RT Journal Article
SR Electronic
T1 Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets
JF Cancer Discovery
JO CANCER DISCOVERY
FD American Association for Cancer Research
DO 10.1158/2159-8290.CD-15-0369
A1 Brastianos, Priscilla K.
A1 Carter, Scott L.
A1 Santagata, Sandro
A1 Cahill, Daniel P.
A1 Taylor-Weiner, Amaro
A1 Jones, Robert T.
A1 Van Allen, Eliezer M.
A1 Lawrence, Michael S.
A1 Horowitz, Peleg M.
A1 Cibulskis, Kristian
A1 Ligon, Keith L.
A1 Tabernero, Josep
A1 Seoane, Joan
A1 Martinez-Saez, Elena
A1 Curry, William T.
A1 Dunn, Ian F.
A1 Paek, Sun Ha
A1 Park, Sung-Hye
A1 McKenna, Aaron
A1 Chevalier, Aaron
A1 Rosenberg, Mara
A1 Barker, Frederick G.
A1 Gill, Corey M.
A1 Van Hummelen, Paul
A1 Thorner, Aaron R.
A1 Johnson, Bruce E.
A1 Hoang, Mai P.
A1 Choueiri, Toni K.
A1 Signoretti, Sabina
A1 Sougnez, Carrie
A1 Rabin, Michael S.
A1 Lin, Nancy U.
A1 Winer, Eric P.
A1 Stemmer-Rachamimov, Anat
A1 Meyerson, Matthew
A1 Garraway, Levi
A1 Gabriel, Stacey
A1 Lander, Eric S.
A1 Beroukhim, Rameen
A1 Batchelor, Tracy T.
A1 Baselga, José
A1 Louis, David N.
A1 Getz, Gad
A1 Hahn, William C.
YR 2015
UL http://cancerdiscovery.aacrjournals.org/content/early/2015/09/23/2159-8290.CD-15-0369.abstract
AB 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); 1–13. ©2015 AACR.