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

Jodi M. Saunus, Michael C J Quinn, Ann Marie Patch, John V. Pearson, Peter J. Bailey, Katia Nones, Amy E. McCart Reed, David Miller, Peter J. Wilson, Fares Al-Ejeh, Mythily Mariasegaram, Queenie Lau, Teresa Withers, Rosalind L. Jeffree, Lynne E. Reid, Leonard Da Silva, Admire Matsika, Colleen M. Niland, Margaret C. Cummings, Timothy J C BruxnerAngelika N. Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Craig Nourse, Ehsan Nourbakhsh, Shivangi Wani, Matthew J. Anderson, J. Lynn Fink, Oliver Holmes, Stephen Kazakoff, Conrad Leonard, Felicity Newell, Darrin Taylor, Nick Waddell, Scott Wood, Qinying Xu, Karin S. Kassahn, Vairavan Narayanan, Nur Aishah Taib, Soo Hwang Teo, Chow Yock Ping, B. Kconfa, Parmjit S. Jat, Sebastian Brandner, Adrienne M. Flanagan, Kum Kum Khanna, Georgia Chenevix-Trench, Sean M. Grimmond, Peter T. Simpson, Nicola Waddell, Sunil R. Lakhani

Research output: Contribution to journalArticle

46 Citations (Scopus)

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 (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-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.

Original languageEnglish
Pages (from-to)363-378
Number of pages16
JournalJournal of Pathology
Volume237
Issue number3
DOIs
Publication statusPublished - 1 Nov 2015
Externally publishedYes

Fingerprint

Neoplasm Metastasis
Brain
Brain Neoplasms
Breast Neoplasms
Ligands
Exome
RNA Sequence Analysis
Therapeutics
Esophageal Neoplasms
Cyclic AMP-Dependent Protein Kinases
DNA Repair
Melanoma
Lung Neoplasms
Membranes
Mortality
DNA
Genes
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Saunus, J. M., Quinn, M. C. J., Patch, A. M., Pearson, J. V., Bailey, P. J., Nones, K., ... Lakhani, S. R. (2015). Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance. Journal of Pathology, 237(3), 363-378. https://doi.org/10.1002/path.4583

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations 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; Wilson, Peter J.; 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; Waddell, Nick; Wood, Scott; Xu, Qinying; Kassahn, Karin S.; Narayanan, Vairavan; Taib, Nur Aishah; Teo, Soo Hwang; Yock Ping, Chow; Kconfa, B.; Jat, Parmjit S.; Brandner, Sebastian; Flanagan, Adrienne M.; Khanna, Kum Kum; Chenevix-Trench, Georgia; Grimmond, Sean M.; Simpson, Peter T.; Waddell, Nicola; Lakhani, Sunil R.

In: Journal of Pathology, Vol. 237, No. 3, 01.11.2015, p. 363-378.

Research output: Contribution to journalArticle

Saunus, JM, Quinn, MCJ, Patch, AM, Pearson, JV, Bailey, PJ, Nones, K, McCart Reed, AE, Miller, D, Wilson, PJ, Al-Ejeh, F, Mariasegaram, M, Lau, Q, Withers, T, Jeffree, RL, Reid, LE, Da Silva, L, Matsika, A, Niland, CM, Cummings, MC, Bruxner, TJC, Christ, AN, Harliwong, I, Idrisoglu, S, Manning, S, Nourse, C, Nourbakhsh, E, Wani, S, Anderson, MJ, Fink, JL, Holmes, O, Kazakoff, S, Leonard, C, Newell, F, Taylor, D, Waddell, N, Wood, S, Xu, Q, Kassahn, KS, Narayanan, V, Taib, NA, Teo, SH, Yock Ping, C, Kconfa, B, Jat, PS, Brandner, S, Flanagan, AM, Khanna, KK, Chenevix-Trench, G, Grimmond, SM, Simpson, PT, Waddell, N & Lakhani, SR 2015, 'Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance', Journal of Pathology, vol. 237, no. 3, pp. 363-378. https://doi.org/10.1002/path.4583
Saunus, Jodi M. ; Quinn, Michael C J ; Patch, Ann Marie ; Pearson, John V. ; Bailey, Peter J. ; Nones, Katia ; McCart Reed, Amy E. ; Miller, David ; Wilson, Peter J. ; 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 ; Waddell, Nick ; Wood, Scott ; Xu, Qinying ; Kassahn, Karin S. ; Narayanan, Vairavan ; Taib, Nur Aishah ; Teo, Soo Hwang ; Yock Ping, Chow ; Kconfa, B. ; Jat, Parmjit S. ; Brandner, Sebastian ; Flanagan, Adrienne M. ; Khanna, Kum Kum ; Chenevix-Trench, Georgia ; Grimmond, Sean M. ; Simpson, Peter T. ; Waddell, Nicola ; Lakhani, Sunil R. / Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance. In: Journal of Pathology. 2015 ; Vol. 237, No. 3. pp. 363-378.
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T1 - Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance

AU - Saunus, Jodi M.

AU - Quinn, Michael C J

AU - Patch, Ann Marie

AU - Pearson, John V.

AU - Bailey, Peter J.

AU - Nones, Katia

AU - McCart Reed, Amy E.

AU - Miller, David

AU - Wilson, Peter J.

AU - Al-Ejeh, Fares

AU - Mariasegaram, Mythily

AU - Lau, Queenie

AU - Withers, Teresa

AU - Jeffree, Rosalind L.

AU - Reid, Lynne E.

AU - Da Silva, Leonard

AU - Matsika, Admire

AU - Niland, Colleen M.

AU - Cummings, Margaret C.

AU - Bruxner, Timothy J C

AU - Christ, Angelika N.

AU - Harliwong, Ivon

AU - Idrisoglu, Senel

AU - Manning, Suzanne

AU - Nourse, Craig

AU - Nourbakhsh, Ehsan

AU - Wani, Shivangi

AU - Anderson, Matthew J.

AU - Fink, J. Lynn

AU - Holmes, Oliver

AU - Kazakoff, Stephen

AU - Leonard, Conrad

AU - Newell, Felicity

AU - Taylor, Darrin

AU - Waddell, Nick

AU - Wood, Scott

AU - Xu, Qinying

AU - Kassahn, Karin S.

AU - Narayanan, Vairavan

AU - Taib, Nur Aishah

AU - Teo, Soo Hwang

AU - Yock Ping, Chow

AU - Kconfa, B.

AU - Jat, Parmjit S.

AU - Brandner, Sebastian

AU - Flanagan, Adrienne M.

AU - Khanna, Kum Kum

AU - Chenevix-Trench, Georgia

AU - Grimmond, Sean M.

AU - Simpson, Peter T.

AU - Waddell, Nicola

AU - Lakhani, Sunil R.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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 (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-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.

AB - 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 (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-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.

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