Risk Stratification for Breast Cancer Patient by Simultaneous Learning of Molecular Subtype and Survival Outcome Using Genetic Algorithm-Based Gene Set Selection†

SIMPLE SUMMARY: Patient stratification is clinically important because it allows us to understand the characteristics and establish treatment strategies for a group. Transcriptomic data play an important role in determining molecular subtypes and predicting survival. In the case of breast cancer, although the order of prognosis according to molecular subtypes is well known, there is heterogeneity even within a subtype. Therefore, patient stratification considering both molecular subtypes and survival outcomes is required. In this study, a methodology to handle this problem is presented. A genetic algorithm is used to select a set of genes, and a risk score is assigned to each patient using their expression level. According to the risk score, patients are ordered and stratified considering molecular subtypes and survival outcomes. Consequently, informative genes for patient stratification with respect to both aspects could be nominated, and the usefulness of the risk score was shown through comparison with other indicators. ABSTRACT: Patient stratification is a clinically important task because it allows us to establish and develop efficient treatment strategies for particular groups of patients. Molecular subtypes have been successfully defined using transcriptomic profiles, and they are used effectively in clinical practice, e.g., PAM50 subtypes of breast cancer. Survival prediction contributed to understanding diseases and also identifying genes related to prognosis. It is desirable to stratify patients considering these two aspects simultaneously. However, there are no methods for patient stratification that consider molecular subtypes and survival outcomes at once. Here, we propose a methodology to deal with the problem. A genetic algorithm is used to select a gene set from transcriptome data, and their expression quantities are utilized to assign a risk score to each patient. The patients are ordered and stratified according to the score. A gene set was selected by our method on a breast cancer cohort (TCGA-BRCA), and we examined its clinical utility using an independent cohort (SCAN-B). In this experiment, our method was successful in stratifying patients with respect to both molecular subtype and survival outcome. We demonstrated that the orders of patients were consistent across repeated experiments, and prognostic genes were successfully nominated. Additionally, it was observed that the risk score can be used to evaluate the molecular aggressiveness of individual patients.