Robust identification of target genes and outliers in triple-negative breast cancer data

© The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Correct classification of breast cancer subtypes is of high importance as it directly affects the therapeutic options. We focus on triple-negative breast cancer which has the worst prognosis among breast cancer types. Using cutting edge methods from the field of robust statistics, we analyze Breast Invasive Carcinoma transcriptomic data publicly available from The Cancer Genome Atlas data portal. Our analysis identifies statistical outliers that may correspond to misdiagnosed patients. Furthermore, it is illustrated that classical statistical methods may fail to identify outliers due to their heavy influence, prompting the need for robust statistics. Using robust sparse logistic regression we obtain 36 relevant genes, of which ca. 60% have been previously reported as biologically relevant to triple-negative breast cancer, reinforcing the validity of the method. The remaining 14 genes identified are new potential biomarkers for triple-negative breast cancer. Out of these, JAM3, SFT2D2, and PAPSS1 were previously associated to breast tumors or other types of cancer. The relevance of these genes is confirmed by the new DetectDeviatingCells outlier detection technique. A comparison of gene networks on the selected genes showed significant differences between triple-negative breast cancer and non-triple-negative breast cancer data. The individual role of FOXA1 in triple-negative breast cancer and non-triple-negative breast cancer, and the strong FOXA1-AGR2 connection in triple-negative breast cancer stand out. The goal of our paper is to contribute to the breast cancer/triple-negative breast cancer understanding and management. At the same time it demonstrates that robust regression and outlier detection constitute key strategies to cope with high-dimensional clinical data such as omics data.This work was supported by the International Funds KU Leuven (grant C16/15/068); the European Union Horizon 2020 research and innovation program (grant no. 633974 (SOUND project)), and the Portuguese Foundation for Science & Technology (FCT), through projects UID/EMS/50022/2013 (IDMEC, LAETA), UID/CEC/50021/2013 (INESC-ID), PTDC/EMS-SIS/0642/2014, and IF/00653/2012. The computational resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by the Flemish Research Foundation (FWO) and the Flemish Government, department EWI