Serum DNA can define tumor-specific genetic and epigenetic markers in gliomas of various grades.
We evaluated whether cell-free circulating DNA can be used as a noninvasive approach for detection of genetic/epigenetic alterations in brain tumors during the course of the disease. Paired tumor-serum samples from 70 patients with either high-grade astrocytomas (n = 41) or oligodendrogliomas of various grades were analyzed. The median interval between surgery and serum sampling was 1 month (range 0.5-168 months). DNA was extracted from whole blood, serum, and paraffin-embedded tumor sections. Loss of heterozygosity (LOH) in chromosomes 1p, 19q, and 10q was assessed by polymerase chain reaction (PCR)-based microsatellite analysis. The methylation status of O(6)-methyl guanine methyltransferase (MGMT) and phosphatase and tensin homolog promoters was studied by methylation-specific PCR. LOH and/or methylation that could identify DNA as tumor-specific was found in 80.5% of astrocytic tumors and in all oligodendrogliomas. The rate of serum detection of these biomarkers was 51% and 55%, respectively, with specificity around 100%. The rate of serum detection did not differ between low- and high-grade oligodendrogliomas. Statistically significant tumor-serum concordance was found for MGMT methylation in both astrocytic tumors (83%; P < .001) and oligodendroglial tumors (72%; P < .003) and for LOH of 10q (79%; P < .002) and 1p (62%; P < .03) in oligodendrogliomas. We conclude that serum DNA in glial tumors is informative for both LOH and aberrant gene promoter methylation analysis during the course of the disease. The sensitivity is moderate and specificity is high for both low- and high-grade tumors. Future studies should identify a panel of biomarkers that bear the highest potential for clinical application.
Lavon
Iris
I
Gaffin Center for Neuro-Oncology and the Department of Neurology, Hadassah Hebrew University Medical Center, Ein Kerem, PO Box 12000, Jerusalem 91120, Israel.
Refael
Miri
M
Zelikovitch
Bracha
B
Shalom
Edna
E
Siegal
Tali
T
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D001932:Brain Neoplasms / Q000097:blood / Q000235:genetics*; D004247:DNA / Q000097:blood*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D005910:Glioma / Q000097:blood / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics; D016133:Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D004247:DNA; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D045643:DNA Repair Enzymes