Dataset Information

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.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.

SUBMITTER: Brastianos PK

PROVIDER: S-EPMC4916970 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Brastianos Priscilla K PK Carter Scott L SL Santagata Sandro S Cahill Daniel P DP Taylor-Weiner Amaro A Jones Robert T RT Van Allen Eliezer M EM Lawrence Michael S MS Horowitz Peleg M PM Cibulskis Kristian K Ligon Keith L KL Tabernero Josep J Seoane Joan J Martinez-Saez Elena E Curry William T WT Dunn Ian F IF Paek Sun Ha SH Park Sung-Hye SH McKenna Aaron A Chevalier Aaron A Rosenberg Mara M Barker Frederick G FG Gill Corey M CM Van Hummelen Paul P Thorner Aaron R AR Johnson Bruce E BE Hoang Mai P MP Choueiri Toni K TK Signoretti Sabina S Sougnez Carrie C Rabin Michael S MS Lin Nancy U NU Winer Eric P EP Stemmer-Rachamimov Anat A Meyerson Matthew M Garraway Levi L Gabriel Stacey S Lander Eric S ES Beroukhim Rameen R Batchelor Tracy T TT Baselga Jose J Louis David N DN Getz Gad G Hahn William C WC

Cancer discovery 20150926 11

<h4>Unlabelled</h4>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 potenti ...[more]

PMID: 26410082

Similar Datasets

Project description:Metastatic spine disease is a heterogeneous clinical condition commonly requiring surgical intervention. Despite this heterogeneity, all cases share the common theme of altered tumor metabolism, characterized by aerobic glycolysis and high lactate production. Here we review the existing literature on lactate metabolism as it pertains to tumor progression, metastasis, and the formation of painful bone lesions. We included articles from the English literature addressing the role of lactate metabolism in the following: (I) primary tumor aggressiveness, (II) local tissue invasion, (III) metastasis formation, and (IV) generation of oncologic pain. We also report current investigations into restoring normal lactate metabolism as a means of impeding tumor growth and the formation of bony metastases. Both in vivo and in vitro experiments suggest that high lactate levels may be necessary for tumor cell growth, as small molecules inhibitors of lactate dehydrogenase (LDH5/LDHA) decrease both the rate of tumor growth and formation of metastases. Additionally, in vitro evidence strongly implicates lactate in tumor cell migration by driving the amoeboid movements of these cells. Acidification of the local bony tissue by excess lactate production activates CGRP+ neurons in the bone marrow and periosteum to generate oncologic bone pain. High lactate may also increase expression of acid sensing receptors in these neurons to generate the neuropathic pain seen in some patients with metastatic disease. Lastly, investigation into lactate-directed therapeutics is still early in development. Initial preclinical trials looking at LDH5/LDHA inhibitors as well as inhibitors of lactate transporters (MCT1) have demonstrated promise, but clinical work has been restricted to a single phase I trial. Lactate appears to play a crucial role in the pathogenesis of metastatic spine disease. Efforts are ongoing to identify small molecules inhibitors of targets in the lactogenic pathway capable of preventing the formation of osseous metastatic disease.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets