|
|
Evaluation of
expression of DNA repair molecules as a prognostic factor for long-term
survivors with glioblastoma multiforme (GBM) treated on RTOG protocols with
irradiation and nitrosoureas
C. Ford, W. Seiferheld, A. K. Choucair, J. Hansen, B. Dabbas, C. Schultz, A.
Schulsinger, M. Mehta, W. Curran
LDS Hospital, Salt Lake City, UT; American College of Radiology,
Philadelphia, PA; Medical College of Wisconsin, Milwaukee, WI; Sunny Health
Science Center, Brooklyn, NY; University of Wisconsin, Madison, WI; Thomas
Jefferson University Hospital, Philadelphia, PA
Background. Adding BCNU to irradiation appears to modestly increase one
and two year survival in GBM patients.
BCNU attaches a chloroethyl adduct to the O6 position of guanine
followed by formation of a DNA interstrand cross-link.
These lesions may be repaired by alkyl-guanine transferase (AGT) and nucleotide
excision repair (NER)/homologous recombinational repair (HRR) pathways,
respectively.
BCNU-initiated apoptosis signaling depends on intact DNA mismatch repair
(MMR).
Defects in MMR and intact NER/HRR and p53 expression may be linked to BCNU
insensitivity.
We hypothesized that these may also be prognostic factors in GBM.
Methods. We compared the expression of AGT, ERCC1 (involved in the DNA
nicking step of NER/HRR), the MMR proteins hMLH1 and hMSH2, and p53 between
tumor samples, selected from the RTOG tissue bank, from 28 long term (>18
months) and 35 short term (< 6 months) GBM survivors receiving irradiation
and nitrosoureas on RTOG protocols.
Tumor cell nuclear expression was determined by immunohistochemistry using the
Chromovision automated cell imaging system.
Results. The two groups vary in age (p=0.003) and KPS (p=0.02) but not
extent of resection (p=0.12).
|
|
Short Term
|
Long Term
|
p=(univariate)
|
p=(multivariate)+
|
|
AGT
|
10.2*
|
14.1
|
0.21
|
0.30
|
|
ERCC1
|
64.0
|
60.3
|
0.54
|
0.26
|
|
P53
|
31.0
|
33.6
|
0.68
|
0.42
|
|
hMLH1
|
40.2
|
49.8
|
0.16
|
0.85
|
|
hMLH1 (Low AGT)
|
29.9
|
45.1
|
0.18
|
0.46
|
|
hMSH2
|
17.0
|
19.4
|
0.48
|
0.88
|
|
hMSH2 (Low AGT)
|
9.3
|
14.6
|
0.19
|
0.49
|
Conclusions. Within this patient population the levels of the DNA repair
molecules examined do not predict for long term survivorship.
No interaction between MMR and AGT was observed.
Larger future studies should examine the expression of these and additional
factors involved in the repair of nitrosourea induced DNA adducts.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-00687,00.asp
|
