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Specific genetic predictors of
chemotherapeutic response and survival in patients with anaplastic
oligodendrogliomas
JG Cairncross, K Ueki, MC
Zlatescu, DK Lisle, DM Finkelstein, RR Hammond, JS Silver, PC Stark,
DR Macdonald, Y Ino, DA Ramsay and DN Louis
Department of Medical and
Experimental Oncology, London Regional Cancer Centre, Ontario, Canada.
Background/Methods.
Gliomas are common malignant neoplasms of the central nervous
system.
Among the major subtypes of gliomas, oligodendrogliomas are distinguished
by their remarkable sensitivity to chemotherapy, with approximately
two thirds of anaplastic (malignant) oligodendrogliomas responding
dramatically to combination treatment with procarbazine, lomustine,
and vincristine (termed PCV).
Unfortunately, no clinical or pathologic feature of these
tumors allows accurate prediction of their response to
chemotherapy.
Anaplastic oligodendrogliomas also are distinguished by a
unique constellation of molecular genetic alterations, including
coincident loss of chromosomal arms 1p and 19q in 50%-70% of tumors.
We have hypothesized that these or other specific genetic changes
might predict the response to chemotherapy and prognosis in
patients with anaplastic oligodendrogliomas.
Therefore, we have analyzed molecular genetic alterations
involving chromosomes 1p, 10q, and 19q and the TP53 (on chromosome
17p) and CDKN2A (on chromosome 9p) genes, in addition to clinicopathologic
features in 39 patients with anaplastic oligodendrogliomas
for whom chemotherapeutic response and survival could be assessed.
Result/Conclusions.
Allelic loss (or loss of heterozygosity) of chromosome 1p
is a statistically significant predictor of chemosensitivity, and
combined loss involving chromosomes 1p and 19q is statistically significantly
associated with both chemosensitivity and longer recurrence-free
survival after chemotherapy.
Moreover, in both univariate and multivariate analyses,
losses involving both chromosomes 1p and 19q were strongly
associated with longer overall survival, whereas CDKN2A gene deletions
and ring enhancement (i.e., contrast enhancement forming a rim around
the tumor) on neuroimaging were associated with a significantly worse
prognosis.
The inverse relationship between CDKN2A gene deletions and losses
of chromosomes 1p and 19q further implies that these differential
clinical behaviors reflect two independent genetic subtypes of
anaplastic oligodendroglioma.
These results suggest that molecular genetic analysis may
aid therapeutic decisions and predict outcome in patients with anaplastic
oligodendrogliomas.
Copyright © 1998 by Oxford
University Press
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