Profiles of brain metastases: Prioritization of therapeutic targets

Sherise D. Ferguson, Siyuan Zheng, Joanne Xiu, Shouhao Zhou, Mustafa Khasraw, Priscilla K. Brastianos, Santosh Kesari, Jethro Hu, Jeremy Rudnick, Michael E. Salacz, David Piccioni, Suyun Huang, Michael A. Davies, Isabella C. Glitza, John V. Heymach, Jianjun Zhang, Nuhad K. Ibrahim, John F. DeGroot, Joseph McCarty, Barbara J. O'BrienRaymond Sawaya, Roeland G.W. Verhaak, Sandeep K. Reddy, Waldemar Priebe, Zoran Gatalica, David Spetzler, Amy B. Heimberger

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

Original languageEnglish (US)
Pages (from-to)3019-3026
Number of pages8
JournalInternational Journal of Cancer
Volume143
Issue number11
DOIs
StatePublished - Dec 1 2018

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Neoplasm Metastasis
Brain
Therapeutics
Melanoma
Neoplasms
Gene Amplification
Non-Small Cell Lung Carcinoma
Brain Neoplasms
DNA Repair
Breast Neoplasms
Proteins
Biological Science Disciplines
DNA Replication
In Situ Hybridization
Cluster Analysis
Immunohistochemistry
Drug Therapy
Skin
Mutation
Enzymes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Ferguson, S. D., Zheng, S., Xiu, J., Zhou, S., Khasraw, M., Brastianos, P. K., ... Heimberger, A. B. (2018). Profiles of brain metastases: Prioritization of therapeutic targets. International Journal of Cancer, 143(11), 3019-3026. https://doi.org/10.1002/ijc.31624
Ferguson, Sherise D. ; Zheng, Siyuan ; Xiu, Joanne ; Zhou, Shouhao ; Khasraw, Mustafa ; Brastianos, Priscilla K. ; Kesari, Santosh ; Hu, Jethro ; Rudnick, Jeremy ; Salacz, Michael E. ; Piccioni, David ; Huang, Suyun ; Davies, Michael A. ; Glitza, Isabella C. ; Heymach, John V. ; Zhang, Jianjun ; Ibrahim, Nuhad K. ; DeGroot, John F. ; McCarty, Joseph ; O'Brien, Barbara J. ; Sawaya, Raymond ; Verhaak, Roeland G.W. ; Reddy, Sandeep K. ; Priebe, Waldemar ; Gatalica, Zoran ; Spetzler, David ; Heimberger, Amy B. / Profiles of brain metastases : Prioritization of therapeutic targets. In: International Journal of Cancer. 2018 ; Vol. 143, No. 11. pp. 3019-3026.
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abstract = "We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.",
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Ferguson, SD, Zheng, S, Xiu, J, Zhou, S, Khasraw, M, Brastianos, PK, Kesari, S, Hu, J, Rudnick, J, Salacz, ME, Piccioni, D, Huang, S, Davies, MA, Glitza, IC, Heymach, JV, Zhang, J, Ibrahim, NK, DeGroot, JF, McCarty, J, O'Brien, BJ, Sawaya, R, Verhaak, RGW, Reddy, SK, Priebe, W, Gatalica, Z, Spetzler, D & Heimberger, AB 2018, 'Profiles of brain metastases: Prioritization of therapeutic targets', International Journal of Cancer, vol. 143, no. 11, pp. 3019-3026. https://doi.org/10.1002/ijc.31624

Profiles of brain metastases : Prioritization of therapeutic targets. / Ferguson, Sherise D.; Zheng, Siyuan; Xiu, Joanne; Zhou, Shouhao; Khasraw, Mustafa; Brastianos, Priscilla K.; Kesari, Santosh; Hu, Jethro; Rudnick, Jeremy; Salacz, Michael E.; Piccioni, David; Huang, Suyun; Davies, Michael A.; Glitza, Isabella C.; Heymach, John V.; Zhang, Jianjun; Ibrahim, Nuhad K.; DeGroot, John F.; McCarty, Joseph; O'Brien, Barbara J.; Sawaya, Raymond; Verhaak, Roeland G.W.; Reddy, Sandeep K.; Priebe, Waldemar; Gatalica, Zoran; Spetzler, David; Heimberger, Amy B.

In: International Journal of Cancer, Vol. 143, No. 11, 01.12.2018, p. 3019-3026.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Profiles of brain metastases

T2 - Prioritization of therapeutic targets

AU - Ferguson, Sherise D.

AU - Zheng, Siyuan

AU - Xiu, Joanne

AU - Zhou, Shouhao

AU - Khasraw, Mustafa

AU - Brastianos, Priscilla K.

AU - Kesari, Santosh

AU - Hu, Jethro

AU - Rudnick, Jeremy

AU - Salacz, Michael E.

AU - Piccioni, David

AU - Huang, Suyun

AU - Davies, Michael A.

AU - Glitza, Isabella C.

AU - Heymach, John V.

AU - Zhang, Jianjun

AU - Ibrahim, Nuhad K.

AU - DeGroot, John F.

AU - McCarty, Joseph

AU - O'Brien, Barbara J.

AU - Sawaya, Raymond

AU - Verhaak, Roeland G.W.

AU - Reddy, Sandeep K.

AU - Priebe, Waldemar

AU - Gatalica, Zoran

AU - Spetzler, David

AU - Heimberger, Amy B.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

AB - We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

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Ferguson SD, Zheng S, Xiu J, Zhou S, Khasraw M, Brastianos PK et al. Profiles of brain metastases: Prioritization of therapeutic targets. International Journal of Cancer. 2018 Dec 1;143(11):3019-3026. https://doi.org/10.1002/ijc.31624