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

Research output: Contribution to journalArticle

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 - Jan 1 2018

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Adjuvant Chemotherapy
Colonic Neoplasms
Biomarkers
Recurrence
Neoplasms
Gene Expression
Proteins
Survival
Research Design
Immunohistochemistry
Genotype
Apoptosis
Mutation
Population

Keywords

  • Bcl-xL
  • Colon cancer
  • Gene expression profiling
  • Molecular stratification
  • Relapse risk

ASJC Scopus subject areas

  • Oncology

Cite this

Dunne, P. D., Coleman, H. G., Bankhead, P., Alderdice, M., Gray, R. T., McQuaid, S., ... Lawler, M. (2018). Bcl-xL as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in BRAF-mutant stage II and III colon cancer. Oncotarget, 9(17), 13834-13847. https://doi.org/10.18632/oncotarget.24481

Bcl-xL as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in BRAF-mutant stage II and III colon cancer. / Dunne, Philip D.; Coleman, Helen G.; Bankhead, Peter; Alderdice, Matthew; Gray, Ronan T.; McQuaid, Stephen; Bingham, Victoria; Loughrey, Maurice B.; James, Jacqueline A.; McCorry, Amy M.B.; Gilmore, Alan; Holohan, Caitriona; Klingbiel, Dirk; Tejpar, Sabine; Johnston, Patrick G.; McArt, Darragh G.; Di Nicolantonio, Federica; Longley, Daniel B.; Lawler, Mark.

In: Oncotarget, Vol. 9, No. 17, 01.01.2018, p. 13834-13847.

Research output: Contribution to journalArticle

Dunne, PD, Coleman, HG, Bankhead, P, Alderdice, M, Gray, RT, McQuaid, S, Bingham, V, Loughrey, MB, James, JA, McCorry, AMB, Gilmore, A, Holohan, C, Klingbiel, D, Tejpar, S, Johnston, PG, McArt, DG, Di Nicolantonio, F, Longley, DB & Lawler, M 2018, 'Bcl-xL as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in BRAF-mutant stage II and III colon cancer', Oncotarget, vol. 9, no. 17, pp. 13834-13847. https://doi.org/10.18632/oncotarget.24481
Dunne, Philip D. ; Coleman, Helen G. ; Bankhead, Peter ; Alderdice, Matthew ; Gray, Ronan T. ; McQuaid, Stephen ; Bingham, Victoria ; Loughrey, Maurice B. ; James, Jacqueline A. ; McCorry, Amy M.B. ; Gilmore, Alan ; Holohan, Caitriona ; Klingbiel, Dirk ; Tejpar, Sabine ; Johnston, Patrick G. ; McArt, Darragh G. ; Di Nicolantonio, Federica ; Longley, Daniel B. ; Lawler, Mark. / Bcl-xL as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in BRAF-mutant stage II and III colon cancer. In: Oncotarget. 2018 ; Vol. 9, No. 17. pp. 13834-13847.
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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.",
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T1 - Bcl-xL as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in BRAF-mutant stage II and III colon cancer

AU - Dunne, Philip D.

AU - Coleman, Helen G.

AU - Bankhead, Peter

AU - Alderdice, Matthew

AU - Gray, Ronan T.

AU - McQuaid, Stephen

AU - Bingham, Victoria

AU - Loughrey, Maurice B.

AU - James, Jacqueline A.

AU - McCorry, Amy M.B.

AU - Gilmore, Alan

AU - Holohan, Caitriona

AU - Klingbiel, Dirk

AU - Tejpar, Sabine

AU - Johnston, Patrick G.

AU - McArt, Darragh G.

AU - Di Nicolantonio, Federica

AU - Longley, Daniel B.

AU - Lawler, Mark

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Bcl-xL

KW - Colon cancer

KW - Gene expression profiling

KW - Molecular stratification

KW - Relapse risk

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