original article
Annals of Oncology 22: 1088–1093, 2011
doi:10.1093/annonc/mdq569
Published online 1 December 2010
Lower ataxia telangiectasia mutated (ATM) mRNA
expression is correlated with poor outcome of laryngeal
and pharyngeal cancer patients
K.-W. Lee1,2,3, Y.-S. Tsai4,5, F.-Y. Chiang1,2, J.-L. Huang6, K.-Y. Ho1,2, Y.-H. Yang7,
W.-R. Kuo1,2, M.-K. Chen8,9 & C.-S. Lin4,5*
1
Department of Otolaryngology, Kaohsiung Medical University Hospital, Kaohsiung; 2Department of Otolaryngology, Faculty of Medicine, College of Medicine; Kaohsiung
Medical University, Kaohsiung; 3Department of Otolaryngology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung; 4Graduate Institute of Medicine, College of
Medicine, Kaohsiung; 5Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung; 6Department of Bioscience Technology, Chang
Jung Christian University, Tainan; 7Department of Dental Hygiene, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung; 8Department of
Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua; 9School of Medicine, Chung Shan Medical University, Taichung, Taiwan
original
article
Received 12 September 2009; revised 13 March 2010 & revised 8 June 2010; accepted 16 August 2010
Background: Ataxia telangiectasia mutated (ATM) kinase is a critical regulator in initiating DNA damage response
and activating DNA repair. However, the correlation between ATM expression and the outcome of laryngopharyngeal
cancer patients is unknown. We hypothesize that ATM expression is correlated with a worse outcome in
laryngopharyngeal cancer patients.
Patients and methods: The ATM messenger RNA (mRNA) expression of 80 tumors of laryngeal and pharyngeal
cancer was examined by real-time quantitative RT-PCR. Overall survival rates were measured using Kaplan–Meier
estimates and the log-rank tests. The adjusted hazard rate ratios (HRRs) were computed by multivariate Cox
regressions.
Results: Reduced ATM mRNA was found in 65 of 80 studied cases. Lower ATM expression [tumor/normal <0.3,
HRR = 2.49; 95% confidence interval (CI) 1.27–4.88], younger age (<55 years, HRR = 2.71; 95% CI 1.16–6.32), and
larger tumor (T3/T4, HRR = 2.21; 95% CI 1.10–4.44) were independent risk factors for survival. Patients with lower
ATM and younger age (HRR = 6.51; 95% CI 2.05–20.66) or with lower ATM and T3/T4 tumor (HRR = 5.23; 95% CI
2.04–13.40) exhibited the poorest outcome.
Conclusion: The expression of ATM mRNA, which is frequently downregulated in laryngeal and pharyngeal cancers,
could be a valuable prognostic marker.
Key words: ataxia telangiectasia mutated, laryngeal cancer, pharyngeal cancer, survival analysis
introduction
DNA damage response plays an important role in the
maintenance of genome integrity. Defects or dysregulation of
genes involved in DNA damage response and DNA repair can
result in genomic instability, which is a common feature of cancer
cells [1]. Head and neck squamous cell carcinoma (HNSCC) is
the sixth most common cancer in the world. It has been suggested
that genomic instability may be involved in the development of
HNSCC [2–4]. Some studies have shown that DNA repair
activity is reduced in the peripheral blood cells of HNSCC
patients when compared with normal individuals [5, 6]. These
indicate that interference of DNA damage repair may contribute
*Correspondence to: Dr C.-S. Lin, Graduate Institute of Medicine, College of Medicine,
Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan.
Tel: +886-7-3121101-2019; Fax: +886-7-3218309; E-mail: [email protected]
to tumorigenesis of HNSCC. Nevertheless, studies on DNA repair
gene expression in head and neck cancers are limited so far.
