Biology Reference
In-Depth Information
by promoter methylationwas a strong prognostic factor.
77
This study was independently validated five years later
by Hegi
et al.
, who noted that a loss of MGMT expression
through promoter methylation was a significant prog-
nostic factor in patients treated with radiation and temo-
zolomide, with a significant prolongation of survival in
patientswithmethylatedMGMT promoterwith amedian
six-month improvement in survival and a much higher
rate of long-term survival of over two years. There did
not appear to be benefit of temozolomide in patients
with MGMT expressing gliomas.
87
This similar survival benefit had been observed by Paz
et al.
88
for patients treatedwithBCNUor procarbazine and
noted a strong correlation with partial and complete
responses. It was also confirmed in a study of pediatric
patients with glioblastoma in which the median survival
of patients with promoter methylated MGMT was
almost 14 months compared to only 2.5 months for
patients whose tumors expressed MGMT.
89
More
recently, the German Glioma Network confirmed that
MGMT promoter methylation combined with treatment
including temozolomide and radiation resulted in
improved overall survival and response rate with signifi-
cantly reduced risk for progression. As a prognostic factor,
promotermethylationofMGMTwasmore important than
another molecular marker, IDH1 mutations.
90
Of note,
however, a study involving the use of CENU in patients
with glioma failed to showa relationship betweenmethyl-
ation pattern of MGMT and response or survival.
91
In summary, there is ample evidence linking
promoter methylation of MGMT to loss of protein
expression, increased sensitivity to chemotherapeutic
agents, in particular, temozolomide, and to the prog-
nostic outcome of patients treated with either Massa
letting agents or chloroethylating agents. The etiology
of MGMT promoter methylation in tumorigenesis is still
to be determined. It may be that loss of gene expression
is important both in tumorigenesis and has an overall
global prognostic factor given that many genes have
altered expression when chromatin is remodeled in the
process of carcinogenesis in tumor progression. Mean-
while, active attention to promoter methylation assess-
ment in tumors prior to chemotherapy treatment is
a reasonable approach and is being investigated in
a number of clinical settings.
concentrated on the prognostic factors associated with
altered promoter methylation and gene expression as
a factor in the aggressiveness of tumor growth.
Loss of MGMT expression due to altered alterations in
promoter methylation are linked to loss of expression of
mismatch repair proteins,
K
-
ras
mutations, due to
increased susceptibility to O
6
meG induced mutations,
and to tumor progression.
74,75
Esteller
et al.
reported
a very high frequency of G to A transitions in K-
ras
in
colon cancers that showed evidence of promoter hypome-
thylation due to the inability of MGMT to remove the
O
6
meG lesion. Since this lesion is known to induce G to
A transitions in
K
-
ras
, it is logical to conclude that there
is a physiological link between silencing of MGMT and
colon cancer progression of K-
ras
mutation.
76,77
In
a number of tumors, a pattern in which multiple oncoge-
nes expression is altered associated with hyper-
methylation of the MGMT promoter has been shown.
These include retinoblastoma tumors,
78
gastric carci-
noma,
79
and lung cancers in which 36% of patients with
human lung adenocarcinomas were observed to have
hypomethylation of the
MGMT
gene independent of
smoking history but associated with more undifferenti-
ated tumors compared to well-differentiated adenocarci-
nomas.
80,81
These studies were followed by Belinsky and
coworkers who found that the level of MGMT methyla-
tion in the non-small cell lung cancer adenocarcinomas
was higher in non-smokers and perhaps in those exposed
to radon and other agents and was linked to
K
-
ras
muta-
tions.
82
In contrast, G to A mutations have been observed
in astrocytomas within the
TP53
gene associated with
promoter methylation of MGMT.
83
Likewise, squamous
cell esophageal carcinomas were also found to have
ahighrateofMGMTpromotermethylationinlossof
MGMTexpression that was not correlatedwithmutations
in
p53.
84
A similar study made the same observation in
head and neck squamous cell carcinoma.
85
Promoter
methylation of MGMT may also be important in tumor
progression, particularly in sporadic colon cancer. A
study published in the
JNCI
found MGMT promoter
methylation in the normal mucosa surrounding a colon
carcinoma suggesting that MGMT promoter methylation
was involved in tumor progression.
86
Perhaps the most cited observation established a high
rate of MGMT promoter methylation in patients with
glioma undergoing treatment with alkylating agents and
linked thiswith overall survival, suggesting a relationship
between MGMT promoter methylation and sensitivity
and impact of either BCNU or temozolomide. Since both
agents form alkylations at the O
6
position of guanine,
the role of MGMT in resistance had been clinically
expected. This carefully done study provided the first
evidence of a clinical impact of MGMT expression on
outcome of treatment in patients with glioma. In fact, in
this patient population, MGMT expression as predicted
MGMT IN GENE THERAPY
With the successful cloning of MGMT cDNA by
several labs in the early 1990s,
92
e
94
detailed analyses of
the amino acids responsible for MGMT function were
performed, leading to the identification of a crucial
cysteine-145 residue as the acceptor of methyl or alkyl
adduct within human MGMT protein.
95
After repairing
