ATM missense variant P1054R ...

ATM missense variant P1054R predisposes to prostate cancer, ATM

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Radiotherapy and Oncology 83 (2007) 283–288
www.thegreenjournal.com
Molecular oncology
ATM missense variant P1054R predisposes to prostate cancer
Andreas Meyer
a,
*
, Bettina Wilhelm
b
, Thilo D¨rk
b
, Michael Bremer
a
,
Rolf Baumann
a
, Johann Hinrich Karstens
a
, Stefan Machtens
c,d
a
Department of Radiation Oncology,
b
Department of Gynaecology and Obstetrics, and,
c
Department of Urology, Hannover Medical
School, Germany,
d
Department of Urology, Marien-Krankenhaus Bergisch Gladbach, Germany
Abstract
Background: Prostate cancer is associated with defective DNA strand break repair after DNA damage leading to genetic
instability and prostate cancer progression. The ATM (ataxia–telangiectasia mutated) gene product is known to play an
important role in cell cycle regulation and maintenance of genomic integrity. We investigated whether the prevalence of
the ATM missense substitution P1054R is increased in a hospital-based series of prostate cancer patients and whether
carriers are at increased risk for treatment-related side effects.
Materials and methods: A consecutive series of 261 patients treated for early-stage prostate cancer with I-125
brachytherapy (permanent seed implantation) between 10/2000 and 04/2006 at our institution and a comparison group
of 460 male control individuals were screened for the presence of the P1054R variant. Outcome of therapy regarding
morbidity was assessed prospectively and compared between carriers vs. non-carriers with the International Prostate
Symptom Score (IPSS), a Quality-of-Life-index (QoL) and the International Index of Erectile Function (IIEF-15) with its
subgroups (IIEF-5 and EF).
Results: The proportion of carriers of the P1054R variant was signiﬁcantly higher among prostate cancer patients than
in the general population (25 out of 261 vs. 22 out of 460; OR 2.1; 95\% CI 1.2–3.8, p < 0.01). A subgroup of the carriers
additionally harboured the ATM missense variant F858L that was associated with a similar risk (OR = 2.2; 95% CI 1.1–4.6;
p = 0.03). After a mean follow-up of 18 months there were no statistically signiﬁcant differences regarding IPSS
(p = 0.48), QoL (p = 0.61), IIEF-15 score (p = 0.78), IIEF-5 score (p = 0.83), and EF score (p = 0.80), respectively.
Conclusions: The ATM missense variant P1054R confers an about twofold increased risk for prostate cancer in our
series. The subgroup of patients with the second-site variant F858L is not at signiﬁcantly higher risk. After 18 months,
there was no evidence for an increased adverse radiotherapy response in P1054R carriers.
c
2007 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 83 (2007) 283–288.
Keywords: Prostate cancer; Brachytherapy; ATM germline mutation; Late effects
Prostate cancer is the most common malignancy in the
male population in the European Union. The etiology of
prostate cancer is incompletely understood. Prostate can-
cer aggregates in families, indicating that genetic suscepti-
bility may be important, but the genes that may be involved
are largely unknown. The products of at least some suscep-
tibility genes might be involved in double-strand break (DSB)
repair as evidence has been presented that prostate cancer
is associated with genetic instability after DNA damage
[9]
.
DSB repair is initiated and monitored by ATM, the serine/
threonine kinase mutated in ataxia–telangiectasia (A–T)
[22]
and ATM activation is accompanied with earlier stages
of prostate tumorigenesis
[8]
.
Patients with A–T show hypersensitivity to ionising radi-
ation with devastating side effects
[11,17]
. In A–T hetero-
zygotes there is evidence for intermediate cellular
radiosensitivity and an increased risk of developing cancer
[3,18,19,25,29]
. One study has provided evidence that the
ATM missense substitution P1054R could be associated with
inherited prostate cancer risk
[1]
. Furthermore, it was re-
cently reported that ATM gene variants were predictive of
adverse radiotherapy reactions among patients treated for
prostate cancer with I-125 brachytherapy
[5]
.