Ataxia telangiectasia mutated (ATM) kinase is a critical
regulator in DNA damage response and is conserved in all
eukaryotes from yeast to human. It is activated immediately upon
DNA damage and then phosphorylates p53, BRCA1, CHEK1/2,
and many others, which lead to activation of DNA repair and cell
cycle arrest [7]. Germline mutation of ATM gene results in ataxia
telangiectasia, a syndrome susceptible to various cancers. Loss of
ATM gene or decreased ATM expression is found in human
cancers [8–14]. Parikh et al. [14] found that the ATM locus was
partially lost in 8 of 11 HNSCC cell lines examined and in at least
60% of human malignancies including HNSCC. This partial loss of
ATM locus was correlated with a reduced expression of ATM
protein level in HNSCC cell lines [14]. In addition, Ai et al. [15]
and Bolt et al. [16] have shown hypermethylation of ATM
promoter in head and neck cancer, suggesting that ATM
expression might be repressed. Indeed, He et al. [10] found an
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]
original article
Annals of Oncology
absent or reduced ATM protein expression in 31.25% of oral
squamous cell carcinoma, and the patients with reduced/absent
ATM expression had poorer differentiated tumor and more lymph
node invasion. Bose et al. [8] also showed that ATM messenger
RNA (mRNA) and protein were downregulated in Epstein–Barr
virus-associated nasopharyngeal carcinoma. However, whether
ATM expression is also repressed in HNSCC at larynx and pharynx
subsites and whether ATM expression is correlated with HNSCC
patient outcome are unclear. In these regards, we examined ATM
expression in laryngeal and pharyngeal cancers and correlated
ATM expression with clinicopathologic parameters to explore the
role of ATM expression in the prediction of patient outcome.
patients and methods
subjects
The specimens of 40 laryngeal cancer patients (17 paired tumor and adjacent
normal tissues plus 23 tumors only) and 40 pharyngeal cancer patients (15
paired tumor and adjacent normal tissues plus 25 tumors only) were obtained
from the Department of Otolaryngology, Kaohsiung Medical University
Hospital. These specimens were collected after obtaining patient’s informed
consent, and the study was approved by the Institutional Review Board.
Specimens were snap frozen in liquid nitrogen and were stored at 280C
until use. The age of patients was between 33 and 82 years, with the median of
61 years, the first quartile of 54 years, and the third quartile of 70 years.
RNA isolation, reverse transcription, and real-time
quantitative PCR
The method for quantitatively analyzing mRNA expression was as described
in our previous paper [17]. Briefly, total RNA was isolated by Tri-reagent
(Sigma–Aldrich, St Louis, MO). Reverse transcription was conducted with 1
lg of total RNA and the High-Capacity cDNA Archive Kit (Applied
BioSystems, Foster City, CA) in 20 ll. The resulting complementary DNA
(cDNA) was subsequently diluted to a total volume of 100 ll and 2 ll of
diluted cDNA was used as templates for real-time quantitative PCR
(Q-PCR). Q-PCR was carried out in a total volume of 20 ll using
PowerSYBR Green reagent (Applied BioSystems) and ABI Prism 7500
Sequence Detection System instrument (Applied BioSystems). The PCR
condition was 50C for 2 min, 95C for 10 min followed by 50 cycles at 95C
for 15 s and 60C for 1 min. Dissociation curve was added at the final step to
validate that only the specific target was amplified. The PCR primers were
designed using the ProbeFinder software (Roche Applied Science,
Mannheim, Germany) and were
ATM-F: ATAGATTGTGTAGGTTCCGATGG, ATM-R:
CATCTTGTCTCAGGTCATCACG; ACTB-F: ATTGGCAATGAGCGGTTC,
ACTB-R: GGATGCCACAGGACTCCAT. The ATM mRNA level in each
sample was calculated by 22DDCT method [18] and ACTB was used as an
internal control. Each specimen was examined by at least two independent
rounds of reverse transcription and Q-PCR reactions for ATM and internal
control. In all cases with paired specimens, the ATM mRNA expression of
each case was represented by the ratio of ATM mRNA level in each tumor to
that of the corresponding normal part. For the cases with tumor parts only,
the mean ATM mRNA levels of all normal tissue specimens were used for
comparison with those from each individual tumor.
statistical analyses
The ATM mRNA expressions were categorized into two groups (<0.3 and
‡0.3) according to Receiver-Operating Characteristic analysis. Its
relationship with clinicopathologic variables was analyzed by Chi-square or
Fisher’s exact test. Kaplan–Meier estimates and the log-rank tests were
Volume 22 | No. 5 | May 2011
employed to compare the survival rates for clinicopathologic variables. The
hazard rate ratios (HRRs) and adjusted HRRs were further computed by
univariate and multivariate Cox regressions.
results
ATM mRNA is downregulated in laryngeal and
pharyngeal cancers
To examine ATM expression in laryngeal and pharyngeal
cancers, we harvested total RNA from 80 surgically resected and
previously untreated tumors. The characteristics of patients were
shown in Table 1. The ATM mRNA expression was determined
by real-time quantitative RT-PCR using ACTB as an internal
control. The results showed that ATM mRNA expression was
decreased (tumor/normal <1) in 65 of 80 (81.3%) laryngeal and
pharyngeal cancers (Table 1). The median of ATM mRNA
expression (tumor/normal) in the 80 cases was 0.364, and the
25% and 75% quartiles were 0.222 and 0.762, respectively
(Figure 1). These results demonstrated that ATM mRNA was
frequently downregulated in laryngeal and pharyngeal cancers.
