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.
N1 - Publisher Copyright:
© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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.
KW - DNA repair enzymes
KW - TOP2A
KW - brain metastases
KW - molecular profiling
KW - multiplatform analysis
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U2 - 10.1002/ijc.31624
DO - 10.1002/ijc.31624
M3 - Article
C2 - 29923182
AN - SCOPUS:85054677556
SN - 0020-7136
VL - 143
SP - 3019
EP - 3026
JO - International journal of cancer
JF - International journal of cancer
IS - 11
ER -