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polymorphisms at codon 6 are significant predictors of
progression and survival. 236
The inter-patient variability in normal tissue toler-
ance to radiation may not only depend on fractionation
schedule, fraction size, volume of treatment field and
total dose of radiation given but also on the ability of
DSB repair to process radiation-induced DNA damage.
The Genetic Predictors of Adverse Radiotherapy Effects
(Gene-PARE) project aims to develop a validated test
capable of predicting which patients would be most
likely to develop adverse responses to radiation treat-
ment. 237 A clinical database and continuously expand-
ing biorepository consisting of frozen lymphocytes
and DNA isolated from patients treated with radio-
therapy allows a systematic screen of variants of
ATM, TGFB1, XRCC1, XRCC3, SOD2, and hHR21. It is
anticipated that the Gene-PARE project will provide
valuable information to allow radiation oncologists
to use genetic data to personalize radiotherapy. 237 The
ATM gene is mutated in the recessive cancer-prone
disease ataxia telangiectasia (AT). Ataxia telangiectasia
is also characterized by cerebellar ataxia, skin, and
ocular telangiectasias, immunodeficiency, and extreme
radiosensitivity. 238,239 Accordingly a number of SNPs
have been described and several studies suggest that
a disproportionate number of cancer patients who
experience enhanced clinical radiation sensitivity and
severe late responses to radiotherapy are heterozygous
for ATM variant alleles. In breast cancer patients treated
with adjuvant
Thr/Thr genotype in XRCC3 codon 241 was correlated
to increased risk of subcutaneous fibrosis as well as
telangiectasia, and the Arg/Arg genotype in XRCC1
codon 399 was associated with increased risk of
radiation-induced subcutaneous fibrosis. 248 However,
a further study found no association between polymor-
phisms in codons 194, 280, and 399 of XRCC1, codon 241
of XRCC3, codon 1853 of ATM, and codon 148 of APE1
and risk of subcutaneous fibrosis. 242 Similarly, polymor-
phisms within XRCC1 (codon 399), XRCC3 (codon 241),
APE1 (codon148), and ATM (codon 1853) were also not
associated with increased risk of change in breast
appearance post radiotherapy. 241 In BRCA1/BRCA2
mutation carriers undergoing radiotherapy for breast
cancer, no association between acute or late effects of
radiation and BRCA1/BRCA2 mutations were found. 249
Similarly another study demonstrated no association
between BRCA mutations and acute chemotherapy
toxicity in breast cancer. 250
A further study of radiosensitivity in breast cancer
patients investigated the association between genetic
polymorphisms in DNA repair genes XRCC1
(Arg399Gln and Arg194Trp), XRCC3 (Thr241Met),
XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-
6T
C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT
(Leu84Phe). XRCC3-241 Met, MSH2 gIVS12-6nt-C, and
MSH3-1045Ala variant allele carriers were all associated
with increased radiosensitivity. The combination of
XRCC1-Arg194Trp variant allele and XRCC1-
Arg399Gln wild-type allele was associated with a high
risk of radiosensitivity. 251 The risk of a grade 2 or higher
acute skin reaction from breast cancer radiotherapy is
increased nearly three-fold in Chinese patients carrying
the XRCC1-77TC and CC genotypes. 252
In prostate cancer patients treated with three-dimen-
sional conformal radiotherapy, 240 significant univariate
associations with late rectal or bladder toxicity were
found for XRCC3 (A
>
radiotherapy ATM polymorphisms
IVS22-77 T
G may be associated
with clinical radioprotection when present in the
heterozygote state, whereas the G5557A variant in the
homozygote state was associated with enhanced clin-
ical radiosensitivity. 239 This observation, however, has
not been confirmed in other studies. 240 e 243
In a prospective study of breast cancer patients who
received radiotherapy after breast-conserving surgery,
APE1 148Glu and the XRCC1 399Gln alleles had
decreased risk of acute skin reactions after radiotherapy
whereas in homozygote carriers of the wild-type allele
in both genes, the risk was most strongly reduced in
carriers of both APE1 148Glu and XRCC1 399Gln
alleles. 244 Another study of 254 breast cancer patients,
XRCC1 Arg194Trp, and XRCC1 Arg399Gln polymor-
phisms were more frequently associated with radiation
sensitivity. 245 A small pilot study of patients with
various cancers found an association between microsa-
tellite polymorphisms in XRCC1 and XRCC3 and radia-
tion sensitivity. 246 A prospective study found no
significant association between risk of acute skin toxicity
and XRCC3 Thr241Met, XRCC2 Arg188His, and NBS1
Glu185Gln polymorphisms in patients with breast
cancer receiving radiotherapy. 247 A study of 41 patients
given post-mastectomy radiotherapy found that
CandIVS48
þ
238 C
>
>
G 5' untranslated region NT
4541), LIG4 Asp568Asp and MLH1 Val219Ile). Cox
multivariate analysis showed significant associations
with toxicity and LIG4 Asp568Asp and ERCC2
Asp711Asp. 240 In cervical or endometrial cancer treated
with radiotherapy, XRCC3 IVS5-14 polymorphic allele
was significantly associated with the risk of developing
late radiotherapy reactions, whereas XRCC1 codon 194
variant was protective against radiotherapy. 253 Polymor-
phisms in hHR21 gene, involved in DNA double-strand
break repair and sister chromatid cohesion has also been
linked to radiosensitivity. 254
Lys/Gln
>
Gln/Gln genotypes of XPD Lys751Gln
polymorphism have been found to be associated with
a significantly reduced risk of radiation-induced esoph-
ageal toxicity in patients with locally advanced lung
cancer treated with radiotherapy. 255 In a pilot case-
control study of 60 patients treated with radiotherapy
þ
the
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