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The era of big data and precision medicine has led to accumulation of massive datasets of gene expression data and clinical information of patients. For a new patient, we propose that identification of a highly similar reference patient from an existing patient database via similarity matching of both clinical and expression data could be useful for predicting the prognostic risk or therapeutic efficacy.Here, we propose a novel methodology to predict disease/treatment outcome via analysis of the similarity between any pair of patients who are each characterized by a certain set of pre-defined biological variables (biomarkers or clinical features) represented initially as a prognostic binary variable vector (PBVV) and subsequently transformed to a prognostic signature vector (PSV). Our analyses revealed that Euclidean distance rather correlation distance measure was effective in defining an unbiased similarity measure calculated between two PSVs.We implemented our methods to high-grade serous ovarian cancer (HGSC) based on a 36-mRNA predictor that was previously shown to stratify patients into 3 distinct prognostic subgroups. We studied and revealed that patient's age, when converted into binary variable, was positively correlated with the overall risk of succumbing to the disease. When applied to an independent testing dataset, the inclusion of age into the molecular predictor provided more robust personalized prognosis of overall survival correlated with the therapeutic response of HGSC and provided benefit for treatment targeting of the tumors in HGSC patients.Finally, our method can be generalized and implemented in many other diseases to accurately predict personalized patients' outcomes. ASTAR (Agency for Sci., Tech. and Research, S’pore) Published version

More than 30% of human protein-coding genes form hereditary complex genome architectures composed of sense-antisense (SA) gene pairs (SAGPs) transcribing their RNAs from both strands of a given locus. Such architectures represent important novel components of genome complexity contributing to gene expression deregulation in cancer cells. Therefore, the architectures might be involved in cancer pathways and, in turn, be used for novel drug targets discovery. However, the global roles of SAGPs in cancer pathways has not been studied. Here we investigated SAGPs associated with breast cancer (BC)-related pathways using systems biology, prognostic survival and experimental methods. Gene expression analysis identified 73 BC-relevant SAGPs that are highly correlated in BC. Survival modelling and metadata analysis of the 1161 BC patients allowed us to develop a novel patient prognostic grouping method selecting the 12 survival-significant SAGPs. The qRT-PCR-validated 12-SAGP prognostic signature reproducibly stratified BC patients into low- and high-risk prognostic subgroups. The 1381 SAGP-defined differentially expressed genes common across three studied cohorts were identified. The functional enrichment analysis of these genes revealed the GABPA gene network, including BC-relevant SAGPs, specific gene sets involved in cell cycle, spliceosomal and proteasomal pathways. The co-regulatory function of GABPA in BC cells was supported using siRNA knockdown studies. Thus, we demonstrated SAGPs as the synergistically functional genome architectures interconnected with cancer-related pathways and associated with BC patient clinical outcomes. Taken together, SAGPs represent an important component of genome complexity which can be used to identify novel aspects of coordinated pathological gene networks in cancers. ASTAR (Agency for Sci., Tech. and Research, S’pore) Published version