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Background: Differential expression analysis of (individual) genes is oftenused to study their roles in diseases. However, diseases such as cancer are aresult of the combined effect of multiple genes. Gene products such as proteinsseldom act in isolation, but instead constitute stable multi-protein complexesperforming dedicated functions. Therefore, complexes aggregate the effect ofindividual genes (proteins) and can be used to gain a better understanding ofcancer mechanisms. Here, we observe that complexes show considerable changes intheir expression, in turn directed by the concerted action of transcriptionfactors (TFs), across cancer conditions. We seek to gain novel insights intocancer mechanisms through a systematic analysis of complexes and theirtranscriptional regulation.  Results: We integrated large-scale protein-interaction (PPI) andgene-expression datasets to identify complexes that exhibit significant changesin their expression across different conditions in cancer. We devised alog-linear model to relate these changes to the differential regulation ofcomplexes by TFs. The application of our model on two case studies involvingpancreatic and familial breast tumour conditions revealed: (i) complexes incore cellular processes, especially those responsible for maintaining genomestability and cell proliferation (e.g. DNA damage repair and cell cycle) showconsiderable changes in expression; (ii) these changes include decrease andcountering increase for different sets of complexes indicative of compensatorymechanisms coming into play in tumours; and (iii) TFs work in cooperative andcounteractive ways to regulate these mechanisms. Such aberrant complexes andtheir regulating TFs play vital roles in the initiation and progression ofcancer.

Complex-based analysis of dysregulated cellular processes in cancer