In the present study, we aimed to replicate the associa-
tion of ATM variant P1054R with prostate cancer susceptibil-
ity and to investigate its potential association with deﬁned
clinical variables in a hospital-based series of patients trea-
ted with I-125 brachytherapy for early stage prostate
cancer.
Materials and methods
A hospital-based series of 261 unselected patients, who
were treated for prostate cancer between 10/2000 and
04/2006 at our institution, was screened for the presence
0167-8140/$ - see front matter
c
2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2007.04.029
284
ATM variant and prostate cancer
of the ATM missense variant P1054R (
Table 1
). Indications
for permanent brachytherapy were biopsy-proven adenocar-
cinoma of the prostate, clinically localised low risk early
prostate cancer (T classiﬁcation cT1a–cT2a) with a PSA
serum level <10 ng/ml and a Gleason sum <7. Brachytherapy
was administered via the transperineal approach. Intraoper-
ative dynamic planning and seed placement were performed
by using biplanar transrectal ultrasound imaging to direct
the placement of each radioactive source within the pros-
tate. The prescription dose for I-125 was 160 Gy. Post im-
plant dosimetry was carried out six weeks after the
implantation by using computed tomography. Outcome of
therapy regarding morbidity and PSA-response was com-
pared between carriers vs. non-carriers. Functional out-
come was measured prospectively with the International
Prostate Symptom Score (IPSS, ranging from 5 to 35 points
with a low score showing good function), the Quality-of-
Life-index (QoL, ranging from 0 to 6 points with a low score
showing good function), the International Index of Erectile
Function (IIEF-15, ranging from 5 to 75 points), a subgroup
of this test with 5 questions (IIEF-5, ranging from 1 to 25
points) and a subgroup consisting of 6 questions evaluating
the erectile function (EF, ranging from 1 to 30 points with
a high score showing good function), respectively. Biochem-
ical failure was deﬁned using the ASTRO consensus deﬁni-
tion
[2]
. Mean follow-up was 18 months for the total
cohort of prostate cancer patients. At the discretion of
the treating urologist, short-term (2–4 months pre-implan-
tation) neoadjuvant hormone therapy was given in 71 out of
the 261 patients. For comparison a series of 460 genomic
DNA samples was established at our hospital from random
healthy male blood donors.
We selectively chose the P1054R substitution (nucleotide
c.3161 C/G, rs1800057 in the SNP database at
) as candidate poly-
morphism in the ATM gene based on the ﬁndings of Angele
et al.
[1]
. Allele frequencies were assessed using restriction
fragment length polymorphism (RFLP) analysis with AlwI
after polymerase chain reaction (PCR) ampliﬁcation of a
genomic DNA fragment spanning the exons 23–24 with pre-
viously described primers
[21]
. PCR was carried out in a
total volume of 15 ll containing 50 ng DNA, 120 lM of each
dNTP, 1.5 mM MgCl
2
, 0.5 lM primer and 0.1 U Taq DNA poly-
merase. The cycling conditions were 94 C 5 min, followed
by 37 cycles of 94 C60s,59C60s,72C 60 s, with a ﬁnal
extension at 72 C for 5 min. PCR products were digested
with AlwI (New England BioLabs) according to the manufac-
turer’s instructions and the fragments were analysed by
electrophoresis on a 3% NuSieve agarose gel (FMC Biozym).
