title: Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.
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.
authors.affiliation: University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia.|QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Jodi M
authors.identifier: http://orcid.org/0000-0002-4604-4709
authors.initials: JM
authors.lastname: Saunus
authors.affiliation: University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia.|QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Michael C J
authors.initials: MC
authors.lastname: Quinn
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Patch
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: John V
authors.initials: JV
authors.lastname: Pearson
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.|Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bailey
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Katia
authors.initials: K
authors.lastname: Nones
authors.affiliation: University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia.|QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Amy E
authors.initials: AE
authors.lastname: McCart Reed
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.|Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Miller
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wilson
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Fares
authors.initials: F
authors.lastname: Al-Ejeh
authors.affiliation: University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia.|QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Mythily
authors.initials: M
authors.lastname: Mariasegaram
authors.affiliation: Pathology Queensland, Gold Coast Hospital, Southport, Queensland, Australia.
authors.forename: Queenie
authors.initials: Q
authors.lastname: Lau
authors.affiliation: Department of Neurosurgery, Gold Coast Hospital, Southport, Queensland, Australia.
authors.forename: Teresa
authors.initials: T
authors.lastname: Withers
authors.affiliation: Kenneth G Jamieson Department of Neurosurgery, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
authors.forename: Rosalind L
authors.initials: RL
authors.lastname: Jeffree
authors.affiliation: University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia.|QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Reid
authors.affiliation: University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia.|University of Queensland School of Medicine, Herston, Queensland, Australia.
authors.forename: Leonard
authors.initials: L
authors.lastname: Da Silva
authors.affiliation: University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia.|Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
authors.forename: Admire
authors.initials: A
authors.lastname: Matsika
authors.affiliation: University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia.|QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niland
authors.affiliation: University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia.|University of Queensland School of Medicine, Herston, Queensland, Australia.|Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Cummings
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Timothy J C
authors.initials: TJ
authors.lastname: Bruxner
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Angelika N
authors.initials: AN
authors.lastname: Christ
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Ivon
authors.initials: I
authors.lastname: Harliwong
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Senel
authors.initials: S
authors.lastname: Idrisoglu
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Manning
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.|Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Nourse
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Nourbakhsh
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Shivangi
authors.initials: S
authors.lastname: Wani
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Anderson
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: J Lynn
authors.initials: JL
authors.lastname: Fink
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Holmes
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kazakoff
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Conrad
authors.initials: C
authors.lastname: Leonard
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Felicity
authors.initials: F
authors.lastname: Newell
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Darrin
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Nick
authors.initials: N
authors.lastname: Waddell
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Wood
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Qinying
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.|Genetic and Molecular Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia.|School of Molecular and Biomedical Science, University of Adelaide, South Australia, Australia.
authors.forename: Karin S
authors.initials: KS
authors.lastname: Kassahn
authors.affiliation: Division of Neurosurgery, Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Vairavan
authors.initials: V
authors.lastname: Narayanan
authors.affiliation: Breast Unit, Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.|University Malaya Cancer Research Institute, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Nur Aishah
authors.initials: NA
authors.lastname: Taib
authors.affiliation: University Malaya Cancer Research Institute, University of Malaya, Kuala Lumpur, Malaysia.|Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Selangor, Malaysia.
authors.forename: Soo-Hwang
authors.initials: SH
authors.lastname: Teo
authors.affiliation: Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Selangor, Malaysia.
authors.forename: Yock Ping
authors.initials: YP
authors.lastname: Chow
authors.affiliation: Peter MacCallum Cancer Centre, University of Melbourne, Victoria, Australia.
authors.lastname: kConFab
authors.affiliation: Department of Neurodegenerative Disease and MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: Parmjit S
authors.initials: PS
authors.lastname: Jat
authors.affiliation: Division of Neuropathology and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, UK.|University College London Cancer Institute, London, UK.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.affiliation: Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.|Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, UK.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.affiliation: University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia.|QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|University of Queensland School of Medicine, Herston, Queensland, Australia.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Simpson
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Queensland Centre for Medical Genomics, IMB, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Waddell
authors.affiliation: University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia.|University of Queensland School of Medicine, Herston, Queensland, Australia.|Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000556:secondary*; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D058990:Molecular Targeted Therapy; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D057285:Precision Medicine; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D008024:Ligands; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C587689:ERBB4 protein, human
keywords: HER2; HER3; RNA sequencing; brain metastasis; exome sequencing; genomic signature; targeted therapy