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Pan-cancer transcriptional signatures predictive of oncogenic mutations reveal that Fbw7 regulates cancer cell oxidative metabolism.

ABSTRACT: The Fbw7 (F-box/WD repeat-containing protein 7) ubiquitin ligase targets multiple oncoproteins for degradation and is commonly mutated in cancers. Like other pleiotropic tumor suppressors, Fbw7's complex biology has impeded our understanding of how Fbw7 mutations promote tumorigenesis and hindered the development of targeted therapies. To address these needs, we employed a transfer learning approach to derive gene-expression signatures from The Cancer Gene Atlas datasets that predict Fbw7 mutational status across tumor types and identified the pathways enriched within these signatures. Genes involved in mitochondrial function were highly enriched in pan-cancer signatures that predict Fbw7 mutations. Studies in isogenic colorectal cancer cell lines that differed in Fbw7 mutational status confirmed that Fbw7 mutations increase mitochondrial gene expression. Surprisingly, Fbw7 mutations shifted cellular metabolism toward oxidative phosphorylation and caused context-specific metabolic vulnerabilities. Our approach revealed unexpected metabolic reprogramming and possible therapeutic targets in Fbw7-mutant cancers and provides a framework to study other complex, oncogenic mutations.

SUBMITTER: Davis RJ

PROVIDER: S-EPMC6003503 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Pan-cancer transcriptional signatures predictive of oncogenic mutations reveal that Fbw7 regulates cancer cell oxidative metabolism.

Davis Ryan J RJ Gönen Mehmet M Margineantu Daciana H DH Handeli Shlomo S Swanger Jherek J Hoellerbauer Pia P Paddison Patrick J PJ Gu Haiwei H Raftery Daniel D Grim Jonathan E JE Hockenbery David M DM Margolin Adam A AA Clurman Bruce E BE

Proceedings of the National Academy of Sciences of the United States of America 20180507 21

The Fbw7 (F-box/WD repeat-containing protein 7) ubiquitin ligase targets multiple oncoproteins for degradation and is commonly mutated in cancers. Like other pleiotropic tumor suppressors, Fbw7's complex biology has impeded our understanding of how Fbw7 mutations promote tumorigenesis and hindered the development of targeted therapies. To address these needs, we employed a transfer learning approach to derive gene-expression signatures from The Cancer Gene Atlas datasets that predict Fbw7 mutati ...[more]

PMID: 29735700

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Project description:The F-box protein 22 (FBXO22), an F-box E3 ligase, has been identified to be critically involved in carcinogenesis. However, a systematic assessment of the role of FBXO22 across human cancers is lacking. Here, we performed a pan-cancer analysis to explore the role of FBXO22 in 33 cancer types using multiomic data from The Cancer Genome Atlas (TCGA). First, we found that high FBXO22 expression in multiple cancers was closely associated with poor overall survival and relapse-free survival. Next, we identified ten proteins that interact with FBXO22 and 13 of its target substrates using the STRING database and a literature search to explore the regulatory role of FBXO22 in tumorigenesis. Genes encoding these proteins were found to be significantly enriched in cell cycle negative regulation and ubiquitination pathways. This was confirmed in nonsmall cell lung cancer A549 cells, where FBXO22 overexpression enhanced cyclin-dependent kinase 4 (CDK4) protein levels and promoted cell proliferation. Similarly, overexpression or interference of FBXO22 changed the protein level of one of its substrates, PTEN. Additionally, we found that FBXO22 mutations were accompanied by altered substrate expression, especially in uterine corpus endometrial carcinoma and lung adenocarcinoma; endometrial carcinoma patients with FBXO22 genetic alterations also had better overall and relapse-free survival. Notably, FBXO22 methylation levels were also decreased in most tumors, and hypomethylation of FBXO22 was associated with poor overall survival, relapse-free interval, and progression-free interval in pancreatic adenocarcinoma. Finally, we analyzed the correlation between the abundance of tumor infiltrating lymphocytes (TILs) and FBXO22 expression, copy number variation, and methylation. Multiple algorithms revealed that high FBXO22 expression was associated with lower TIL levels, especially in lung adenocarcinoma, lung squamous cell carcinoma, and sarcoma. Taken together, our findings demonstrate that FBXO22 degrades tumor suppressor genes by ubiquitination and inhibits the cell cycle to promote nonsmall cell lung cancer progression. Our study also provides a relatively comprehensive understanding of the oncogenic role of FBXO22 in different tumors.

Project description:BackgroundSomatic alterations in cancer cause dysregulation of signaling pathways that control cell-cycle progression, apoptosis, and cell growth. The effect of individual alterations in these pathways differs between individual tumors and tumor types. Recognizing driver events is a complex task requiring integrating multiple molecular data, including genomics, epigenomics, and functional genomics. A common hypothesis is that these driver events share similar effects on the hallmarks of cancer. The availability of large-scale multi-omics studies allows for inferring these common effects from data. Once these effects are known, one can then deconvolve in every individual patient whether a given genomics alteration is a driver event.MethodsHere, we develop a novel data-driven approach to identify shared oncogenic expression signatures among tumors. We aim to identify gene onco-signature for classifying tumor patients in homogeneous subclasses with distinct prognoses and specific genomic alterations. We derive expression pan-cancer onco-signatures from TCGA gene expression data using a discovery set of 9107 primary pan-tumor samples together with respective matched mutational data and a list of known cancer-related genes from COSMIC database.ResultsWe use the derived ono-signatures to state their prognostic significance and apply them to the TCGA breast cancer dataset as proof of principle of our approach. We uncover a "mitochondrial" sub-group of Luminal patients characterized by its biological features and regulated by specific genetic modulators. Collectively, our results demonstrate the effectiveness of onco-signatures-based methodologies, and they also contribute to a comprehensive understanding of the metabolic heterogeneity of Luminal tumors.ConclusionsThese findings provide novel genomics evidence for developing personalized breast cancer patient treatments. The onco-signature approach, demonstrated here on breast cancer, is general and can be applied to other cancer types.

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Pan-cancer transcriptional signatures predictive of oncogenic mutations reveal that Fbw7 regulates cancer cell oxidative metabolism.

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Pan-cancer transcriptional signatures predictive of oncogenic mutations reveal that Fbw7 regulates cancer cell oxidative metabolism.

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