Methylation-to-Expression Feature Models of Breast Cancer Accurately Predict Overall Survival, Distant-Recurrence Free Survival, and Pathologic Complete Response in Multiple Cohorts

• Type of Material: Article
• Authors: Jeffrey Thompson, University of Kansas; Brock C. Christensen, Dartmouth College; Carmen Marsit, Emory University
• Language: English
• Date: 2018-03-26
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-018-23494-0
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 8
• Issue: 1
• Start Page: 5190
• End Page: 5190
• Grant/Funding Information: The analyses described in this report were supported by NIH grants R01ES022223, P30CA138292, P30ES019776, and R01DE022772.
• Keywords: THERAPIES; Science & Technology - Other Topics; Science & Technology; CHEMOTHERAPY; PACKAGE; BIOMARKER; Multidisciplinary Sciences; SUBTYPES; GENE-EXPRESSION
• Research Categories: Health Sciences, Public Health; Health Sciences, Epidemiology

Abstract

Prognostic biomarkers serve a variety of purposes in cancer treatment and research, such as prediction of cancer progression, and treatment eligibility. Despite growing interest in multi-omic data integration for defining prognostic biomarkers, validated methods have been slow to emerge. Given that breast cancer has been the focus of intense research, it is amenable to studying the benefits of multi-omic prognostic models due to the availability of datasets. Thus, we examined the efficacy of our methylation-to-expression feature model (M2EFM) approach to combining molecular and clinical predictors to create risk scores for overall survival, distant metastasis, and chemosensitivity in breast cancer. Gene expression, DNA methylation, and clinical variables were integrated via M2EFM to build models of overall survival using 1028 breast tumor samples and applied to validation cohorts of 61 and 327 samples. Models of distant recurrence-free survival and pathologic complete response were built using 306 samples and validated on 182 samples. Despite different populations and assays, M2EFM models validated with good accuracy (C-index or AUC ≥ 0.7) for all outcomes and had the most consistent performance compared to other methods. Finally, we demonstrated that M2EFM identifies functionally relevant genes, which could be useful in translating an M2EFM biomarker to the clinic.