Next, we investigated a second-site missense variant,
F858L (rs1800056), that is known to be located in cis on a
subset of P1054R alleles and may be associated with a
Table 1
Patient’s characteristics of carriers vs. non-carriers of P1054R variant
Carrier
Non-carrier
p-value
Mean age at diagnosis (years)
63.8
65.5
0.14
T classiﬁcation
0.20
cT1c
0
5
cT2a
20
174
cT2b
3
45
cT2c
2
4
Unknown
0
8
Mean Gleason sum
5.88
5.67
0.17
3
0
4
4
3
14
5
2
47
6
15
164
7
5
6
8
0
1
Mean PSA level at diagnosis (ng/ml)
6.6
7.0
0.43
</= 4
3
25
>4–10
20
185
>10–20
2
26
Neoadjuvant hormone therapy
7
67
0.52
Mean preimplant ultrasound prostate volume (ccm)
37.3
38.9
0.59
Total activity (mCi)
28.4
30.3
0.40
Mean number of needles
22.4
22.5
0.91
Mean number of seeds
63.5
65.5
0.41
Mean dose to 90% of the prostate (Gy)
173.1
170.1
0.73
Mean dose to 90% of the apex of the prostate (Gy)
171.7
161.1
0.35
Mean dose to 90% of the base of the prostate (Gy)
146.7
147.6
0.93
Mean dose to 90% of the penile bulb (Gy)
77.5
83.7
0.66
Mean volume of rectum receiving 100% of prescription dose (ccm)
1.0
1.1
0.72
Mean volume of the apex of the prostate receiving 100% of prescription dose (ccm)
3.2
3.0
0.65
Mean volume of the base of the prostate receiving 100% of prescription dose (ccm)
4.1
3.7
0.5
Mean volume of the penile bulb receiving 100% of prescription dose (ccm)
0.5
0.5
0.81
A. Meyer et al. / Radiotherapy and Oncology 83 (2007) 283–288
285
similar or even higher increase in risk for certain malignan-
cies
[20,26,27]
. The F858L variant was assessed by RFLP
analysis following a previously published protocol
[7]
. In-
formed consent was obtained from all patients before blood
sampling, and the research project has been approved by
the local Ethical Committee.
Statistical considerations regarding differences in allele
and genotype frequencies between cases and controls
were made using Pearson’s v
2
and Log Odds Ratio tests
(Statistix 7.0). No adjustments for multiple testing were
required as the P1054R variant was the ﬁrst genetic variant
tested in this case-control series. Analyses were performed
using the Statistical Package for Social Sciences (SPSS
V14.0) software. Differences in proportions were derived
using the Fisher’s exact t-test. A two-sided p value of
<0.05 was considered to be signiﬁcant. The outcomes
regarding changes of the different functional scores during
time were statistically compared using the mixed model
analysis of variance.
18
16
14
12
10
8
6
4
Carrier
Non-Carrier
2
0
before impl. 1,5 months
post impl.
6 months
post impl.
12 months
post impl.
18 months
post impl.
24 months
post impl.
Fig. 1. Illustration of the International Prostate Symptom Score
(IPSS) of carrier vs. non-carrier. The IPSS ranges from 5 to 35 points
with a low score showing a good function.
50
45
40
35
Results
Twenty-ﬁve out of 261 prostate cancer patients (9.6%)
were identiﬁed as heterozygous carriers of the ATM se-
quence variant P1054R. In the control series, 22 out of
460 males (4.8%) were found to be carriers, including 1
homozygote. The proportion of P1054R carriers was signiﬁ-
cantly higher among the prostate cancer patients than in
the controls (OR 2.1; 95% CI 1.2–3.8; p = 0.01). Among
these, 17 out of the 25 prostate cancer patients and 14
out of the 22 male controls (incl. 1 homozygote) were iden-
tiﬁed to be carriers of the second-site variant F858L in exon
19 of the ATM gene (OR = 2.2; 95% CI 1.1–4.6; p = 0.03). The
P1054R allele in the absence of the F858L substitution still
appeared to confer a non-signiﬁcant increase in prostate
cancer risk (OR 1.8; 95% CI 0.7–4.8).
Patients who were heterozygous for the P1054R substitu-
tion tended to have an earlier age at diagnosis than non-car-
riers but this observation did not reach statistical
signiﬁcance (p = 0.14, 1-sided median test). We then inves-
tigated whether P1054R carriers showed a different clinical
outcome of brachytherapy compared with non-carriers.
There were no statistically signiﬁcant differences between
the two groups regarding the dose volume histograms
(DVH) obtained from the postimplant CT. Before implanta-
tion the mean IPSS for carriers vs. non-carriers was 6.0 vs.
