Acta Neuropathologica

, Volume 123, Issue 2, pp 223–233 | Cite as

Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases

  • David Capper
  • Anna Sophie Berghoff
  • Manuel Magerle
  • Aysegül Ilhan
  • Adelheid Wöhrer
  • Monika Hackl
  • Josef Pichler
  • Stefan Pusch
  • Jochen Meyer
  • Antje Habel
  • Peter Petzelbauer
  • Peter Birner
  • Andreas von Deimling
  • Matthias Preusser
Original Paper

Abstract

Brain metastases (BM) are frequent and carry a dismal prognosis. BRAF V600E mutations are found in a broad range of tumor types and specific inhibitors targeting BRAF V600E protein exist. We analyzed tumoral BRAF V600E-mutant protein expression using the novel mutation-specific antibody VE1 in a series of 1,120 tumor specimens (885 BM, 157 primary tumors, 78 extra-cranial metastases) of 874 BM patients. In 85 cases, we performed validation of immunohistochemical results by BRAF exon 15 gene sequencing. BRAF V600E protein was expressed in BM of 42/76 (55.3%) melanomas, 1/15 (6.7%) ovarian cancers, 4/72 (5.5%) colorectal cancers, 1/355 (0.3%) lung cancers, 2/6 thyroid cancers and 1/2 choriocarcinomas. BRAF V600E expression showed high intra-tumoral homogeneity and was similar in different tumor manifestations of individual patients. VE1 immunohistochemistry and BRAF exon 15 sequencing were congruent in 68/70 (97.1%) cases, but VE1 immunostaining identified small BRAF V600E expressing tumor cell aggregates in 10 cases with inconclusive genetic results. Melanoma patients with BRAF V600E mutant protein expressing tumors were significantly younger at diagnosis of the primary tumor and at operation of BM than patients with non-mutated tumors. In conclusion, expression of BRAF V600E mutant protein occurs in approximately 6% of BM and is consistent in different tumor manifestations of the same patient. Thus, BRAF V600E inhibiting therapies seem feasible in selected BM patients. Immunohistochemical visualization of V600E-mutant BRAF protein is a promising tool for patient stratification. An integrated approach combining both, VE1 immunohistochemistry and genetic analysis may increase the diagnostic accuracy of BRAF mutation analysis.

Keywords

Brain metastases BRAF V600E Mutation Immunohistochemistry VE1 

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • David Capper
    • 1
    • 2
  • Anna Sophie Berghoff
    • 3
    • 4
  • Manuel Magerle
    • 3
    • 4
  • Aysegül Ilhan
    • 3
    • 4
  • Adelheid Wöhrer
    • 4
    • 5
  • Monika Hackl
    • 6
  • Josef Pichler
    • 7
  • Stefan Pusch
    • 1
    • 2
  • Jochen Meyer
    • 1
    • 2
  • Antje Habel
    • 1
  • Peter Petzelbauer
    • 8
  • Peter Birner
    • 9
    • 4
  • Andreas von Deimling
    • 1
    • 2
  • Matthias Preusser
    • 1
    • 3
    • 4
    • 5
  1. 1.Department of NeuropathologyInstitute of Pathology, Ruprecht-Karls-UniversityHeidelbergGermany
  2. 2.Clinical Cooperation Unit NeuropathologyGerman Cancer Research CenterHeidelbergGermany
  3. 3.Department of Medicine IMedical University of ViennaViennaAustria
  4. 4.Comprehensive Cancer Center—CNS Tumors UnitMedical University of ViennaViennaAustria
  5. 5.Institute of NeurologyMedical University of ViennaViennaAustria
  6. 6.Austrian National Cancer RegistryStatistics AustriaViennaAustria
  7. 7.Landes-Nervenklinik Wagner-JaureggLinzAustria
  8. 8.Department of DermatologyMedical University of ViennaViennaAustria
  9. 9.Clinical Institute of PathologyMedical University of ViennaViennaAustria

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