دورية أكاديمية
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
| العنوان: | 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 |
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| المؤلفون: | Domingo, 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 |
| المصدر: | 2468-1253. |
| سنة النشر: | 2019 |
| المجموعة: | Universitet i Oslo: Digitale utgivelser ved UiO (DUO) |
| الوصف: | Background: 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | http://urn.nb.no/URN:NBN:no-71361Test; Domingo, 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; http://hdl.handle.net/10852/68199Test; 1659340; info: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; The Lancet Gastroenterology and Hepatology; URN:NBN:no-71361; Fulltext https://www.duo.uio.no/bitstream/handle/10852/68199/2/30042065_PIIS2468125318301171.pdfTest |
| DOI: | 10.1016/S2468-1253(18)30117-1 |
| الإتاحة: | https://doi.org/10.1016/S2468-1253Test(18)30117-1 http://hdl.handle.net/10852/68199Test http://urn.nb.no/URN:NBN:no-71361Test |
| حقوق: | Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.3E9C66B3 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/S2468-1253(18)30117-1 |
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