Analysis of loss of heterozygosity for chromosome 10 in patients with malignant astrocytic tumors: correlation with patient age and survival

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Object. The most frequent genetic abnormality in human malignant gliomas is loss of heterozygosity (LOH) on chromosome 10. Candidate genes on chromosome 10 that are associated with the prognosis of patients with anaplastic astrocytoma (AA) and glioblastoma (GBM) were evaluated.

Methods. The authors used 12 fluorescent microsatellite markers on both arms of chromosome 10 to study LOH in 108 primary astrocytic tumors. The LOH on chromosome 10 was observed in 11 (32%) of 34 AAs and 34 (56%) of 61 GBMs. No LOH was detected in 13 low-grade gliomas. Loss of heterozygosity was not detected in any AA in the seven patients younger than 35 years, but it was discovered in 41% of the patients older than 35 years. The prognostic significance of LOH at each locus was evaluated in 89 patients older than 15 years; 33 (37%) had supratentorial AAs and 56 (63%) had supratentorial GBMs. The Cox proportional hazards model, adjusted for patient age at surgery, the preoperative Karnofsky Performance Scale score, and the extent of surgical resection revealed that LOH on marker D10S209 near the FGFR2 and DMBT1 genes was significantly associated with shorter survival in patients with AA. The LOH on markers D10S215 and D10S541, which contain the PTEN/MMAC1 gene between them, was significantly associated with shorter survival in patients with GBM.

Conclusions. In the present study it is found that LOH on chromosome 10 is an age-dependent event for patients with AAs and that LOH on marker D10S209 near the FGFR2 and DMBT1 loci is a significantly unfavorable prognostic factor. It is also reported that LOH on the PTEN/MMAC1 gene is a significantly unfavorable prognostic factor in patients with GBM.

Article Information

Address reprint requests to: Kenji Tada, M.D., Department of Neurosurgery, Kumamoto University Medical School, 1–1–1 Honjo, Kumamoto 860–8556, Japan. email: ktada@fc.kuh.kumamoto-u.ac.jp.

© AANS, except where prohibited by US copyright law.

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Figures

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    Map of chromosome 10 (Chr. 10) showing cytogenetic localization of 12 microsatellite markers used in this study. Markers D10S189 and D10S547 are located on 10p15. Markers D10S215 and D10S541 contain the PTEN/MMAC1 (10q23.3) locus between them, and D10S209 and D10S587 contain the FGFR2 (10q25.3–26) and DMBT1 (10q25.3–26.1) loci between them.

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    Tracings showing representative examples of fluorescent microsatellite analysis of LOH (arrows) on chromosome 10 in two patients with GBM. Blue curves represent FAM fluorescent dye and green curves are HEX dye. N = normal DNA from peripheral blood; T = DNA from tumor.

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    Bar graphs showing the frequency of LOH on chromosome 10 at 5-year age intervals in patients with AA (a) and GBM (b). Percentages in each column indicate the frequency of LOH.

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    Bar graphs showing the frequency of LOH on chromosome 10 at each locus studied in patients with AA (a) and GBM (b). Percentages in each column indicate the frequency of LOH.

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    Graph showing Kaplan—Meier survival curves in patients with GBM with or without LOH on markers D10S215 (a) and D10S541 (b). The difference in survival is statistically significant for both markers, according to the log-rank test.

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