Bcl-xL as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in BRAF-mutant stage II and III colon cancer
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Philip D. Dunne1,*, Helen G. Coleman1,2,*, Peter Bankhead1, Matthew Alderdice1, Ronan T. Gray2, Stephen McQuaid1, Victoria Bingham1, Maurice B. Loughrey2, Jacqueline A. James1, Amy M.B. McCorry1, Alan Gilmore1, Caitriona Holohan1, Dirk Klingbiel3,7, Sabine Tejpar4, Patrick G. Johnston1, Darragh G. McArt1, Federica Di Nicolantonio5,6, Daniel B. Longley1 and Mark Lawler1
1Centre for Cancer Research and Cell Biology, Queens’s University Belfast, Belfast, UK
2Centre for Public Health, Queens’s University Belfast, Belfast, UK
3SAKK Swiss Group for Clinical Cancer Research, Coordinating Center, Bern, Switzerland
4Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium
5University of Turin, Department of Oncology, Candiolo, Turin, Italy
6Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Turin, Italy
7SIB Swiss Institute of Bioinformatics, Bioinformatics Core Facility, University of Lausanne, Lausanne, Switzerland
*Joint first authors
Philip D. Dunne, email: firstname.lastname@example.org
Mark Lawler, email: email@example.com
Keywords: colon cancer; gene expression profiling; molecular stratification; relapse risk; Bcl-xL
Received: January 30, 2018 Accepted: February 05, 2018 Published: February 13, 2018
Purpose: BRAF mutation occurs in 8–15% of colon cancers (CC), and is associated with poor prognosis in metastatic disease. Compared to wild-type BRAF (BRAFWT) disease, stage II/III CC patients with BRAF mutant (BRAFMT) tumors have shorter overall survival after relapse; however, time-to-relapse is not significantly different. The aim of this investigation was to identify, and validate, novel predictors of relapse of stage II/III BRAFMT CC.
Experimental design: We used gene expression data from a cohort of 460 patients (GSE39582) to perform a supervised classification analysis based on risk-of-relapse within BRAFMT stage II/III CC, to identify transcriptomic biomarkers associated with prognosis within this genotype. These findings were validated using immunohistochemistry in an independent population-based cohort of Stage II/III CC (n = 691), applying Cox proportional hazards analysis to determine associations with survival.
Results: High gene expression levels of Bcl-xL, a key regulator of apoptosis, were associated with increased risk of relapse, specifically in BRAFMT tumors (HR = 8.3, 95% CI 1.7–41.7), but not KRASMT/BRAFWT or KRASWT/BRAFWT tumors. High Bcl-xL protein expression in BRAFMT, untreated, stage II/III CC was confirmed to be associated with an increased risk of death in an independent cohort (HR = 12.13, 95% CI 2.49–59.13). Additionally, BRAFMT tumors with high levels of Bcl-xL protein expression appeared to benefit from adjuvant chemotherapy (P for interaction = 0.006), indicating the potential predictive value of Bcl-xL expression in this setting.
Conclusions: These findings provide evidence that Bcl-xL gene and/or protein expression identifies a poor prognostic subgroup of BRAFMT stage II/III CC patients, who may benefit from adjuvant chemotherapy.
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