Protein biomarker identification in the CSF of patients with CNS lymphoma.
OBJECTIVE
Elucidation of the CSF proteome may yield insights into the pathogenesis of CNS disease. We tested the hypothesis that individual CSF proteins distinguish CNS lymphoma from benign focal brain lesions.


METHODS
We used a liquid chromatography/mass spectrometry-based method to differentially quantify and identify several hundred CSF proteins in CNS lymphoma and control patients. We used enzyme-linked immunosorbent assay (ELISA) to confirm one of these markers in an additional validation set of 101 cases.


RESULTS
Approximately 80 CSF proteins were identified and found to be present at significantly different concentrations, both higher and lower, in training and test studies, which were highly concordant. To further validate these observations, we defined in detail the expression of one of these candidate biomarkers, antithrombin III (ATIII). ATIII RNA transcripts were identified within CNS lymphomas, and ATIII protein was localized selectively to tumor neovasculature. Determination of ATIII concentration by ELISA was significantly more accurate (> 75% sensitivity; > 98% specificity) than cytology in the identification of cancer. Measurement of CSF ATIII levels was found to potentially enhance the ability to diagnose and predict outcome.


CONCLUSIONS
Our findings demonstrate for the first time that proteomic analysis of CSF yields individual biomarkers with greater sensitivity in the identification of cancer than does CSF cytology. We propose that the discovery of CSF protein biomarkers will facilitate early and noninvasive diagnosis in patients with lesions not amenable to brain biopsy, as well as provide improved surrogates of prognosis and treatment response in CNS lymphoma and brain metastasis.
Roy
Sushmita
S
PPD Biomarker Discovery Sciences, LLC, Menlo Park, CA, USA.
Josephson
S Andrew
SA
Fridlyand
Jane
J
Karch
Jon
J
Kadoch
Cigall
C
Karrim
Juliana
J
Damon
Lloyd
L
Treseler
Patrick
P
Kunwar
Sandeep
S
Shuman
Marc A
MA
Jones
Ted
T
Becker
Christopher H
CH
Schulman
Howard
H
Rubenstein
James L
JL
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000990:Antithrombin III / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000134:cerebrospinal fluid*; D001932:Brain Neoplasms / Q000134:cerebrospinal fluid* / Q000473:pathology; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D003937:Diagnosis, Differential; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007951:Leukemia, Myeloid / Q000134:cerebrospinal fluid / Q000473:pathology; D008223:Lymphoma / Q000134:cerebrospinal fluid* / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000134:cerebrospinal fluid / Q000473:pathology; D018442:Lymphoma, B-Cell, Marginal Zone / Q000134:cerebrospinal fluid / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000134:cerebrospinal fluid / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000134:cerebrospinal fluid / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000134:cerebrospinal fluid*; D040901:Proteomics; D012680:Sensitivity and Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015996:Survival Rate
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D000990:Antithrombin III