Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets
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- 1 November 2015
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 5 (11), 1164-1177
- https://doi.org/10.1158/2159-8290.cd-15-0369
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. 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. Cancer Discov; 5(11); 1164–77. ©2015 AACR. See related commentary by Stricker and Arteaga, p. 1124. This article is highlighted in the In This Issue feature, p. 1111Keywords
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This publication has 54 references indexed in Scilit:
- Melanoma Brain Metastases and Vemurafenib: Need for Further InvestigationMayo Clinic Proceedings, 2012
- Mutational Processes Molding the Genomes of 21 Breast CancersCell, 2012
- Distant metastasis occurs late during the genetic evolution of pancreatic cancerNature, 2010
- The patterns and dynamics of genomic instability in metastatic pancreatic cancerNature, 2010
- Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trialThe Lancet, 2010
- Genome remodelling in a basal-like breast cancer metastasis and xenograftNature, 2010
- Somatic Mutations in p85α Promote Tumorigenesis through Class IA PI3K ActivationCancer Cell, 2009
- Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancersNature Medicine, 2008
- Comprehensive genomic characterization defines human glioblastoma genes and core pathwaysNature, 2008
- Postoperative Radiotherapy in the Treatment of Single Metastases to the BrainJAMA, 1998