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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 13/2017

01-12-2017 | Translational Research and Biomarkers

Proteomic Features of Colorectal Cancer Identify Tumor Subtypes Independent of Oncogenic Mutations and Independently Predict Relapse-Free Survival

Authors: Callisia N. Clarke, MD, Michael S. Lee, MD, Wei Wei, PhD, Ganiraju Manyam, PhD, Zhi-Qin Jiang, PhD, Yiling Lu, MD, Jeffrey Morris, PhD, Bradley Broom, PhD, David Menter, PhD, Eduardo Vilar-Sanchez, MD, PhD, Kanwal Raghav, MD, Cathy Eng, MD, George J. Chang, MD, Iris Simon, PhD, Rene Bernards, PhD, Michael Overman, MD, Gordon B. Mills, MD, PhD, Dipen Maru, MD, Scott Kopetz, MD, PhD

Published in: Annals of Surgical Oncology | Issue 13/2017

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Abstract

Background

The directed study of the functional proteome in colorectal cancer (CRC) has identified critical protein markers and signaling pathways; however, the prognostic relevance of many of these proteins remains unclear.

Methods

We determined the prognostic implications of the functional proteome in 263 CRC tumor samples from patients treated at MD Anderson Cancer Center (MDACC) and 462 patients from The Cancer Genome Atlas (TCGA) to identify patterns of protein expression that drive tumorigenesis. A total of 163 validated proteins were analyzed by reverse phase protein array (RPPA). Unsupervised hierarchical clustering of the tumor proteins from the MDACC cohort was performed, and clustering was validated using RPPA data from TCGA CRC. Cox regression was used to identify predictors of tumor recurrence.

Results

Clustering revealed dichotomization, with subtype A notable for a high epithelial-mesenchymal transition (EMT) protein signature, while subtype B was notable for high Akt/TSC/mTOR pathway components. Survival data were only available for the MDACC cohort and were used to evaluate prognostic relevance of these protein signatures. Group B demonstrated worse relapse-free survival (hazard ratio 2.11, 95% confidence interval 1.04–4.27, p = 0.039), although there was no difference in known genomic drivers between the two proteomic groups. Proteomic grouping and stage were significant predictors of recurrence on multivariate analysis. Eight proteins were found to be significant predictors of tumor recurrence on multivariate analysis: Collagen VI, FOXO3a, INPP4B, LcK, phospho-PEA15, phospho-PRAS40, Rad51, phospho-S6.

Conclusion

CRC can be classified into distinct subtypes by proteomic features independent of common oncogenic driver mutations. Proteomic analysis has identified key biomarkers with prognostic importance, however these findings require further validation in an independent cohort.
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Metadata
Title
Proteomic Features of Colorectal Cancer Identify Tumor Subtypes Independent of Oncogenic Mutations and Independently Predict Relapse-Free Survival
Authors
Callisia N. Clarke, MD
Michael S. Lee, MD
Wei Wei, PhD
Ganiraju Manyam, PhD
Zhi-Qin Jiang, PhD
Yiling Lu, MD
Jeffrey Morris, PhD
Bradley Broom, PhD
David Menter, PhD
Eduardo Vilar-Sanchez, MD, PhD
Kanwal Raghav, MD
Cathy Eng, MD
George J. Chang, MD
Iris Simon, PhD
Rene Bernards, PhD
Michael Overman, MD
Gordon B. Mills, MD, PhD
Dipen Maru, MD
Scott Kopetz, MD, PhD
Publication date
01-12-2017
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 13/2017
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-017-6054-5

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