Proteogenomics connects somatic mutations to signalling in breast cancer
Somatic mutations have been extensively characterized in breast cancer, but the
effects of these genetic alterations on the proteomic landscape remain poorly
understood. Here we describe quantitative mass-spectrometry-based proteomic and
phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77
provided high-quality data. Integrated analyses provided insights into the somatic
cancer genome including the consequences of chromosomal loss, such as the 5q
deletion characteristic of basal-like breast cancer. Interrogation of the 5q
trans-effects against the Library of Integrated Network-based Cellular
Signatures, connected loss of CETN3 and SKP1 to elevated expression of
epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC
tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of
proteins in addition to basal and luminal clusters, and pathway analysis of the
phosphoproteome identified a G-protein-coupled receptor cluster that was not readily
identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly
phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2.
We demonstrate that proteogenomic analysis of breast cancer elucidates the
functional consequences of somatic mutations, narrows candidate nominations for
driver genes within large deletions and amplified regions, and identifies
therapeutic targets.
Nature doi: 10.1038/nature18003
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