Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization

Abstract

Oligodendroglial neoplasms are a subgroup of gliomas with distinctive morphological characteristics. In the present study we have evaluated a series of these tumors to define their molecular profiles and to determine whether there is a relationship between molecular genetic parameters and histological pattern in this tumor type. Loss of heterozygosity (LOH) for 1p and 19q was seen in 17/23 (74%) well-differentiated oligodendrogliomas, in 18/23 (83%) anaplastic oligodendrogliomas, and in 3/8 (38%) oligoastrocytomas grades II and III. LOH for 17p and/or mutations of the TP53 gene occurred in 14 of these 55 tumors. Only one of the 14 cases with 17p LOH/TP53 gene mutation also had LOH for 1p and 19q, and significant astrocytic elements were seen histologically in the majority of these 14 tumors. LOH for 9p and/or deletion of the CDKN2A gene occurred in 15 of these 55 tumors, and 11 of these cases were among the 24 (42%) anaplastic oligodendrogliomas. Comparative genomic hybridization (CGH) identified the majority of cases with 1p and 19q loss and, in addition, showed frequent loss of chromosomes 4, 14, 15, and 18. These findings demonstrate that oligodendroglial neoplasms usually have loss of 1p and 19q whereas astrocytomas of the progressive type frequently contain mutations of the TP53 gene, and that 9p loss and CDKN2A deletions are associated with progression from well-differentiated to anaplastic oligodendrogliomas.

Figure 1.

CGH profile of well-differentiated oligodendroglioma 969A, which shows only loss of 1p and 19q.

Figure 2.

Composite of CGH findings for the 23 well-differentiated oligodendrogliomas. In addition to the frequent losses of 1p and 19q, losses of all or part of chromosomes 4, 14, and Y are noted.

Figure 3.

CGH profile of anaplastic oligodendroglioma 969B, which is the recurrence (6 years later) of the well-differentiated tumor shown in Figure 1 ▶ . In addition to the 1p and 19q loss seen originally, loss of chromosomes 4, 9, and 18 and gain of portions of chromosome 11 and X are seen.

Figure 4.

Composite of CGH findings for 24 anaplastic oligodendrogliomas. Although these tumors share with the well-differentiated lesions a high incidence of loss of 1p and 19q, this group has more numerous chromosomal deviations. The most frequent changes are losses of all or part of chromosomes 4, 9p, 15, and 18.

Figure 5.

CGH profile of case 1072, which was classified as a glioblastoma based on the presence of necrosis with pseudopalisading (see Figure 8, A and B ▶ ). Loss of 1p and 19q, seen here, along with amplification of 17q, suggests that this lesion should be considered an anaplastic oligodendroglioma.

Figure 6.

CGH profile of case 905, which is a glioblastoma with oligodendroglial features (see Figure 8, C and D ▶ ). The gain of chromosome 7, amplification at the EGFR locus, and loss of 9p and chromosome 10 support classification of this tumor as a glioblastoma.

Figure 7.

A and B: Well-differentiated oligodendroglioma 969A is composed of a uniform population of cells with round regular nuclei. C and D: Anaplastic oligodendroglioma 969B is the recurrence (6 years later) of the lesion shown in A and B. This tumor is hypercellular and is composed of anaplastic cells with hyperchromatic nuclei. Endothelial proliferation and necrosis are present. H&E, ×200 (A); ×400 (B); ×200 (C); ×200 (D).

Figure 8.

A and B: Case 1072 was originally classified as a glioblastoma based on necrosis with pseudopalisading (A). The presence of oligodendroglial areas (B) and the molecular profile showing loss of 1p, 9p, and 19q (Figure 5 ▶ , Table 2 ▶ ) suggest that it should be considered an anaplastic oligodendroglioma instead. H&E, ×100 (A); ×400 (B). C and D: Case 905 was classified as a glioblastoma, with necrosis and pseudopalisading and endothelial proliferation (C). Although the histological pattern was reminiscent of an oligodendroglial lesion in some areas (D), the molecular profile supports classification as a glioblastoma (Figure 4 ▶ , Table 3 ▶ ). H&E, ×200 (C); ×800 (D).