BRAF V600E mutant colorectal cancer subtypes based on gene expression

David Barras, Edoardo Missiaglia, Pratyaksha Wirapati, Oliver M. Sieber, Robert Jorissen, Chris Love, Peter L. Molloy, Ian T. Jones, Stephen McLaughlin, Peter Gibbs, Justin Guinney, Iris M. Simon, Arnaud D. Roth, Fred T. Bosman, Sabine Tejpar, Mauro Delorenzi

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Purpose: Mutation of BRAF at the valine 600 residue occurs in approximately 10% of colorectal cancers, a group with particularly poor prognosis. The response of BRAF mutant colorectal cancer to recent targeted strategies such as anti-BRAF or combinations with MEK and EGFR inhibitors remains limited and highly heterogeneous within BRAF V600E cohorts. There is clearly an unmet need in understanding the biology of BRAF V600E colorectal cancers and potential subgroups within this population. Experimental Design: In the biggest yet reported cohort of 218 BRAF V600E with gene expression data,we performed unsupervised clustering using non-negative matrix factorization to identify gene expression-based subgroups and characterized pathway activation. Results: We found strong support for a split into two distinct groups, called BM1 and BM2. These subtypes are independent of MSI status, PI3K mutation, gender, and sidedness. Pathway analyses revealed that BM1 is characterized by KRAS/AKT pathway activation, mTOR/4EBP deregulation, and EMT whereas BM2 displays important deregulation of the cell cycle. Proteomics data validated these observations as BM1 is characterized by high phosphorylation levels of AKT and 4EBP1, and BM2 patients display high CDK1 and low cyclin D1 levels. We provide a global assessment of gene expression motifs that differentiate BRAF V600E subtypes from other colorectal cancers. Conclusions: We suggest that BRAF mutant patients should not be considered as having a unique biology and provide an in depth characterization of heterogeneous motifs that may be exploited for drug targeting.

LanguageEnglish
Pages104-115
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Barras, D., Missiaglia, E., Wirapati, P., Sieber, O. M., Jorissen, R., Love, C., ... Delorenzi, M. (2017). BRAF V600E mutant colorectal cancer subtypes based on gene expression. Clinical Cancer Research, 23(1), 104-115. https://doi.org/10.1158/1078-0432.CCR-16-0140
Barras, David ; Missiaglia, Edoardo ; Wirapati, Pratyaksha ; Sieber, Oliver M. ; Jorissen, Robert ; Love, Chris ; Molloy, Peter L. ; Jones, Ian T. ; McLaughlin, Stephen ; Gibbs, Peter ; Guinney, Justin ; Simon, Iris M. ; Roth, Arnaud D. ; Bosman, Fred T. ; Tejpar, Sabine ; Delorenzi, Mauro. / BRAF V600E mutant colorectal cancer subtypes based on gene expression. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 1. pp. 104-115.
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abstract = "Purpose: Mutation of BRAF at the valine 600 residue occurs in approximately 10{\%} of colorectal cancers, a group with particularly poor prognosis. The response of BRAF mutant colorectal cancer to recent targeted strategies such as anti-BRAF or combinations with MEK and EGFR inhibitors remains limited and highly heterogeneous within BRAF V600E cohorts. There is clearly an unmet need in understanding the biology of BRAF V600E colorectal cancers and potential subgroups within this population. Experimental Design: In the biggest yet reported cohort of 218 BRAF V600E with gene expression data,we performed unsupervised clustering using non-negative matrix factorization to identify gene expression-based subgroups and characterized pathway activation. Results: We found strong support for a split into two distinct groups, called BM1 and BM2. These subtypes are independent of MSI status, PI3K mutation, gender, and sidedness. Pathway analyses revealed that BM1 is characterized by KRAS/AKT pathway activation, mTOR/4EBP deregulation, and EMT whereas BM2 displays important deregulation of the cell cycle. Proteomics data validated these observations as BM1 is characterized by high phosphorylation levels of AKT and 4EBP1, and BM2 patients display high CDK1 and low cyclin D1 levels. We provide a global assessment of gene expression motifs that differentiate BRAF V600E subtypes from other colorectal cancers. Conclusions: We suggest that BRAF mutant patients should not be considered as having a unique biology and provide an in depth characterization of heterogeneous motifs that may be exploited for drug targeting.",
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Barras, D, Missiaglia, E, Wirapati, P, Sieber, OM, Jorissen, R, Love, C, Molloy, PL, Jones, IT, McLaughlin, S, Gibbs, P, Guinney, J, Simon, IM, Roth, AD, Bosman, FT, Tejpar, S & Delorenzi, M 2017, 'BRAF V600E mutant colorectal cancer subtypes based on gene expression', Clinical Cancer Research, vol. 23, no. 1, pp. 104-115. https://doi.org/10.1158/1078-0432.CCR-16-0140

BRAF V600E mutant colorectal cancer subtypes based on gene expression. / Barras, David; Missiaglia, Edoardo; Wirapati, Pratyaksha; Sieber, Oliver M.; Jorissen, Robert; Love, Chris; Molloy, Peter L.; Jones, Ian T.; McLaughlin, Stephen; Gibbs, Peter; Guinney, Justin; Simon, Iris M.; Roth, Arnaud D.; Bosman, Fred T.; Tejpar, Sabine; Delorenzi, Mauro.

In: Clinical Cancer Research, Vol. 23, No. 1, 01.01.2017, p. 104-115.

Research output: Contribution to journalArticle

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T1 - BRAF V600E mutant colorectal cancer subtypes based on gene expression

AU - Barras, David

AU - Missiaglia, Edoardo

AU - Wirapati, Pratyaksha

AU - Sieber, Oliver M.

AU - Jorissen, Robert

AU - Love, Chris

AU - Molloy, Peter L.

AU - Jones, Ian T.

AU - McLaughlin, Stephen

AU - Gibbs, Peter

AU - Guinney, Justin

AU - Simon, Iris M.

AU - Roth, Arnaud D.

AU - Bosman, Fred T.

AU - Tejpar, Sabine

AU - Delorenzi, Mauro

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Purpose: Mutation of BRAF at the valine 600 residue occurs in approximately 10% of colorectal cancers, a group with particularly poor prognosis. The response of BRAF mutant colorectal cancer to recent targeted strategies such as anti-BRAF or combinations with MEK and EGFR inhibitors remains limited and highly heterogeneous within BRAF V600E cohorts. There is clearly an unmet need in understanding the biology of BRAF V600E colorectal cancers and potential subgroups within this population. Experimental Design: In the biggest yet reported cohort of 218 BRAF V600E with gene expression data,we performed unsupervised clustering using non-negative matrix factorization to identify gene expression-based subgroups and characterized pathway activation. Results: We found strong support for a split into two distinct groups, called BM1 and BM2. These subtypes are independent of MSI status, PI3K mutation, gender, and sidedness. Pathway analyses revealed that BM1 is characterized by KRAS/AKT pathway activation, mTOR/4EBP deregulation, and EMT whereas BM2 displays important deregulation of the cell cycle. Proteomics data validated these observations as BM1 is characterized by high phosphorylation levels of AKT and 4EBP1, and BM2 patients display high CDK1 and low cyclin D1 levels. We provide a global assessment of gene expression motifs that differentiate BRAF V600E subtypes from other colorectal cancers. Conclusions: We suggest that BRAF mutant patients should not be considered as having a unique biology and provide an in depth characterization of heterogeneous motifs that may be exploited for drug targeting.

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