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J Pathol. 2015 Nov;237(3):363-78. doi: 10.1002/path.4583. Epub 2015 Aug 19.

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.

Author information

1
University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia.
2
QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
3
Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
4
Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, UK.
5
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
6
Pathology Queensland, Gold Coast Hospital, Southport, Queensland, Australia.
7
Department of Neurosurgery, Gold Coast Hospital, Southport, Queensland, Australia.
8
Kenneth G Jamieson Department of Neurosurgery, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
9
University of Queensland School of Medicine, Herston, Queensland, Australia.
10
Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
11
Genetic and Molecular Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
12
School of Molecular and Biomedical Science, University of Adelaide, South Australia, Australia.
13
Division of Neurosurgery, Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
14
Breast Unit, Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
15
University Malaya Cancer Research Institute, University of Malaya, Kuala Lumpur, Malaysia.
16
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Selangor, Malaysia.
17
Peter MacCallum Cancer Centre, University of Melbourne, Victoria, Australia.
18
Department of Neurodegenerative Disease and MRC Prion Unit, UCL Institute of Neurology, London, UK.
19
Division of Neuropathology and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
20
Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, UK.
21
University College London Cancer Institute, London, UK.

Abstract

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2)  = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.

KEYWORDS:

HER2; HER3; RNA sequencing; brain metastasis; exome sequencing; genomic signature; targeted therapy

PMID:
26172396
DOI:
10.1002/path.4583
[Indexed for MEDLINE]

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