ATM mRNA expression is correlated with survival
of laryngeal and pharyngeal cancer patients
To explore the possible role of decreased ATM expression in
laryngeal and pharyngeal cancers, the correlation between ATM
mRNA expression and clinicopathologic features was analyzed.
We used the ratio of ATM mRNA expression of tumor versus
normal at 0.3 as a cut-off point according to the ReceiverOperating Characteristic curve analysis, by which an association
(P = 0.048, Chi-square analysis) between patient survival status
and ATM mRNA expression was observed (Table 2). Patients
Table 1. Characteristics of patients
Variable
Total
Gender
Age (years)
Tumor site
Tumor size (T)
Lymph node (N)
Distant metastasis (M)
Ataxia telangiectasia mutated
(ATM) expressionb
Category
Na
%
Male
Female
<55
‡55
Larynx
Pharynx
T1
T2
T3
T4
N0
N1
N2
N3
M0
M1
‡1
80
73
7
25
55
40
40
19
18
18
20
42
14
14
5
74
1
15
100.0
91.3
8.7
31.3
68.7
50.0
50.0
25.3
24.0
24.0
26.7
56.0
18.7
18.7
7.7
98.7
1.3
18.7
<1
65
81.3
a
Five missing data for tumor size, lymph node, and distant metastasis.
Ratio of tumor/normal.
b
doi:10.1093/annonc/mdq569 | 1089
original article
Annals of Oncology
with lower ATM mRNA expression (<0.3) exhibited a poorer
overall survival (9 alive versus 20 dead) than those with ATM
mRNA expression ‡0.3 (25 alive versus 21 dead). There was no
significant association between ATM mRNA expression and
other clinicopathologic parameters (Table 2).
We next analyzed 3-year and 5-year survival rates using Kaplan–
Meier estimates with log-rank tests. The results demonstrated that
patients with age <55 years (P = 0.004), with larger tumor size (T3
and T4, P = 0.012), and with lower ATM mRNA expression (<0.3,
P = 0.015) had poorer survival rates (Table 3). Figure 2 shows
a significant difference in survival rates between individuals with
higher and lower ATM mRNA expression. These data indicated
that ATM mRNA expression could be a prognostic marker for
laryngeal and pharyngeal cancers.
lower ATM mRNA expression is an independent
risk factor for survival of laryngeal and pharyngeal
cancer patients
To investigate whether lower ATM mRNA expression (<0.3) alone
could predict poor outcome of laryngeal and pharyngeal cancers,
Table 3. Kaplan–Meier survival rates
Variable
Overall
Gender
Age (years)
Tumor size (T)
Figure 1. Ataxia telangiectasia mutated (ATM) messenger RNA (mRNA)
was downregulated in 65 of 80 laryngeal and pharyngeal cancers. The
expression of ATM mRNA was determined using real-time quantitative
RT-PCR and shown as a box plot that comprised the average of, at least,
two independent experiments for each sample. The box represents upper
(0.762) and lower (0.222) quartiles; the line in the box stands for the
median (0.364).
Lymph node (N)
Ataxia telangiectasia
mutated (ATM)
expressionb
Category
3 years (%)
5 years (%)
Male
Female
<55
‡55
T1–T2
T3–T4
N0
N1–N3
<0.3
53.1
52.5
60.0
36.4
60.3
75.9
35.4
66.0
41.7
36.1
42.0
41.0
–
19.5
52.3
52.2
35.4
53.2
30.9
28.0
‡0.3
64.0
51.3
P-valuea
0.502
0.004
0.012
0.053
0.015
a
Log-rank test.
