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. 2018 Feb 13;9(17):13834-13847.
doi: 10.18632/oncotarget.24481. eCollection 2018 Mar 2.

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  1 , Helen G Coleman  1   2 , Peter Bankhead  1 , Matthew Alderdice  1 , Ronan T Gray  2 , Stephen McQuaid  1 , Victoria Bingham  1 , Maurice B Loughrey  2 , Jacqueline A James  1 , Amy M B McCorry  1 , Alan Gilmore  1 , Caitriona Holohan  1 , Dirk Klingbiel  3   4 , Sabine Tejpar  5 , Patrick G Johnston  1 , Darragh G McArt  1 , Federica Di Nicolantonio  6   7 , Daniel B Longley  1 , Mark Lawler  1
Affiliations

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 et al. Oncotarget. .

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.

Keywords: Bcl-xL; colon cancer; gene expression profiling; molecular stratification; relapse risk.

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Conflict of interest statement

CONFLICTS OF INTEREST None.

Figures

Figure 1
Figure 1. Relapse risk analysis of BRAFMT tumors indicates that Bcl-xL gene expression is associated with prognosis in BRAFMT tumors
(A) BCL2L1 (Bcl-xL) was represented by 3 individual probesets in relapse risk analysis in BRAFMT tumors. (B and C) Relapse-free survival (RFS) curve using Kaplan-Meier estimation in the “Initial Consolidation” dataset comparing tertile stratified Bcl-xL gene expression levels in all BRAFMT (A) and untreated BRAFMT (B) stage II/III CRC patients. Unadjusted and adjusted HR statistics are detailed in Table 3.
Figure 2
Figure 2. Optimization of immunohistochemistry staining protocol for Bcl-xL protein expression in CC
(A) Whole-face CC tissue sections were used to optimize IHC protocol. A low level of protein expression was observed in the normal glands compared to surrounding stroma (Blue box) Elevated levels of expression were observed in neoplastic glands compared to both the normal glands and surrounding stroma (Red box). Some staining in the stroma is evident in both normal and cancer-associated regions. (B) Representative images of high, medium and low Bcl-xL protein expression by IHC in an independent “Northern Ireland cohort” of stage II/III CRC (Northern Ireland cohort; n = 740).
Figure 3
Figure 3. Independent validation of the prognostic value of Bcl-xL protein expression in BRAFMT CC
(A) Colorectal cancer disease-specific survival (DSS) curve using Kaplan-Meier estimation in the “Northern Ireland cohort” comparing tertiles stratification of Bcl-xL protein expression (by IHC H-score) in untreated BRAFMT stage II/III CC patients. (B) DSS of patients in the highest tertile of Bcl-xL protein expression stratified according to adjuvant chemotherapy treatment received. (C) DSS of patients in the lowest tertile of Bcl-xL protein expression stratified according to adjuvant chemotherapy treatment received. Unadjusted and adjusted HR statistics are detailed in Table 4.
See this image and copyright information in PMC

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