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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
- Source :
- Oncotarget, 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, vol. 9, no. 17, pp. 13834-13847 . https://doi.org/10.18632/oncotarget.24481
- Publication Year :
- 2018
- Publisher :
- Impact Journals LLC, 2018.
-
Abstract
- BackgroundBRAF 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.Patients and methodsWe 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.ResultsHigh 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.ConclusionsThese 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.Key MessageUsing a combination of computational biology discovery and immunohistochemistry validation in independent patient cohorts, we show that high expression of the apoptosis regulator Bcl-xL is associated with disease relapse specifically within BRAF mutant stage II/III colon cancer.This data could enable tailored disease management to reduce relapse rates in the most aggressive subtype.
- Subjects :
- Oncology
medicine.medical_specialty
education.field_of_study
molecular stratification
Bcl-xL
Colorectal cancer
Proportional hazards model
business.industry
Population
Disease
relapse risk
medicine.disease
Colon cancer
Gene expression profiling
Molecular stratification
Relapse risk
colon cancer
Internal medicine
Genotype
Gene expression
Cohort
medicine
gene expression profiling
Immunohistochemistry
education
business
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 19492553
- Volume :
- 9
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....ea8f2c98e348d1ec4c9c6d4d725396ec