BRAF V600E mutant colorectal cancer subtypes based on gene expression

Barras, D; Missiaglia, E; Wirapati, P; Sieber, OM; Jorissen, RN; Love, C; Molloy, PL; Jones, IT; McLaughlin, S; Gibbs, P; Guinney, J; Simon, IM; Roth, A; Bosman, FT; Tejpar, S; Delorenzi, M

Author(s): Barras, D; Missiaglia, E; Wirapati, P; Sieber, OM; Jorissen, RN; Love, C; Molloy, PL; Jones, IT; McLaughlin, S; Gibbs, P; Guinney, J; Simon, IM; Roth, A; Bosman, FT; Tejpar, S; Delorenzi, M;
Details: Publication Year 2017,Volume 23,Issue #1,Page 104-115
Journal Title: Clinical Cancer Research
Publication Type: Journal Article
Abstract: PURPOSE: Mutation of BRAF at the valine 600 residue occurs in ~10% of colorectal cancers (CRC), a group with particularly poor prognosis. The response of BRAF mutant CRC to recent targeted strategies such as anti-BRAF or combinations with MEK and EGFR inhibitors remains minimal and highly heterogeneous within BRAF V600E cohorts. There is clearly an unmet need in understanding the biology of BRAF V600E CRC 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 while 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 CRC. 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.
Publisher: AACR
Research Division(s): Systems Biology And Personalised Medicine
PubMed ID: 27354468
Publisher's Version: https://doi.org/10.1158/1078-0432.CCR-16-0140
NHMRC Grants: NHMRC/1050177, NHMRC/1062226,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2016-08-09 12:01:44

Last Modified: 2018-07-04 03:24:27