De novo individualized disease modules reveal the synthetic penetrance of genes and inform personalized treatment regimens

Current understandings of individual disease etiology and therapeutics are limited despite great need. To fill the gap, we propose a novel computational pipeline that collects potent disease gene cooperative pathways to envision individualized disease etiology and therapies. Our algorithm constructs individualized disease modules de novo, which enables us to elucidate the importance of mutated genes in specific patients and to understand the synthetic penetrance of these genes across patients. We reveal that importance of the notorious cancer drivers TP53 and PIK3CA fluctuate widely across breast cancers and peak in tumors with distinct numbers of mutations and that rarely mutated genes such as XPO1 and PLEKHA1 have high disease module importance in specific individuals. Furthermore, individualized module disruption enables us to devise customized singular and combinatorial target therapies that were highly varied across patients, showing the need for precision therapeutics pipelines. As the first analysis of de novo individualized disease modules, we illustrate the power of individualized disease modules for precision medicine by providing deep novel insights on the activity of diseased genes in individuals.

Automated summary

Despite the limited understanding of individual disease etiology and therapeutics, a novel computational pipeline has been proposed to collect potent disease gene cooperative pathways for individualized disease etiology and therapies. The importance of mutated genes in specific patients and the synthetic penetrance of these genes across patients can be elucidated through individualized disease modules. This study reveals the fluctuation of importance for notorious cancer drivers in breast cancers and the high disease module importance of rarely mutated genes in specific individuals. Furthermore, customized singular and combinatorial target therapies can be devised through individualized module disruption, emphasizing the need for precision therapeutics pipelines. This analysis demonstrates the power of individualized disease modules for precision medicine, offering deep novel insights on the activity of diseased genes in individuals.