep and/or LNmet, but not in PTsup. Conversely, only 6% of mutations were present in PTsup and were absent in PTdeep and LNmet. MLPA demonstrated significant ITH between subregions and progressive genomic changes from PTsup to PTdeep/LNmet. CONCLUSION: In GC, regional lymph node metastases are likely to originate from deeper subregions of the primary tumour. Future clinical trials of novel targeted therapies must consider assessment of deeper subregions of the primary tumour and/or metastases as several therapeutically relevant genes are only mutated, overexpressed or amplified in these regions.
dc.languageen
dc.publisherBMJ
dc.rightsEmbargo: ends 2020-11-23
dc.subjectStomach
dc.subject1506
dc.subject2312
dc.subjectgastric cancer
dc.subjectendoscopy
dc.subjectmolecular pathology
dc.subjecthistopathology
dc.titleSpatial profiling of gastric cancer patient-matched primary and locoregional metastases reveals principles of tumour dissemination.
dc.typeArticle
dc.date.updated2021-10-18T15:28:03Z
prism.endingPage1832
prism.issueIdentifier10
prism.publicationNameGut
prism.startingPage1823
prism.volume70
dc.identifier.doi10.17863/CAM.77019
dcterms.dateAccepted2020-11-05
rioxxterms.versionofrecord10.1136/gutjnl-2020-320805
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by-nc/4.0/
rioxxterms.licenseref.startdate2020-11-23
dc.contributor.orcidSundar, Raghav [0000-0001-9423-1368]
dc.contributor.orcidHutchins, Gordon Ga [0000-0002-1707-4415]
dc.contributor.orcidSilva, Arnaldo Ns [0000-0003-2779-9572]
dc.contributor.orcidOosting, Jan [0000-0001-8894-1742]
dc.contributor.orcidNg, Cedric Cy [0000-0002-7150-4674]
dc.contributor.orcidTan, Patrick [0000-0002-0179-8048]
dc.contributor.orcidGrabsch, Heike I [0000-0001-9520-6228]
dc.identifier.eissn1468-3288
pubs.funder-project-idNational Medical Research Council (OF-LCG18May-0023, TCR/009-NUHS/2013, NR13NMR111OM, MOH-STAR18Nov-0001, NMRC/Fellowship/0059/2018)
pubs.funder-project-idAcademy of Medical Sciences Starter Grant for Clinical Lecturers (SGCL14/GH)
pubs.funder-project-idPathological Society Career Development Fellowship (CDF2015/01)
cam.issuedOnline2020-11-23
rioxxterms.freetoread.startdate2020-11-23


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record