Penalized regression elucidates aberration hotspots mediating subtype-specific transcriptional responses in breast cancer

Abstract

Copy number alterations (CNAs) associated with cancer are known to contribute to genomic instability and gene deregulation. Integrating CNAs with gene expression helps to elucidate the mechanisms by which CNAs act and to identify the transcriptional downstream targets of CNAs. Such analyses can help to sort functional driver events from the many accompanying passenger alterations. However, the way CNAs affect gene expression can vary in different cellular contexts, for example between different subtypes of the same cancer. Thus, it is important to develop computational approaches capable of inferring differential connectivity of regulatory networks in different cellular contexts. We propose a statistical deregulation model that integrates copy number and expression data of different disease subtypes to jointly model common and differential regulatory relationships. Our model not only identifies CNAs driving gene expression changes, but at the same time also predicts differences in regulation that distinguish one cancer subtype from the other. We implement our model in a penalized regression framework and demonstrate in a simulation study the feasibility and accuracy of our approach. Subsequently, we show that this model can identify both known and novel aspects of cross-talk between the ER and NOTCH pathways in ER-negative-specific deregulations, when compared with ER-positive breast cancer. This flexible model can be applied on other modalities such as methylation or microRNA and expression to disentangle cancer signaling pathways. The Bioconductor-compliant R package DANCE is available from www.markowetzlab.org/software/ yinyin.yuan@cancer.org.uk; florian.markowetz@cancer.org.uk.