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

被引：804

作者：

Brastianos, Priscilla K. ^{[1
,2
,3
,4
,5
]}

Carter, Scott L. ^{[5
,6
]}

Santagata, Sandro ^{[7
,8
]}

Cahill, Daniel P. ^{[9
]}

Taylor-Weiner, Amaro ^{[5
]}

Jones, Robert T. ^{[4
,10
]}

Van Allen, Eliezer M. ^{[4
,5
]}

Lawrence, Michael S. ^{[5
]}

Horowitz, Peleg M. ^{[11
]}

Cibulskis, Kristian ^{[5
]}

Ligon, Keith L. ^{[4
,8
]}

Tabernero, Josep ^{[12
,13
]}

Seoane, Joan ^{[12
,13
]}

Martinez-Saez, Elena ^{[14
]}

Curry, William T. ^{[9
]}

Dunn, Ian F. ^{[11
]}

Paek, Sun Ha ^{[16
]}

Park, Sung-Hye ^{[15
,16
]}

McKenna, Aaron ^{[5
,15
]}

Chevalier, Aaron ^{[5
]}

Rosenberg, Mara ^{[5
]}

Barker, Frederick G., II ^{[9
]}

Gill, Corey M.

Van Hummelen, Paul ^{[4
,10
]}

Thorner, Aaron R. ^{[4
,10
]}

Johnson, Bruce E. ^{[4
]}

Hoang, Mai P. ^{[17
]}

Choueiri, Toni K. ^{[4
]}

Signoretti, Sabina ^{[8
]}

Sougnez, Carrie ^{[5
]}

Rabin, Michael S. ^{[4
]}

Lin, Nancy U. ^{[4
]}

Winer, Eric P. ^{[4
]}

Stemmer-Rachamimov, Anat ^{[17
]}

Meyerson, Matthew ^{[4
,5
,8
,10
]}

Garraway, Levi ^{[4
,5
,6
]}

Gabriel, Stacey ^{[5
]}

Lander, Eric S. ^{[5
]}

Beroukhim, Rameen ^{[4
,5
,7
]}

Batchelor, Tracy T.

Baselga, Jose ^{[18
]}

Louis, David N. ^{[17
]}

Getz, Gad ^{[3
,5
,17
]}

Hahn, William C. ^{[4
,5
,10
]}

机构：

[1] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA

[2] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Ctr Canc, Massachusetts Gen Hosp, Boston, MA USA

[4] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[5] Broad Inst, Boston, MA USA

[6] Dana Farber Canc Inst, Joint Ctr Canc Precis Med, Boston, MA 02115 USA

[7] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA

[9] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA

[10] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[11] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA USA

[12] Vall dHebron Univ, Dept Med Oncol, Barcelona, Spain

[13] Vall dHebron Univ, Dept Pathol, Barcelona, Spain

[14] Vall dHebron Univ Hosp & Inst Oncol VHIO, Barcelona, Spain

[15] Seoul Natl Univ, Coll Med, Dept Neurosurg, Seoul, South Korea

[16] Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 151, South Korea

[17] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA

[18] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA

来源：

CANCER DISCOVERY | 2015年 / 5卷 / 11期

关键词：

BREAST-CANCER METASTASIS; GROWTH-FACTOR RECEPTOR; DEPENDENT KINASE 4/6; CELL LUNG-CANCER; ANTITUMOR-ACTIVITY; SINGLE METASTASES; PTEN LOSS; INHIBITOR; MUTATIONS; PI3K;

D O I：

10.1158/2159-8290.CD-15-0369

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C)2015 AACR.

引用

页码：1164 / 1177

页数：14

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