6.7 (p = 0.45), QoL 1.17 vs. 1.35 (p = 0.46), IIEF-15 score
44.58 vs. 43.11 (p = 0.78), IIEF-5 score 14.88 vs. 14.13
(p = 0.73), and EF score 18.29 vs. 17.62 (p = 0.79), respec-
tively. Six weeks after implantation the scores for carriers
vs. non-carriers showed their maximum respective minimum
peak with a mean IPSS of 17.1 vs. 16.9 (p = 0.94), QoL of 3.2
vs. 3.1 (p = 0.57), IIEF-15 score of 30.5 vs. 28.8 (p = 0.73),
IIEF-5 score of 9.4 vs. 8.6 (p = 0.72), and EF score of 11.6
vs. 10.8 (p = 0.77), respectively. After mean follow-up of
18 months mean IPSS for carriers vs. non-carriers was 9.9
vs. 11.7 (p = 0.45), QoL 1.7 vs. 2.1 (p = 0.32), IIEF-15 score
37.7 vs. 37.0 (p = 0.92), IIEF-5 score 11.5 vs. 11.5
(p = 0.99), and EF score 14.2 vs. 14.4 (p = 0.95), respectively
30
25
Carrier
Non-Carrier
20
15
10
5
0
before impl. 1,5 months
post impl.
6 months
post impl.
12 months
post impl.
18 months
post impl.
24 months
post impl.
Fig. 2. Illustration of the International Index of Erectile Function
with 15 questions (IIEF-15) of carrier vs. non-carrier. The IIEF-15
ranges from 5 to 75 points with a high score showing good function.
(
Figs. 1 and 2
). If the scores are statistically compared using
the mixed model analysis of variance there were no statisti-
cally signiﬁcant differences regarding IPSS (p = 0.48), QoL
(p = 0.61), IIEF-15 score (p = 0.78), IIEF-5 score (p = 0.83),
and EF score (p = 0.80), respectively. One carrier developed
a proctitis of grade 2 regarding the Common Terminology
Criteria for Adverse Events v3.0 (CTCAE v3.0) vs. 7 non-car-
riers (p = 0.78). One patient not carrying the P1054R variant
showed three consecutive rises of the PSA level 24 months
after seed implantation and was treated with antihormone
therapy.
Discussion
Ionising radiation produces its biological effects mainly
through the generation of short-lived but highly reactive
radicals that result in DNA breaks. These trigger cellular
processes required for DNA damage recognition and DNA re-
pair by means of recombinational repair or nonhomologous
end-joining of DSBs, or base excision repair of other types
of single or simple clustered lesions, all of which are modu-
lated by genetic variation. Despite the advances in radio-
therapy delivery and modalities to increase the
286
ATM variant and prostate cancer
therapeutic ratio, the inherent biological complexity among
individuals due to variations in their genome has been a lim-
iting factor in predicting normal tissue radiosensitivity. The
ATM protein assumes a central role orchestrating the cellu-
lar response to DNA double-strand breaks
[14]
. While biall-
elic ATM gene mutations result in ataxia–telangiectasia
(A–T), a rare radiation sensitivity syndrome, it is estimated
that approximately 1% of the population is heterozygous for
a single ATM mutation and there is evidence for at least
some effect of monoallelic ATM gene mutations manifesting
as intermediate cellular radiosensitivity and an increased
risk of developing cancer in A–T heterozygotes
[3,18,19]
.
In the study presented here, we have addressed the prev-
alence and clinical impact of a particular ATM missense var-
iant, P1054R. Bioinformatic analysis using two different
software tools predicts this variant as damaging (SIFT,
<
>) or probably dam-
aging (PolyPhen, <
>).
A putative role for the P1054R variant in cellular radiosensi-
tivity and prostate cancer etiology was previously suggested
by two lines of evidence. First, P1054R carrying cell lines
have been found to exhibit an increased cellular radiosensi-
tivity in vitro
[12]
. Because genetic instability after DNA
damage is a feature of prostate cancer cells
[9]
, P1054R
could be one of the factors involved. Secondly, a large
case-control study of 624 prostate cancer patients and 417
controls has been reported with a signiﬁcantly higher prev-
alence of the P1054R variant in cases
[1]
, suggesting that
P1054R could be a prostate cancer susceptibility allele.
