Analysis of copy number loss of the ErbB4 receptor tyrosine kinase in glioblastoma.

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Given the severity of GBM and the limitations of its treatment, there is a need for the discovery of novel drug targets for GBM and more personalized treatment approaches based on the characteristics of an individual's tumor. Most receptor tyrosine kinases-such as EGFR-act as oncogenes, but publicly available data from the Cancer Cell Line Encyclopedia (CCLE) indicates copy number loss in the ERBB4 RTK gene across dozens of GBM cell lines, suggesting a potential tumor suppressor role. This loss is mutually exclusive with loss of its cognate ligand NRG1 in CCLE as well, more strongly suggesting a functional role. The availability of higher resolution copy number data from clinical GBM patients in The Cancer Genome Atlas (TCGA) revealed that a region in Intron 1 of the ERBB4 gene was deleted in 69.1% of tumor samples harboring ERBB4 copy number loss; however, it was also found to be deleted in the matched normal tissue samples from these GBM patients (n = 81). Using the DECIPHER Genome Browser, we also discovered that this mutation occurs at approximately the same frequency in the general population as it does in the disease population. We conclude from these results that this loss in Intron 1 of the ERBB4 gene is neither a de novo driver mutation nor a predisposing factor to GBM, despite the indications from CCLE. A biological role of this significantly occurring genetic alteration is still unknown. While this is a negative result, the broader conclusion is that while copy number data from large cell line-based data repositories may yield compelling hypotheses, careful follow up with higher resolution copy number assays, patient data, and general population analyses are essential to codify initial hypotheses prior to investing experimental resources.", "claims": [{"id": "claim-data-access", "statement": "All downloaded data from CCLE and TCGA can be found in S1 Table.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:29342193", "locator": "sections[3] \"Data curation\" paragraph 2", "quote": "All downloaded data from CCLE and TCGA can be found in S1 Table."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Analysis of publicly available copy-number data from CCLE, TCGA, and DECIPHER showed that ERBB4 intron 1 copy-number loss is neither a de novo GBM driver mutation nor a predisposing factor to GBM, and its biological role remains unknown.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:29342193", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "We conclude from these results that this loss in Intron 1 of the ERBB4 gene is neither a de novo driver mutation nor a predisposing factor to GBM, despite the indications from CCLE."}, {"asset": "source:pmid:29342193", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "A biological role of this significantly occurring genetic alteration is still unknown."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "Analysis of publicly available copy-number data from CCLE, TCGA, and DECIPHER showed that ERBB4 intron 1 copy-number loss is neither a de novo GBM driver mutation nor a predisposing factor to GBM, and its biological role remains unknown.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:29342193"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "blocked", "blocked_on": "data:accession_absent", "description": "The GEO series accession resolves and its sample accessions are listed. 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