Integrated genomic and transcriptomic analysis of human brain metastases identifies recurrently altered pathways of potential clinical significance

Saunus, Jodi M., Quinn, MIchael C. J., Patch, Ann-Marie, Pearson, John V., Bailey, Peter J., Nones, Katia, McCart Reed, Amy E., Miller, David, Peter J. Wilson, Al-Ejeh, Fares, Mariasegaram, Mythily, Lau, Queenie, Withers, Teresa, Jeffree, Rosalind L., Reid, Lynne E., Da Silva, Leonard, Matsika, Admire, Niland, Colleen M., Cummings, Margaret C., Bruxner, Timothy J. C., Christ, Angelika N., Harliwong, Ivon, Idrisoglu, Senel, Manning, Suzanne, Nourse, Craig, Nourbakhsh, Ehsan, Wani, Shivangi, Anderson, Matthew J., Fink, J. Lynn, Holmes, Oliver, Kazakoff, Stephen, Leonard, Conrad, Newell, Felicity, Taylor, Darrin, Wood, Scott, Xu, Qinying, Kassahn, Karin S., Narayanan, Vairavan, Taib, Nur Aishah, Teo, Soo-Hwang, Chow, Yock Ping, kConFab, Jat, Parmjit S., Brandner, Sebastian, Flanagan, Adrienne M., Khanna, KumKum, Chenevix-Trench, Georgia, Grimmond, Sean M., Simpson, Peter T., Waddell, Nicola and Lakhani, Sunil R. (2015) Integrated genomic and transcriptomic analysis of human brain metastases identifies recurrently altered pathways of potential clinical significance. Journal of Pathology, 237 3: 363-378. doi:10.1002/path.4583

Author Saunus, Jodi M.
Quinn, MIchael C. J.
Patch, Ann-Marie
Pearson, John V.
Bailey, Peter J.
Nones, Katia
McCart Reed, Amy E.
Miller, David
Peter J. Wilson
Al-Ejeh, Fares
Mariasegaram, Mythily
Lau, Queenie
Withers, Teresa
Jeffree, Rosalind L.
Reid, Lynne E.
Da Silva, Leonard
Matsika, Admire
Niland, Colleen M.
Cummings, Margaret C.
Bruxner, Timothy J. C.
Christ, Angelika N.
Harliwong, Ivon
Idrisoglu, Senel
Manning, Suzanne
Nourse, Craig
Nourbakhsh, Ehsan
Wani, Shivangi
Anderson, Matthew J.
Fink, J. Lynn
Holmes, Oliver
Kazakoff, Stephen
Leonard, Conrad
Newell, Felicity
Taylor, Darrin
Wood, Scott
Xu, Qinying
Kassahn, Karin S.
Narayanan, Vairavan
Taib, Nur Aishah
Teo, Soo-Hwang
Chow, Yock Ping
Jat, Parmjit S.
Brandner, Sebastian
Flanagan, Adrienne M.
Khanna, KumKum
Chenevix-Trench, Georgia
Grimmond, Sean M.
Simpson, Peter T.
Waddell, Nicola
Lakhani, Sunil R.
Title Integrated genomic and transcriptomic analysis of human brain metastases identifies recurrently altered pathways of potential clinical significance
Journal name Journal of Pathology   Check publisher's open access policy
ISSN 0022-3417
Publication date 2015-07-14
Year available 2015
Sub-type Article (original research)
DOI 10.1002/path.4583
Open Access Status Not Open Access
Volume 237
Issue 3
Start page 363
End page 378
Total pages 30
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley and Sons
Language eng
Formatted abstract
Treatment options for patients with brain metastases (BM) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilised, 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 BM (from breast, lung, melanoma and oesophageal cancers) using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were: (1) identification of novel candidates with possible roles in brain metastasis 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. (2) Mutational signature analysis was applied to successfully identify the primary cancer type for two BM with unknown origins. (3) Actionable genomic alterations were identified in 31/36 BM (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. (4) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r2 = 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-HER3Y1222 or phospho-HER4Y1162 membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq (with NRG1 (8p12) genomic loss in 63.6% breast cancer-BM), suggesting a microenvironmental source of ligand. In summary, this is the first study to characterise the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BM, and highlight the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BM independent of primary site and systemic therapy.
Keyword Brain metastasis
Exome sequencing
RNA sequencing
Genomic signature
Targeted therapy
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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Created: Tue, 18 Aug 2015, 04:11:16 EST by Dr Jodi Saunus on behalf of UQ Centre for Clinical Research