Genomic and prognostic heterogeneity among RAS/BRAFV600E/TP53 co‐mutated resectable colorectal liver metastases
Hepatic resection is potentially curative for patients with colorectal liver metastases, but the treatment benefit varies. KRAS/NRAS (RAS)/TP53 co‐mutations are associated with a poor prognosis after resection, but there is large variation in patient outcome within the mutation groups, and genetic t...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-04-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.12885 |
| _version_ | 1819076713074655232 |
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| author | Kaja C. G. Berg Tuva H. Brunsell Anita Sveen Sharmini Alagaratnam Merete Bjørnslett Merete Hektoen Kristoffer W. Brudvik Bård I. Røsok Bjørn Atle Bjørnbeth Arild Nesbakken Ragnhild A. Lothe |
| author_facet | Kaja C. G. Berg Tuva H. Brunsell Anita Sveen Sharmini Alagaratnam Merete Bjørnslett Merete Hektoen Kristoffer W. Brudvik Bård I. Røsok Bjørn Atle Bjørnbeth Arild Nesbakken Ragnhild A. Lothe |
| author_sort | Kaja C. G. Berg |
| collection | DOAJ |
| description | Hepatic resection is potentially curative for patients with colorectal liver metastases, but the treatment benefit varies. KRAS/NRAS (RAS)/TP53 co‐mutations are associated with a poor prognosis after resection, but there is large variation in patient outcome within the mutation groups, and genetic testing is currently not used to evaluate benefit from surgery. We have investigated the potential for improved prognostic stratification by combined biomarker analysis with DNA copy number aberrations (CNAs), and taking tumor heterogeneity into account. We determined the mutation status of RAS, BRAFV600, and TP53 in 441 liver lesions from 171 patients treated by partial hepatectomy for metastatic colorectal cancer. CNAs were profiled in 232 tumors from 67 of the patients. Mutations and high‐level amplifications of cancer‐critical genes, the latter including ERBB2 and EGFR, were predominantly homogeneous within patients. RAS/BRAFV600E and TP53 co‐mutations were associated with a poor patient outcome (hazard ratio, HR, 3.9, 95% confidence interval, CI, 1.3–11.1, P = 0.012) in multivariable analyses with clinicopathological variables. The genome‐wide CNA burden and intrapatient intermetastatic CNA heterogeneity varied within the mutation groups, and the CNA burden had prognostic associations in univariable analysis. Combined prognostic analyses of RAS/BRAFV600E/TP53 mutations and CNAs, either as a high CNA burden or high intermetastatic CNA heterogeneity, identified patients with a particularly poor outcome (co‐mutation/high CNA burden: HR 2.7, 95% CI 1.2–5.9, P = 0.013; co‐mutation/high CNA heterogeneity: HR 2.5, 95% CI 1.1–5.6, P = 0.022). In conclusion, DNA copy number profiling identified genomic and prognostic heterogeneity among patients with resectable colorectal liver metastases with co‐mutated RAS/BRAFV600E/TP53. |
| first_indexed | 2024-12-21T18:45:40Z |
| format | Article |
| id | doaj.art-d2dbfb57bdf24a8294717b68cf6264b2 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-21T18:45:40Z |
| publishDate | 2021-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-d2dbfb57bdf24a8294717b68cf6264b22022-12-21T18:53:54ZengWileyMolecular Oncology1574-78911878-02612021-04-0115483084510.1002/1878-0261.12885Genomic and prognostic heterogeneity among RAS/BRAFV600E/TP53 co‐mutated resectable colorectal liver metastasesKaja C. G. Berg0Tuva H. Brunsell1Anita Sveen2Sharmini Alagaratnam3Merete Bjørnslett4Merete Hektoen5Kristoffer W. Brudvik6Bård I. Røsok7Bjørn Atle Bjørnbeth8Arild Nesbakken9Ragnhild A. Lothe10Department of Molecular Oncology Institute for Cancer Research Oslo University Hospital NorwayDepartment of Molecular Oncology Institute for Cancer Research Oslo University Hospital NorwayDepartment of Molecular Oncology Institute for Cancer Research Oslo University Hospital NorwayDepartment of Molecular Oncology Institute for Cancer Research Oslo University Hospital NorwayDepartment of Molecular Oncology