title: Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, all in Boston.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, all in Boston.|Cancer Center, Massachusetts General Hospital, Harvard Medical School, all in Boston.|Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.initials: PK
authors.lastname: Brastianos
authors.affiliation: Joint Center for Cancer Precision Medicine, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Department of Cancer Biology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Department of Pathology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.lastname: Santagata
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, all in Boston.
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authors.initials: DP
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authors.affiliation: Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.initials: RT
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authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.initials: EM
authors.lastname: Van Allen
authors.affiliation: Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.initials: PM
authors.lastname: Horowitz
authors.affiliation: Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.lastname: Cibulskis
authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Department of Pathology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.initials: KL
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authors.affiliation: Department of Medical Oncology, Department of Pathology, Barcelona - all in Spain.
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authors.affiliation: Department of Medical Oncology, Department of Pathology, Barcelona - all in Spain.
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authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona - all in Spain.
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authors.initials: E
authors.lastname: Martinez-Saez
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, all in Boston.
authors.forename: William T
authors.initials: WT
authors.lastname: Curry
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.initials: IF
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authors.affiliation: Department of Neurosurgery and Department of Pathology, Seoul National University College of Medicine - all in Korea.
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authors.initials: SH
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authors.affiliation: Department of Neurosurgery and Department of Pathology, Seoul National University College of Medicine - all in Korea.
authors.forename: Sung-Hye
authors.initials: SH
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authors.affiliation: Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, all in Boston.
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authors.initials: FG
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authors.affiliation: Cancer Center, Massachusetts General Hospital, Harvard Medical School, all in Boston.
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authors.initials: CM
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authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, all in Boston.
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authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.initials: TK
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authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.initials: MS
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authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.initials: EP
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authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, all in Boston.
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authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Department of Pathology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.lastname: Meyerson
authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Joint Center for Cancer Precision Medicine, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.initials: ES
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authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Department of Cancer Biology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.initials: R
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authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, all in Boston.
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authors.initials: TT
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authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York City.
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authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, all in Boston.
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authors.initials: DN
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authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, all in Boston.|Cancer Center, Massachusetts General Hospital, Harvard Medical School, all in Boston.|Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.|Broad Institute, Brigham and Women's Hospital, Harvard Medical School - all in Boston.
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mesh_terms: D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary*; D016000:Cluster Analysis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects