Bcl-xL as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in BRAF-mutant stage II and III colon cancer

Philip D Dunne, Helen G Coleman, Peter Bankhead, Matthew Alderdice, Ronan T Gray, Stephen McQuaid, Victoria Bingham, Maurice B Loughrey, Jacqueline A James, Amy M B McCorry, Alan Gilmore, Caitriona Holohan, Dirk Klingbiel, Sabine Tejpar, Patrick G Johnston, Darragh G McArt, Federica Di Nicolantonio, Daniel B Longley, Mark Lawler

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Abstract

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.
Original languageEnglish
Pages (from-to)13834-13847
Number of pages14
JournalOncotarget
Volume9
Issue number17
DOIs
Publication statusPublished - 13 Feb 2018

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