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.
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.
Authors: Oghenekevwe M Gbenedio; Caroline Bonnans; Delphine Grun; Chih-Yang Wang; Ace J Hatch; Michelle R Mahoney; David Barras; Mary Matli; Yi Miao; K Christopher Garcia; Sabine Tejpar; Mauro Delorenzi; Alan P Venook; Andrew B Nixon; Robert S Warren; Jeroen P Roose; Philippe Depeille Journal: JCI Insight Date: 2019-06-25
Authors: Frank A Sinicrope; Michelle R Mahoney; Harry H Yoon; Thomas C Smyrk; Stephen N Thibodeau; Richard M Goldberg; Garth D Nelson; Daniel J Sargent; Steven R Alberts Journal: Clin Cancer Res Date: 2015-07-17 Impact factor: 12.531
Authors: Felipe De Sousa E Melo; Xin Wang; Marnix Jansen; Evelyn Fessler; Anne Trinh; Laura P M H de Rooij; Joan H de Jong; Onno J de Boer; Ronald van Leersum; Maarten F Bijlsma; Hans Rodermond; Maartje van der Heijden; Carel J M van Noesel; Jurriaan B Tuynman; Evelien Dekker; Florian Markowetz; Jan Paul Medema; Louis Vermeulen Journal: Nat Med Date: 2013-04-14 Impact factor: 53.440
Authors: Shuji Ogino; Xiaoyun Liao; Yu Imamura; Mai Yamauchi; Nadine J McCleary; Kimmie Ng; Donna Niedzwiecki; Leonard B Saltz; Robert J Mayer; Renaud Whittom; Alexander Hantel; Al B Benson; Rex B Mowat; Donna Spiegelman; Richard M Goldberg; Monica M Bertagnolli; Jeffrey A Meyerhardt; Charles S Fuchs Journal: J Natl Cancer Inst Date: 2013-11-14 Impact factor: 13.506