Institute for Cancer Research Oslo University Hospital NorwayDepartment of Molecular Oncology Institute for Cancer Research Oslo University Hospital NorwayK.G.Jebsen Colorectal Cancer Research Centre Division for Cancer Medicine Oslo University Hospital NorwayK.G.Jebsen Colorectal Cancer Research Centre Division for Cancer Medicine Oslo University Hospital NorwayK.G.Jebsen Colorectal Cancer Research Centre Division for Cancer Medicine Oslo University Hospital NorwayK.G.Jebsen Colorectal Cancer Research Centre Division for Cancer Medicine Oslo University Hospital NorwayDepartment of Molecular Oncology Institute for Cancer Research Oslo University Hospital NorwayHepatic resection is potentially curative for patients with colorectal liver metastases, but the treatment benefit varies. KRAS/NRAS (RAS)/TP53 co‐mutations are associated with a poor prognosis after resection, but there is large variation in patient outcome within the mutation groups, and genetic testing is currently not used to evaluate benefit from surgery. We have investigated the potential for improved prognostic stratification by combined biomarker analysis with DNA copy number aberrations (CNAs), and taking tumor heterogeneity into account. We determined the mutation status of RAS, BRAFV600, and TP53 in 441 liver lesions from 171 patients treated by partial hepatectomy for metastatic colorectal cancer. CNAs were profiled in 232 tumors from 67 of the patients. Mutations and high‐level amplifications of cancer‐critical genes, the latter including ERBB2 and EGFR, were predominantly homogeneous within patients. RAS/BRAFV600E and TP53 co‐mutations were associated with a poor patient outcome (hazard ratio, HR, 3.9, 95% confidence interval, CI, 1.3–11.1, P = 0.012) in multivariable analyses with clinicopathological variables. The genome‐wide CNA burden and intrapatient intermetastatic CNA heterogeneity varied within the mutation groups, and the CNA burden had prognostic associations in univariable analysis. Combined prognostic analyses of RAS/BRAFV600E/TP53 mutations and CNAs, either as a high CNA burden or high intermetastatic CNA heterogeneity, identified patients with a particularly poor outcome (co‐mutation/high CNA burden: HR 2.7, 95% CI 1.2–5.9, P = 0.013; co‐mutation/high CNA heterogeneity: HR 2.5, 95% CI 1.1–5.6, P = 0.022). In conclusion, DNA copy number profiling identified genomic and prognostic heterogeneity among patients with resectable colorectal liver metastases with co‐mutated RAS/BRAFV600E/TP53.https://doi.org/10.1002/1878-0261.12885colorectal liver metastasesDNA copy number aberrationsgene mutationstumor heterogeneity |
| spellingShingle | Kaja C. G. Berg Tuva H. Brunsell Anita Sveen Sharmini Alagaratnam Merete Bjørnslett Merete Hektoen Kristoffer W. Brudvik Bård I. Røsok Bjørn Atle Bjørnbeth Arild Nesbakken Ragnhild A. Lothe Genomic and prognostic heterogeneity among RAS/BRAFV600E/TP53 co‐mutated resectable colorectal liver metastases Molecular Oncology colorectal liver metastases DNA copy number aberrations gene mutations tumor heterogeneity |
| title | Genomic and prognostic heterogeneity among RAS/BRAFV600E/TP53 co‐mutated resectable colorectal liver metastases |
| title_full | Genomic and prognostic heterogeneity among RAS/BRAFV600E/TP53 co‐mutated resectable colorectal liver metastases |
| title_fullStr | Genomic and prognostic heterogeneity among RAS/BRAFV600E/TP53 co‐mutated resectable colorectal liver metastases |
| title_full_unstemmed | Genomic and prognostic heterogeneity among RAS/BRAFV600E/TP53 co‐mutated resectable colorectal liver metastases |
| title_short | Genomic and prognostic heterogeneity among RAS/BRAFV600E/TP53 co‐mutated resectable colorectal liver metastases |
| title_sort | genomic and prognostic heterogeneity among ras brafv600e tp53 co mutated resectable colorectal liver metastases |
| topic | colorectal liver metastases DNA copy number aberrations gene mutations tumor heterogeneity |
| url | https://doi.org/10.1002/1878-0261.12885 |
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