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Identification of a Poor-Prognosis BRAF-Mutant–Like Population of Patients With Colon Cancer
Open accessAbstract
Purpose: Our purpose was development and assessment of a BRAF-mutant gene expression signature for colon cancer (CC) and the study of its prognostic implications. Materials and Methods: A set of 668 stage II and III CC samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial were used to assess differential gene expression between c.1799T>A (p.V600E) BRAF mutant and non-BRAF, non-KRAS mutant cancers (double wild type) and to construct a gene expression–based classifier for detecting BRAF mutant samples with high sensitivity. The classifier was validated in independent data sets, and survival rates were compared between classifier positive and negative tumors. Results: A 64 gene-based classifier was developed with 96% sensitivity and 86% specificity for detecting BRAF mutant tumors in PETACC-3 and independent samples. A subpopulation of BRAF wild-type patients (30% of KRAS mutants, 13% of double wild type) showed a gene expression pattern and had poor overall survival and survival after relapse, similar to those observed in BRAF-mutant patients. Thus they form a distinct prognostic subgroup within their mutation class. Conclusion: A characteristic pattern of gene expression is associated with and accurately predicts BRAF mutation status and, in addition, identifies a population of BRAF mutated-like KRAS mutants and double wild-type patients with similarly poor prognosis. This suggests a common biology between these tumors and provides a novel classification tool for cancers, adding prognostic and biologic information that is not captured by the mutation status alone. These results may guide therapeutic strategies for this patient segment and may help in population stratification for clinical trials.
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A recent report highlighted gene expression similarities in KRAS-mutant and BRAF-mutant colorectal cancers, underscoring overlap in signaling downstream from these mutant oncogenes.
“a recent report highlighted gene expression similarities in these two genetically distinct MT CRCs, underscoring the overlap in signaling downstream from these mutant oncogenes (18).”
From mTOR Inhibition Specifically Sensitizes Colorectal Cancers with KRAS or BRAF Mutations to BCL-2/BCL-XL Inhibition by Suppressing MCL-1 (2014) · cites this paper as [18]
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Metadata
- Authors
- Popovici, V., Budinska, E., Tejpar, S., Weinrich, S., Estrella, H., Hodgson, G., Van Cutsem, E., Xie, T., Bosman, F. T., Roth, A. D., & Delorenzi, M.
- Affiliations
- SIB Swiss Institute of Bioinformatics (CH)
- Vlad Popovici, Eva Budinska, and Mauro Delorenzi, Swiss Institute of Bioinformatics; Fred T. Bosman and Mauro Delorenzi, Lausanne University Medical Center, Lausanne; Arnaud D. Roth, Geneva University Hospital, Geneva; Arnaud D. Roth, The Swiss Group for Clinical Cancer Research, Bern, Switzerland; Sabine Tejpar and Eric Van Cutsem, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium; and Scott Weinrich, Heather Estrella, Graeme Hodgson, and Tao Xie, Pfizer, La Jolla, CA.
- Venue
- Journal of Clinical Oncology
- Published
- 2012-04-20
- Volume
- 30
- Issue
- 12
- Pages
- 1288-1295
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2118017554
- Cited by
- 236
- References
- 4
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 23 · 2020: 33 · 2019: 15 · 2018: 20 · 2017: 18 · 2016: 17 · 2015: 20 · 2014: 16 · 2013: 28 · 2012: 19
- FWCI
- 13.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Fondation Medic
- Vlaamse regering
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- colon cancer, BRAF mutation, gene expression signatures, prognostic factors, KRAS mutation, overall survival, relapse, stage II and III colon cancer, molecular classification, patient stratification
- MeSH terms
- Aged, Aged, 80 and over, Colonic Neoplasms, Female, Humans, Male, Middle Aged, Mutation, Neoplasm Staging, Predictive Value of Tests, Prospective Studies, Proto-Oncogene Proteins, Reproducibility of Results, Cohort Studies, Gene Expression Regulation, Neoplastic, Proportional Hazards Models, Survival Analysis, Proto-Oncogene Proteins p21(ras), Risk Assessment, Disease-Free Survival, ras Proteins, Genetic Predisposition to Disease, Proto-Oncogene Proteins B-raf
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