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Mutational landscape of normal epithelial cells in Lynch Syndrome patients.

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cam.issuedOnline2022-05-17
dc.contributor.authorLee, Bernard CH
dc.contributor.authorRobinson, Philip S
dc.contributor.authorCoorens, Tim HH
dc.contributor.authorYan, Helen HN
dc.contributor.authorOlafsson, Sigurgeir
dc.contributor.authorLee-Six, Henry
dc.contributor.authorSanders, Mathijs A
dc.contributor.authorSiu, Hoi Cheong
dc.contributor.authorHewinson, James
dc.contributor.authorYue, Sarah SK
dc.contributor.authorTsui, Wai Yin
dc.contributor.authorChan, Annie SY
dc.contributor.authorChan, Anthony KW
dc.contributor.authorHo, Siu Lun
dc.contributor.authorCampbell, Peter J
dc.contributor.authorMartincorena, Inigo
dc.contributor.authorBuczacki, Simon JA
dc.contributor.authorYuen, Siu Tsan
dc.contributor.authorLeung, Suet Yi
dc.contributor.authorStratton, Michael R
dc.contributor.orcidRobinson, Philip S [0000-0002-6237-7159]
dc.contributor.orcidCoorens, Tim HH [0000-0002-5826-3554]
dc.contributor.orcidYan, Helen HN [0000-0001-5693-8231]
dc.contributor.orcidCampbell, Peter J [0000-0002-3921-0510]
dc.contributor.orcidMartincorena, Inigo [0000-0003-1122-4416]
dc.contributor.orcidLeung, Suet Yi [0000-0001-8614-4619]
dc.contributor.orcidStratton, Michael R [0000-0001-6035-153X]
dc.date.accessioned2022-06-29T19:42:16Z
dc.date.available2022-06-29T19:42:16Z
dc.date.issued2022-05-17
dc.date.updated2022-06-29T19:42:16Z
dc.description.abstractLynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes.
dc.identifier.doi10.17863/CAM.85845
dc.identifier.eissn2041-1723
dc.identifier.issn2041-1723
dc.identifier.other35581206
dc.identifier.otherPMC9114395
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338432
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41467-022-29920-2
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 2041-1723
dc.sourcenlmid: 101528555
dc.subjectColorectal Neoplasms, Hereditary Nonpolyposis
dc.subjectDNA Mismatch Repair
dc.subjectEpithelial Cells
dc.subjectGerm-Line Mutation
dc.subjectHumans
dc.subjectMutation
dc.subjectPhylogeny
dc.titleMutational landscape of normal epithelial cells in Lynch Syndrome patients.
dc.typeArticle
dcterms.dateAccepted2022-04-07
prism.issueIdentifier1
prism.publicationNameNat Commun
prism.volume13
pubs.funder-project-idResearch Grants Council, University Grants Committee (T12-710/16R)
pubs.funder-project-idResearch Grants Council, University Grants Committee (RGC, UGC) (T12-710/16R)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41467-022-29920-2

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