Ratio of tumor/normal.
b
Table 2. Correlation between clinicopathologic variables and ataxia
telangiectasia mutated (ATM) mRNA expressiona
Variable
Total
Gender
Age
Tumor
size (T)
Lymph
node (N)
Survival
Category
Nb
‡0.3
n
% in
category
<0.3
n
% in
category
Male
Female
<55
‡55
T1–T2
80
73
7
25
55
37
50
46
4
17
33
25
62.5
63.0
57.1
68.0
60.0
67.6
30
27
3
8
22
12
37.5
37.0
42.9
32.0
40.0
32.4
T3–T4
N0
38
42
21
28
55.3
66.7
17
14
44.7
33.3
N1–N3
No
Yes
33
41
34
18
21
25
54.5
51.2
73.5
15
20
9
45.5
48.8
26.5
P-valuec
>0.999d
0.493
0.274
0.285
0.048
a
Ratio of tumor/normal; cut-off point (0.3) was determined by the
Receiver-Operating Characteristic curve.
b
Five missing data for tumor size, lymph node, and survival.
c
Chi-square test.
d
Fisher’s exact test.
1090 | Lee et al.
Figure 2. Overall survival curves were analyzed according to ataxia
telangiectasia mutated (ATM) messenger RNA expression by using
Kaplan–Meier estimate with log-rank test. The analyzed numbers (N) of
the two categories are indicated.
Volume 22 | No. 5 | May 2011
original article
Annals of Oncology
we conducted multivariate Cox regression to examine the effect of
lower ATM mRNA expression (Table 4). After adjusting for sex,
age (<55 versus ‡55 years), tumor size (T3–T4 versus T1–T2), and
lymph node metastasis (N1–N3 versus N0), the results showed that
lower ATM mRNA expression (<0.3) remained a significant
prognostic factor [HRR = 2.49; 95% confidence interval (CI) 1.27–
4.88; P = 0.008] for survival. Moreover, age (HRR = 2.71; 95% CI
1.16–6.32; P = 0.021) and tumor size (HRR = 2.21; 95% CI 1.10–
4.44; P = 0.026) were also independent factors for predicting
overall survival (Table 4). These results indicated that lower ATM
mRNA expression could be an independent risk factor for survival
of laryngeal and pharyngeal cancer patients. When considering the
ratio of ATM mRNA expression itself in the multivariate Cox
regression analysis, a trend of association between ATM mRNA
expression and overall survival could be found (supplemental
Table S1, available at Annals of Oncology online), although
statistical significance was not reached (P = 0.071).
patients with lower ATM expression and younger
age or larger tumor size have the poorest outcome
We examined the effect of combining lower ATM mRNA
expression with age or tumor size on predicting patient outcome.
As shown in Figure 3, all seven patients in the <55-year-old group
Table 4. Multivariate Cox model analysis of overall survival
Variable
Hazard
rate
ratio
95% Confidence
interval
Lower
Upper
P-value
Ataxia telangiectasia mutated
(ATM) expression (<0.3
versus ‡0.3)
Gender (male versus female)
Age (<55 versus ‡55 years)
Tumor size (T3–T4
versus T1–T2)
N stage (N1–N3 versus N0)
2.49
1.27
4.88
0.008
1.91
2.71
2.21
0.45
1.16
1.10
8.09
6.32
4.44
0.380
0.021
0.026
0.96
0.42
2.16
0.912
who have lower ATM mRNA expression (<0.3) died within 4 years.
In addition, a significant proportion (13/16, 81.3%) of patients
with lower ATM mRNA expression (<0.3) and larger tumor size
(T3–T4) died within 3 years. On the contrary, patients with T1–T2
tumors or patients whose age was >55 years in combination with
higher ATM mRNA expression (‡0.3) had better survival rates
(Figure 3). Multivariate Cox regression model (Table 5) showed
significant higher risks for individuals with lower ATM mRNA
expression and younger age (HRR = 6.51; 95% CI 2.05–20.66;
P = 0.001) or with lower ATM mRNA expression and T3/T4
tumor size (HRR = 5.23; 95% CI 2.04–13.40; P = 0.001). These
results demonstrated that co-evaluation of ATM mRNA
expression and age or tumor size might be a valuable tool for
predicting patient outcome.
