Gene expression signatures in the peripheral blood after radiosurgery of human cerebral arteriovenous malformations.
OBJECTIVE
To unravel biological mechanisms potentially resulting in the obliteration process after radiosurgery (RS) of human cerebral arteriovenous malformations (AVMs) by investigating molecular signatures on the transcriptomic level in peripheral blood of patients.


METHODS
Venous blood samples were obtained at definite points of time before and after RS. The samples were tested for radiation-induced changes regarding biological markers (mRNA) using cDNA and oligo-microarray technology. The corresponding expression profiles were correlated with clinical data and obliteration signs in radiologic imaging.


RESULTS
The proof of principle that RS outcome can be successfully correlated with transcriptomics of cellular blood components as disease parameter was demonstrated. The authors identified 76 differentially regulated genes (p < 0.001) after RS. Interestingly, in particular genes with known roles in anti-angiogenic and pro-coagulative pathways were identified as potentially relevant. In particularly, the authors found a significant downregulation of neuropilin-2, protein C inhibitor and cyclin-dependent kinase 6. They also found that low pretreatment blood mRNA levels of TLR4 (toll-like receptor 4) and STAT3 (signal transducer and activator of transcription 3) correlated with fast obliteration of AVMs.


CONCLUSIONS
The authors report on a novel technique for molecular biological analysis of blood from patients with cerebral AVM treated with RS. Differential regulation of genes in peripheral blood was successfully correlated with RS and time to obliteration of AVMs. The identified genes indicate a potential new methodology to monitor RS, which may result in an individualized therapy and optimized follow-up.
Zabel-du Bois
Angelika
A
Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany. A.Zabel@dkfz-heidelberg.de.|Department of RadioOncology, University of Heidelberg, Heidelberg, Germany. A.Zabel@dkfz-heidelberg.de.|Department of Radiation Oncology (E050), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. A.Zabel@dkfz-heidelberg.de.
Wagner-Ecker
Mechthild
M
Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany.
Milker-Zabel
Stefanie
S
Department of RadioOncology, University of Heidelberg, Heidelberg, Germany.
Schwager
Christian
C
Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany.
Wirkner
Ute
U
Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany.
Debus
Jürgen
J
Department of RadioOncology, University of Heidelberg, Heidelberg, Germany.
Abdollahi
Amir
A
Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany.|Department of RadioOncology, University of Heidelberg, Heidelberg, Germany.|Center of Cancer Systems Biology, NASA Specialized Center of Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA.
Huber
Peter E
PE
Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany.
D000328:Adult; D000368:Aged; D001798:Blood Proteins / Q000235:genetics*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000528:radiation effects; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000235:genetics* / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D039943:Neuropilin-2 / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D018046:Protein C Inhibitor / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000528:radiation effects; D016634:Radiosurgery; D050796:STAT3 Transcription Factor / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D016896:Treatment Outcome; D055815:Young Adult
D001798:Blood Proteins; D039943:Neuropilin-2; D018046:Protein C Inhibitor; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051361:Cyclin-Dependent Kinase 6