DMBT1 homozygous deletion in diffuse astrocytomas is associated with unfavorable clinical outcome.
Primary glioblastomas develop with a short clinical history, without evidence for less malignant precursor lesions, while secondary glioblastomas slowly develop via progression from diffuse astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III). The time until progression and the clinical outcome of diffuse astrocytomas vary significantly. We have shown that IDH1 mutations reliably distinguish between primary glioblastomas (without IDH1 mutations) and secondary glioblastomas (with IDH1 mutations). The most frequent genetic alteration shared by primary and secondary glioblastomas is loss of heterozygosity at 10q (up to 60% of cases). Here, we first assessed The Cancer Genome Atlas data to identify gene loss at 10q in glioblastomas with or without IDH1 mutations. Using log-ratio thresholds of -1.0, 10 genes were identified; with the log-ratio thresholds of -2.0, only the DMBT1 (deleted in malignant brain tumor 1) gene at 10q26.13 remained as a deleted gene in glioblastomas with or without IDH1 mutations (12.5% vs 8.0%). We then analyzed a total of 404 gliomas by differential polymerase chain reaction and found a DMBT1 homozygous deletion at a similar frequency in primary and secondary glioblastomas (19.6% vs 20.8%). A fraction (11.3%) of diffuse astrocytomas showed a DMBT1 homozygous deletion that was significantly associated with a shorter overall survival (52.8 vs 84.0 months; p = 0.003). These results indicate that a DMBT1 homozygous deletion is present in a fraction of diffuse astrocytomas and that it is associated with an unfavorable clinical outcome.
International Agency for Research on Cancer, Lyon, France.
Kazuya
K
Motomura
Michel
M
Mittelbronn
Werner
W
Paulus
Benjamin
B
Brokinkel
Kathy
K
Keyvani
Ulrich
U
Sure
Karsten
K
Wrede
Yoichi
Y
Nakazato
Yuko
Y
Tanaka
Daniela
D
Pierscianek
Young-Ho
YH
Kim
Luigi
L
Mariani
Anne
A
Vital
Hiroko
H
Ohgaki
D000328:Adult; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology*; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology*; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology; D005910:Glioma / Q000235:genetics / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000235:genetics*; D016019:Survival Analysis; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins
D002135:Calcium-Binding Proteins; C108174:DMBT1 protein, human; D004268:DNA-Binding Proteins; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human