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Longitudinal Assessment of Genetic and Epigenetic Markers in Oligodendrogliomas

Authors' Affiliations: ¹ Leslie and Michael Gaffin Center for Neuro-Oncology, Sharett Institute of Oncology, and Departments of ² Neurology and ³ Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel

Requests for reprints: Tali Siegal, Gaffin Center for Neuro-Oncology, Hadassah Hebrew University Hospital, Ein-Karem, P.O. Box 12000, Jerusalem 91120, Israel. Phone: 972-2677-8854; Fax: 972-2646-8803; E-mail: siegal{at}hadassah.org.il.

Purpose: Because little is known about the evolution of genetic and epigenetic changes that occur during tumor progression in oligodendrogliomas, we evaluated these changes in paired early and progressive oligodendrogliomas.

Experimental Design: 1p36, 19q13, 10q22-26, and O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation status were assessed in 46 paired early and progressive oligodendrogliomas from 23 patients.

Results: In early tumors, 60.8% were of low grade compared with only 17% low-grade tumors at recurrence. Of 17 early tumors described as pure oligodendrogliomas, 76.5% remained in this lineage, regardless of their grade, whereas others changed to astrocytic tumors. Oligoastrocytic tumors had a significantly higher tendency to transform to astrocytic tumors. All pure oligodendrogliomas with 1p/19q codeletions remained phenotypically unchanged, unlike mixed tumors with codeletions, of which 83% changed their cell lineage. Of tumors with early 1p deletion, 80% remained oligodendroglial at progression, whereas 75% of tumors with an intact 1p changed to astrocytic phenotype. 10q loss was uncommon in both early and progressive tumors. The proportional gain in methylation at progression was 31% for tumors with early 1p deletion, unlike tumors with an intact 1p, which had an 87.5% gain of methylation at progression.

Conclusions: Pure oligodendrogliomas with 1p/19q deletion tend to retain their cell phenotype and genetic profile unlike tumors with no deletions or mixed histology. MGMT promoter methylation is more pronounced at tumor progression, particularly in tumors with an intact 1p. These observations suggest that MGMT promoter methylation is a late event in progressive oligodendrogliomas, and therefore, their chemosensitivity is not necessarily related to MGMT methylation status.