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

doi: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

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 language	English
Pages (from-to)	13834-13847
Number of pages	14
Journal	Oncotarget
Volume	9
Issue number	17
DOIs	https://doi.org/10.18632/oncotarget.24481
Publication status	Published - 13 Feb 2018

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Bcl-xL as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in BRAF-mutant stage II and III colon cancer
Copyright 2018 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 1.75 MBLicence: CC BY

Defining the clinical importance of epithelial-stroma-immune signalling in colorectal cancer using a molecular pathology approach
McCorry, A. (Author), Lawler, M. (Supervisor), Dunne, P. (Supervisor) & Salto-Tellez, M. (Supervisor), Jul 2021
Student thesis: Doctoral Thesis › Doctor of Philosophy

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Dunne, P. D., Coleman, H. G., Bankhead, P., Alderdice, M., Gray, R. T., McQuaid, S., Bingham, V., Loughrey, M. B., James, J. A., McCorry, A. M. B., Gilmore, A., Holohan, C., Klingbiel, D., Tejpar, S., Johnston, P. G., McArt, D. G., Nicolantonio, F. D., Longley, D. B., & 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

@article{555fe609439c429f8244cbdc6396b70e,

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

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.",

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

year = "2018",

month = feb,

day = "13",

doi = "10.18632/oncotarget.24481",

language = "English",

volume = "9",

pages = "13834--13847",

journal = "Oncotarget",

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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, Nicolantonio, FD, 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

TY - JOUR

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 - Nicolantonio, Federica Di

AU - Longley, Daniel B

AU - Lawler, Mark

PY - 2018/2/13

Y1 - 2018/2/13

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.

U2 - 10.18632/oncotarget.24481

DO - 10.18632/oncotarget.24481

M3 - Article

C2 - 29568398

SN - 1949-2553

VL - 9

SP - 13834

EP - 13847

JO - Oncotarget

JF - Oncotarget

IS - 17

ER -

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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Student theses

Defining the clinical importance of epithelial-stroma-immune signalling in colorectal cancer using a molecular pathology approach

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