We have conﬁrmed a higher prevalence of the ATM se-
quence variant P1054R in our hospital-based series of pros-
tate cancer patients in comparison to population controls
from the same geographic region, supporting the ﬁndings
of Angele et al. that this variant is associated with an about
twofold increased prostate cancer risk. We furthermore
tested whether P1054R or a second-site variant F858L
underlies this increase in risk. The F858L variant is known
to occur on a subset of P1054R alleles
[7,26]
and has been
reported to confer a higher risk for leukemia than P1054R
[20]
. Our data indicate that the F858L variant, found on
the majority of P1054R alleles, is also associated with pros-
tate cancer susceptibility, but as its relative contribution
was similar in P1054R heterozygous cases and controls, it
does not appear to strongly increase the risk that is con-
ferred by the P1054R allele. The available data thus indicate
that the ATM variant P1054R represents a low-penetrance
prostate cancer susceptibility allele and, combining our
study with the study by Angele et al.
[1]
, is associated with
an about twofold increase in risk (Mantel–Haenszel Odds
Ratio 2.12; 95% CI 1.39–3.24; p < 0.001). Apart from pros-
tate cancer, previous association studies did not ﬁnd strong
support for a role of the P1054R variant in breast cancer sus-
ceptibility although these data may still be compatible with
low to moderate risks
[7,19,23]
. Our results are in line, how-
ever, with recent observations that P1054R may represent a
susceptibility allele for leukemia and for colorectal cancer
[16,20,27]
. Further research will be needed to fully eluci-
date the spectrum of malignancies that are inﬂuenced by
the ATM variant P1054R.
The question whether inherited variations in repair genes
modulate the effectiveness and clinical toxicity of radiation
therapy is important as permanent interstitial brachyther-
apy is an increasingly popular approach for the treatment
of early and localised prostate cancer. Long-term data show
results of biochemical and local tumour control to be as
effective as after radical prostatectomy or external beam
radiotherapy
[10,15]
. Dose escalation has been suggested
to improve prostate cancer control by the use of three-
dimensional conformal radiotherapy, intensity-modulated
radiotherapy and brachytherapy. In prostate seed implanta-
tion correlation between implanted dose and freedom from
PSA failure could be demonstrated by Stock et al., who
found that a D90 value of more than 140 Gy was associated
with an improved biochemical control rate
[24]
. Most pa-
tients with permanent seed implantation have normaliza-
tion of their urinary complaints by one year postimplant,
as could be shown by Bottomley et al.
[4]
. The incontinence
rates vary between 0% and 19%, a grade 3 urinary morbidity
has been found to occur in 1–3% of the patients, and rectal
complications such as proctitis range from 1% to 21%. The
occurrence of erectile dysfunction is most signiﬁcantly
inﬂuenced by the pre-treatment erectile function
[15]
.
The best strategy to identify patients who are potentially
at risk for the development of radiation-induced late effects
on the one hand and for patients who may beneﬁt most from
brachytherapy on the other hand is currently unknown. In
these instances it could be very helpful to predict radiosen-
sitive patients in order to avoid enhanced late toxicities.
Up to now only few studies have examined the relation-
ship of polymorphism in the ATM gene and clinical outcome
of prostate cancer in terms of acute and late side effects
after exposure to ionising radiation. Weissberg et al. evalu-
ated the medical records of obligate A–T heterozygotes
treated with radiation therapy for breast (n = 11) or pros-
tate cancer (n = 2). They found no instances of soft tissue
necrosis or other apparent serious injuries to normal tissues
[28]
. Hall et al. examined 17 prostate cancer patients with
severe late sequela, speciﬁcally proctitis or cystitis, after
high-dose external-beam conformal radiation therapy. They
reported that three of them (17.6%) carried mutations in
the ATM gene vs. no patient in the control group
[13]
. Dam-
araju et al. explored the possible relationship between 49
single nucleotide polymorphisms (SNPs) in certain candidate
genes with clinical radiation toxicity in a retrospective co-
hort of 83 patients previously treated with three-dimen-
sional conformal radiotherapy for prostate cancer.