discussion
ATM kinase plays a key role in initiating several DNA repair
pathways. Downregulation of ATM may lead to broad
dysfunction in DNA repair and the accumulation of genome
alterations. In this study, we found that ATM mRNA was
downregulated in 65/80 (81.3%) of laryngeal and pharyngeal
cancers (Figure 1), and the lower ATM expression (<0.3) was
an independent risk factor for patient’s survival (Table 4). To
our knowledge, this is the first study showing that ATM
expression is a valuable prognostic marker for HNSCC. It has
been demonstrated that ATM expression was repressed in oral
and nasopharyngeal carcinomas [8, 10], but the effect of ATM
downregulation on patient’s outcome of these two
malignancies was not shown. The prognostic role of ATM
expression has been demonstrated in other malignancies,
including breast [13], colon [9], lung [12], and gastric cancer
[11]. All these studies showed that lower ATM expression was
a risk factor for patient’s outcome, except for that in lung
cancer [12]. Given the above, it seems that lower ATM
expression is usually correlated with poor outcome of cancer
patients. Moreover, we noted that the prognostic value of ATM
expression could be largely enhanced by co-evaluating patient’s
age or tumor size (Table 5). Both were also independent risk
factors for patient’s survival (Table 4). Early onset of HNSCC
Figure 3. Overall survival curves according to ataxia telangiectasia mutated (ATM) messenger RNA expression combined with age (left panel) or tumor size
(right panel). Analyses were conducted using Kaplan–Meier estimate with log-rank test. The analyzed number (N) of each category is indicated. Others (à
and §) stand for ATM ‡ 0.3 and age <55 years or ATM < 0.3 and age ‡55 years (left panel); and ATM ‡ 0.3 and T3–T4 tumor or ATM < 0.3 and T1–T2 tumor
(right panel).
Volume 22 | No. 5 | May 2011
doi:10.1093/annonc/mdq569 | 1091
original article
Annals of Oncology
Table 5. Multivariate Cox model analysis of overall survival (combining
two factors)
Variables
Hazard
rate
ratio
95%
Confidence
interval
Lower
Upper
P-value
a
Ataxia telangiectasia mutated (ATM) expression and age
ATM < 0.3 and age < 55 years
6.51
2.05
20.66
ATM ‡ 0.3 and age < 55 years
2.85
1.21
6.76
or ATM < 0.3 and age
‡ 55 years
ATM ‡ 0.3 and age ‡ 55 years
1
ATM expression and tumor sizeb
ATM < 0.3 and T3–T4
5.23
2.04
13.40
1.85
0.76
4.50
ATM ‡ 0.3 and T3–T4 or
ATM < 0.3 and T1–T2
1
ATM ‡ 0.3 and T1–T2
0.001
0.017
0.001
0.179
a
Adjusted by sex, tumor size, lymph node invasion.
Adjusted by sex, age, lymph node invasion.
b
implies that these patients may have certain genetic
susceptibilities for tumor development. Large tumor size may
reflect that the tumor cells have accumulated much more
genetic alterations. Therefore, it is reasonable to combine ATM
expression with these two independent risk factors as predictive
parameters to better estimate the effect.
One of the mechanisms underlying the downregulation of
ATM mRNA expression may be hypermethylation of the ATM
promoter. This results in suppression of promoter activity and
has been demonstrated in HNSCC [15, 16] and other
malignancies [19]. In this regard, our in vitro study showed that
ATM promoter activity could be inhibited by ingredients of betel
nut (C.-S. Lin, H.-Y. Hsieh, Y.-S. Tsai and J.-L. Huang,
unpublished data), which is a popular substance for habitual use
in India and Southeast Asia including Taiwan. However, the
relationship between lower ATM expression and the habit of
betel quid chewing in HNSCC patients remains to be established.
Another mechanism accounting for ATM suppression may be
the loss of ATM gene locus, by which reduced copy numbers at
chromosome 11q22-23 has been demonstrated in HNSCC by
comparative genomic hybridization [3, 20, 21]. In our studied
cases, only one tumor specimen showed negative RT-PCR
amplification (not included in the 80 cases described), implying
that deletion of ATM gene might be possible for this case.
However, since ATM mRNA could more or less be detected in all
80 tumors, complete gene deletions could not be the reason.
Rather, the possibility of loss of one allele at chromosome 11q2223 should not be excluded. Indeed, Parikh et al. [14] found that
ATM locus was partially lost in 8 of 11 HNSCC cell lines and all
five clinical specimens examined. Lazar et al. [22] also showed
loss of heterozygosity (LOH) at 11q23 in 25% (13/52) of primary
HNSCC. These results support that loss of ATM locus is possibly
one of the mechanisms accounting for lower ATM expression
found in HNSCC.
