{"corpus_id":9880383,"paper_sha":"2a4e179b839156f521c3d3fa2335f8b1cade5426","doi":"10.1158/2159-8290.CD-15-0369","arxiv_id":null,"pmid":26410082,"pmcid":"PMC4916970","mag_id":2790576709,"dblp_id":null,"acl_id":null,"title":"Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets.","year":2015,"publication_date":"2015-09-01","venue":"Cancer Discovery","journal":{"name":"Cancer discovery","pages":"\n          1164-1177\n        ","volume":"5 11"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, N.I.H., Extramural","Research Support, Non-U.S. Gov't"],"s2_fields_of_study":["Biology","Medicine"],"reference_count":54,"citation_count":901,"influential_citation_count":33,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Brain Neoplasms","mj":false,"qs":[{"q":"diagnosis","mj":false,"ui":"Q000175"},{"q":"drug therapy","mj":false,"ui":"Q000188"},{"q":"genetics","mj":true,"ui":"Q000235"},{"q":"secondary","mj":true,"ui":"Q000556"}],"ui":"D001932"},{"d":"Cluster Analysis","mj":false,"ui":"D016000"},{"d":"Disease Progression","mj":false,"ui":"D018450"},{"d":"Drug Resistance, Neoplasm","mj":false,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"}],"ui":"D019008"},{"d":"Exome","mj":false,"ui":"D059472"},{"d":"Genetic Heterogeneity","mj":false,"ui":"D018740"},{"d":"Genetic Variation","mj":false,"ui":"D014644"},{"d":"Genome-Wide Association Study","mj":false,"ui":"D055106"},{"d":"High-Throughput Nucleotide Sequencing","mj":false,"ui":"D059014"},{"d":"Humans","mj":false,"ui":"D006801"},{"d":"Lymph Nodes","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"},{"q":"pathology","mj":false,"ui":"Q000473"}],"ui":"D008198"},{"d":"Molecular Targeted Therapy","mj":false,"ui":"D058990"},{"d":"Mutation","mj":false,"ui":"D009154"},{"d":"Neoplasms","mj":false,"qs":[{"q":"genetics","mj":true,"ui":"Q000235"},{"q":"metabolism","mj":false,"ui":"Q000378"},{"q":"pathology","mj":true,"ui":"Q000473"}],"ui":"D009369"},{"d":"Signal Transduction","mj":false,"qs":[{"q":"drug effects","mj":false,"ui":"Q000187"}],"ui":"D015398"}],"chemicals":null,"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"https://cancerdiscovery.aacrjournals.org/content/candisc/5/11/1164.full.pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/21e131b59e4000ad741f23df45e107a641fd7af2","s2_open_access_license":null,"s2_open_access_status":"BRONZE","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"UNLABELLED: Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases. SIGNIFICANCE: Decisions for individualized therapies in patients with brain metastasis are often made from primary-tumor biopsies. We demonstrate that clinically actionable alterations present in brain metastases are frequently not detected in primary biopsies, suggesting that sequencing of primary biopsies alone may miss a substantial number of opportunities for targeted therapy.","claims":[{"public_id":"cl_8725573026ae54c9e6a72b3f4b524e71","status":"active","text":"Alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors were detected in brain metastases, indicating that primary biopsies alone may miss opportunities for targeted therapy.","confidence":0.96,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_8725573026ae54c9e6a72b3f4b524e71"},{"public_id":"cl_61839e962a238473549899c3b0e84399","status":"active","text":"Clonally related cancer samples from brain metastases and primary tumors exhibit branched evolution from a common ancestor with independent continued evolution at each site.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_61839e962a238473549899c3b0e84399"},{"public_id":"cl_0a5cb90d7f1a7543e5a8cf975cd8c3ae","status":"active","text":"Distal extracranial metastases and regional lymph node metastases were highly divergent from brain metastases.","confidence":0.95,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_0a5cb90d7f1a7543e5a8cf975cd8c3ae"},{"public_id":"cl_54fbafa6060763c1af9d85b5b9719efc","status":"active","text":"Potentially clinically informative alterations were present in brain metastases but absent from matched primary-tumor samples in 53% of cases.","confidence":0.97,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_54fbafa6060763c1af9d85b5b9719efc"},{"public_id":"cl_fe5c70804228fc87dd5c41cca80663f8","status":"active","text":"Spatially and temporally separated brain metastasis sites were genetically homogeneous.","confidence":0.94,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_fe5c70804228fc87dd5c41cca80663f8"}],"concepts":[{"public_id":"co_1e0599e6d36216680b679e451f6cf2d8","status":"active","name":"regional lymph node metastases","description":"Metastatic lesions found in lymph nodes near the primary tumor region.","types":["metastasis"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous 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