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dc.date.accessioned2019-06-03T06:00:19Z
dc.date.available2019-06-03T06:00:19Z
dc.date.created2019-01-17T13:23:14Z
dc.date.issued2018
dc.identifier.citationDomingo, Enric Camps, C Kaisaki, Pamela J Parsons, Marie J Mouradov, Dmitri Pentony, Melissa M Makino, S Palmieri, Michelle Ward, Robyn L. Hawkins, Nicholas J. Gibbs, Peter Askautrud, Hanne Arenberg Oukrif, Dahmane Wang, Haitao Wood, J. Tomlinson, E. Bark, Yasmine Kaur, Kulvinder Johnstone, E.C. Palles, Claire Church, David N. Novelli, Marco Danielsen, Håvard Emil Sherlock, Jon Kerr, David Kerr, Rachel Sieber, Oliver Taylor, JC Tomlinson, Ian . Mutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: results from the UASAR 2 clinical trial and an Australian community-based series. The Lancet Gastroenterology and Hepatology. 2018
dc.identifier.urihttp://hdl.handle.net/10852/68199
dc.description.abstractBackground: Molecular indicators of colorectal cancer prognosis have been assessed in several studies, but most analyses have been restricted to a handful of markers. We aimed to identify prognostic biomarkers for colorectal cancer by sequencing panels of multiple driver genes. Methods: In stage II or III colorectal cancers from the QUASAR 2 open-label randomised phase 3 clinical trial and an Australian community-based series, we used targeted next-generation sequencing of 82 and 113 genes, respectively, including the main colorectal cancer drivers. We investigated molecular pathways of tumorigenesis, and analysed individual driver gene mutations, combinations of mutations, or global measures such as microsatellite instability (MSI) and mutation burden (total number of non-synonymous mutations and coding indels) for associations with relapse-free survival in univariable and multivariable models, principally Cox proportional hazards models. Findings: In QUASAR 2 (511 tumours), TP53, KRAS, BRAF, and GNAS mutations were independently associated with shorter relapse-free survival (p<0·035 in all cases), and total somatic mutation burden with longer survival (hazard ratio [HR] 0·81 [95% CI 0·68–0·96]; p=0·014). MSI was not independently associated with survival (HR 1·12 [95% CI 0·57–2·19]; p=0·75). We successfully validated these associations in the Australian sample set (296 tumours). In a combined analysis of both the QUASAR 2 and the Australian sample sets, mutation burden was also associated with longer survival (HR 0·84 [95% CI 0·74–0·94]; p=0·004) after exclusion of MSI-positive and POLE mutant tumours. In an extended analysis of 1732 QUASAR 2 and Australian colorectal cancers for which KRAS, BRAF, and MSI status were available, KRAS and BRAF mutations were specifically associated with poor prognosis in MSI-negative cancers. MSI-positive cancers with KRAS or BRAF mutations had better prognosis than MSI-negative cancers that were wild-type for KRAS or BRAF. Mutations in the genes NF1 and NRAS from the MAPK pathway co-occurred, and mutations in the DNA damage-response genes TP53 and ATM were mutually exclusive. We compared a prognostic model based on the gold standard of clinicopathological variables and MSI with our new model incorporating clinicopathological variables, mutation burden, and driver mutations in KRAS, BRAF, and TP53. In both QUASAR 2 and the Australian cohort, our new model was significantly better (p=0·00004 and p=0·0057, respectively, based on a likelihood ratio test). Interpretation: Multigene panels identified two previously unreported prognostic associations in colorectal cancer involving TP53 mutation and total mutation burden, and confirmed associations with KRAS and BRAF. Even a modest-sized gene panel can provide important information for use in clinical practice and outperform MSI-based prognostic models.
dc.languageEN
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleMutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: results from the UASAR 2 clinical trial and an Australian community-based series
dc.typeJournal article
dc.creator.authorDomingo, Enric
dc.creator.authorCamps, C
dc.creator.authorKaisaki, Pamela J
dc.creator.authorParsons, Marie J
dc.creator.authorMouradov, Dmitri
dc.creator.authorPentony, Melissa M
dc.creator.authorMakino, S
dc.creator.authorPalmieri, Michelle
dc.creator.authorWard, Robyn L.
dc.creator.authorHawkins, Nicholas J.
dc.creator.authorGibbs, Peter
dc.creator.authorAskautrud, Hanne Arenberg
dc.creator.authorOukrif, Dahmane
dc.creator.authorWang, Haitao
dc.creator.authorWood, J.
dc.creator.authorTomlinson, E.
dc.creator.authorBark, Yasmine
dc.creator.authorKaur, Kulvinder
dc.creator.authorJohnstone, E.C.
dc.creator.authorPalles, Claire
dc.creator.authorChurch, David N.
dc.creator.authorNovelli, Marco
dc.creator.authorDanielsen, Håvard Emil
dc.creator.authorSherlock, Jon
dc.creator.authorKerr, David
dc.creator.authorKerr, Rachel
dc.creator.authorSieber, Oliver
dc.creator.authorTaylor, JC
dc.creator.authorTomlinson, Ian
cristin.unitcode185,15,5,51
cristin.unitnameForskningsgruppen for digital signalbehandling og bildeanalyse
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1
dc.identifier.cristin1659340
dc.identifier.bibliographiccitationinfo:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=The Lancet Gastroenterology and Hepatology&rft.volume=&rft.spage=&rft.date=2018
dc.identifier.jtitleThe Lancet Gastroenterology and Hepatology
dc.identifier.doi10.1016/S2468-1253(18)30117-1
dc.identifier.urnURN:NBN:no-71361
dc.type.documentTidsskriftartikkel
dc.type.peerreviewedPeer reviewed
dc.source.issn2468-1253
dc.identifier.fulltextFulltext https://www.duo.uio.no/bitstream/handle/10852/68199/2/30042065_PIIS2468125318301171.pdf
dc.type.versionPublishedVersion


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