In addition to ATM, only a limited number of DNA repair
genes have been examined for their expression and prognostic
1092 | Lee et al.
role in head and neck cancers. Excision repair cross
complementation group 1 (ERCC1), which removes cisplatininduced DNA adducts, plays an important role in both damage
recognition and incision activities of nucleotide excision repair.
It has been shown that lower ERCC1 expression was associated
with a lower risk of death from advanced head and neck cancer
and also benefited from cisplatin induction chemotherapy [23].
This is possibly correlated with the reduced repair of cisplatin–
DNA adducts, which in turn leads to lethal DNA strand breaks
and facilitates the eradication of tumor cells. On the other
hand, the Nijmegen breakage syndrome gene product (NBN)
that works together with MRE11A and RAD50 to recognize
DNA double-strand breaks and initiate the signaling for DNA
repair was shown to be an independent marker of poor
prognosis for advanced HNSCC patients when overexpressed
[24]. The authors also found that overexpression of NBN could
increase cell transformation. These results suggest that the roles
of DNA repair gene expressions in predicting patient outcome
may be dependent on the characteristics of each gene and the
pathways involved.
In the present study, the patients were mostly treated with
concurrent chemoradiotherapy after surgical resection. The
relationship between ATM expression and patient treatments
was not yet explored in detail. However, according to the study
of Parikh et al. [14] that partial loss of ATM gene and reduced
ATM expression is associated with a reduced sensitivity of
HNSCC cells to ionizing irradiation (IR) and the finding of
Lazar et al. [22] that LOH at ATM locus in HNSCC is
associated with recurrent disease among patients who received
radiotherapy, it is proposed that laryngopharyngeal tumors
with lower ATM expression may be less responsive to
radiotherapy and/or chemotherapy than those with higher
ATM expression. As a result, patients with lower ATM mRNA
expression may exhibit a poor outcome as shown in this study.
This hypothesis suggests that a combination regimen exploiting
different cell-killing mechanisms may be superior to
monotherapy. Recent results obtained from several clinical
trials support this hypothesis, by which another cell-killing
mechanism via mitotic catastrophe induced by docetaxel can
add the efficacy of chemotherapy using cisplatin and
fluorouracil and improve the overall survival rates of patients
with no distant metastatic HNSCC [25–27]. Another trial that
combines platinum-based chemotherapy and cetuximab (by
antagonizing the signaling of epidermal growth factor receptor)
also improves the overall survival of head and neck cancer
patients with recurrent or metastatic tumors [28]. Therefore,
the concomitant findings of lower ATM expression and
reduced IR response may, at least partly, explain why these
trials that use combination therapy can improve survival of
HNSCC patients.
Recent studies on modulating DNA repair pathways to
improve cancer treatments have become an attractive
strategy [29]. Tumor cells survived from innumerable
genetic alterations depend largely on multiple DNA repair
pathways. However, defects of specific DNA repair pathway
may arise during tumor development. Inhibition of another
DNA repair pathway can therefore increase selectively killing
of tumor cells that contain certain alterations of DNA
damage response or DNA repair pathway. For example, poly
Volume 22 | No. 5 | May 2011
Annals of Oncology
(ADP-ribose) polymerase 1 (PARP1) inhibitors that interfere
with base excision repair have been successfully used for
treating the breast and ovarian cancer patients with inherited
defects of BRCA1 or BRCA2 genes [30, 31]. Notably, such
kind of treatment is less toxic to normal tissues than
conventional chemoradiotherapy. Therefore, investigations
of the genes involved in DNA damage responses and DNA
repair pathways in HNSCC may help find better prognostic
markers and strategies for patient treatment.
funding
This work was supported by grants from the Ministry of
Education to Kaohsiung Medical University (EM97-1.1ab-3);
Kaohsiung Medical University Hospital (5D-27); Changhwa
Christian Hospital (97-CCH-KMU-003, 95-CCH-KMU-25);
and National Science Council (NSC97-2311-B-037-002-MY3,
NSC 97-2314-B-371-004-MY3).
acknowledgements
We thank Ms Jenny Chang and Cathy Yang for critical reading
of the manuscript. MK Chen and CS Lin contributed equally to
this article.
disclosure
The authors declare no conflict of interest.
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