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 | |
| Publication status | Published - Jan 1 2018 |
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Keywords
- Bcl-xL
- Colon cancer
- Gene expression profiling
- Molecular stratification
- Relapse risk
ASJC Scopus subject areas
- Oncology
Cite this
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 journal › Article
}
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 - 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
UR - http://www.scopus.com/inward/record.url?scp=85042713510&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042713510&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.24481
DO - 10.18632/oncotarget.24481
M3 - Article
AN - SCOPUS:85042713510
VL - 9
SP - 13834
EP - 13847
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 17
ER -