Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets.

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

Brastianos PK#1,2,3,4,5, Carter SL#6,5, Santagata S7,8, Cahill DP9, Taylor-Weiner A5, Jones RT4,10, Van Allen EM4,5, Lawrence MS5, Horowitz PM11, Cibulskis K5, Ligon KL4,8, Tabernero J12, Seoane J12, Martinez-Saez E13, Curry WT9, Dunn IF11, Paek SH14, Park SH14, McKenna A5, Chevalier A5, Rosenberg M5, Barker FG 2nd9, Gill CM3, Van Hummelen P4,10, Thorner AR4,10, Johnson BE4, Hoang MP15, Choueiri TK4, Signoretti S8, Sougnez C5, Rabin MS4, Lin NU4, Winer EP4, Stemmer-Rachamimov A15, Meyerson M4,10,5,8, Garraway L4,6,5, Gabriel S5, Lander ES5, Beroukhim R4,7,5, Batchelor TT2, Baselga J16, Louis DN15, Getz G#15,3,5, Hahn WC#4,10,5.

Cancer Discov. 2015 Nov;5(11):1164-1177. doi: 10.1158/2159-8290.CD-15-0369. Epub 2015 Sep 26.