Signiﬁcant associations with toxicity were found for SNPs
in LIG4, ERCC2 and CYP2D6 genes. The authors suggested
SNPs in the above-mentioned genes as putative markers to
predict individuals at risk for complications arising from
radiation therapy in prostate cancer. However, regarding
SNPs in the ATM gene, only the D1853N and not the
P1054R polymorphism was screened
[6]
. Cesaretti et al.
examined 37 patients treated with I-125 prostate brachy-
therapy with a follow-up of more than 12 months. They
screened for DNA sequence variations in all 62 coding exons
of the ATM gene. Ten out of 16 patients (63%) harbouring
one of 21 ATM sequence alterations exhibited at least one
form of adverse response versus 3 out of 21 patients (14%)
who did not harbour an ATM sequence variation. The
authors suggested that ATM sequence variants, particularly
those encoding amino acid substitutions, were predictive
A. Meyer et al. / Radiotherapy and Oncology 83 (2007) 283–288
287
for the development of adverse radiotherapy responses.
However, only one patient carried a P1054R mutation, and
this patient did not exhibit adverse effects after a follow-
up of 27 months
[5]
.
Given the previously reported association of ATM se-
quence alterations with radiation related side-effects, we
might have expected a higher incidence of adverse radio-
therapy responses among P1054R carriers. However, we
could not demonstrate that heterozygosity for this ATM se-
quence variant is predictive for the development of an ad-
verse radiotherapy response regarding IPSS, erectile
function and proctitis. One reason could be that our fol-
low-up may be too short to detect any statistically signiﬁ-
cant differences. The increased cellular radiosensitivity
may render tumour cells more susceptible to the cell killing
effect of ionising radiation potentially leading to an en-
hanced therapeutic ratio. However, all patients included
in this study had low-risk prostate cancer, and were treated
with optimum implants based upon evaluation of their post-
brachytherapy dosimetric studies. Additionally, the follow-
up is short yet to detect a PSA failure, and therefore, it
was not possible to examine whether carrier showed in-
creased tumour radiosensitivity. Finally, it is likely that
ATM is not the only genetic variant that may predispose pa-
tients to adverse radiotherapy responses. Thus, the patients
in this series who exhibited pronounced radiation-related
morbidity but proved negative for the ATM sequence variant
P1054R may possess other ATM sequence variants or altera-
tions in genes other than ATM associated with adverse nor-
mal tissue radiation response. More comprehensive genetic
screening of radiotherapy patients for DNA sequence varia-
tions in candidate genes associated with adverse radiation
response could contribute to the deﬁnition of predictive risk
models in individual patients with prostate cancer to im-
prove the therapeutic ratio. The knowledge of the interac-
tion of various SNPs in candidate genes may ultimately
result in a prediction of radiotherapy late effects leading
to a more individualised therapy.
In summary, we have conﬁrmed the proposed associa-
tion of the ATM
*
P1054R missense substitution with an in-
creased prostate cancer risk. However, we could not
detect the increased side effects between carriers and
non-carriers previously described by others. Further stud-
ies of candidate gene variants for radiosensitivity will be
needed and might have important clinical implications
for prostate cancer.
*
Corresponding author. Andreas Meyer, Department of Radia-
tion Oncology, Medical School Hannover, Carl-Neuberg-Str. 1, 30625
Hannover, Germany. E-mail address:
Received 22 March 2007; received in revised form 30 April 2007;
accepted 30 April 2007; Available online 14 May 2007
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Conﬂict of Interest Statement
All authors disclose any ﬁnancial and personal relation-
ships with other people or organisations that could inappro-
priately inﬂuence their work.
Acknowledgements
We thank J¨rn Hageman and J¨rgen Serth for their support in
the recruitment of patients. This work was supported by an intra-
mural research grant at Hannover Medical School and by funds from
the Lower Saxonian Cancer Society.
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