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Concomitant dysregulation of the estrogen receptor and BRAF/MEK signaling pathways is common in colorectal cancer and predicts a worse prognosis

  • Dingxie LiuEmail author
Original Paper
  • 49 Downloads

Abstract

Purpose

Recurrence is a major cause of colorectal cancer (CRC)-related death. As yet, the accurate identification of CRC patients at high risk of recurrence is still a major clinical challenge. Previously, we found that an estrogen receptor (ER) pathway gene signature may predict disease recurrence in CRC patients. The aim of this study is to evaluate the potential application of additional pathway-specific gene signatures in the prediction of CRC recurrence.

Methods

The activities of 26 cancer-related pathways in CRC were semi-quantified using gene signature-based Bayesian binary regression analysis, and putative associations of the pathways with cancer recurrence risk were assessed using survival analysis.

Results

Among the 26 pathways tested, inactivation of the estrogen receptor (ER) pathway was found to be one of the most common events in CRC. Inactivation of this pathway was found to be frequently accompanied by over-activation of the BRAF/MEK pathway, and these two pathways were found to be associated with opposite effects on several clinicopathological CRC features, including microsatellite instability, subsite location, advanced stage and recurrence. Survival analysis of four independent CRC patient cohorts revealed that while the BRAF/MEK pathway was more strongly associated with recurrence than the ER pathway in mixed-stage CRCs, the ER pathway was a better predictor of recurrence than the BRAF/MEK pathway in stage II CRC. A combined use of these two pathways improved the prediction of CRC recurrence in both mixed stage CRC (n = 1122; overall HR: 2.518, 95% CI: 1.570–4.038, p < 0.001) and stage II CRC (n = 535; overall HR: 1.976, 95% CI: 1.306–2.989, p = 0.001).

Conclusions

Combined activity of the ER and BRAF/MEK pathways may represent a novel biomarker for CRC prognosis and clinical management.

Keywords

Colorectal cancer Recurrence Estrogen receptor pathway BRAF/MEK pathway BRAF mutation Gene signature 

Notes

Acknowledgements

I want to thank Dr. Jeffrey T Chang from The University of Texas Health Science Center at Houston for his valuable suggestions on BinReg-based pathway activity analysis.

Compliance with ethical standards

Conflict of interest

None declared.

Supplementary material

13402_2018_420_MOESM1_ESM.docx (3.8 mb)
ESM 1 (DOCX 3915 kb)
13402_2018_420_MOESM2_ESM.xlsx (17 kb)
ESM 2 (XLSX 16 kb)

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Copyright information

© International Society for Cellular Oncology 2019

Authors and Affiliations

  1. 1.Bluewater Biotech LLCNew ProvidenceUSA
  2. 2.Division of Endocrinology, Diabetes & Metabolism, Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA

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