CLINICAL INVESTIGATION Lung
ASSOCIATION OF P53 AND ATM POLYMORPHISMS WITH RISK OF
RADIATION-INDUCED PNEUMONITIS IN LUNG CANCER PATIENTS TREATED
, M.D., P
*Departments of Etiology and Carcinogenesis,
Key Laboratory for Carcinogenesis and Cancer Prevention, and
Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing;
Presently at Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology,
Purpose: Radiation-induced pneumonitis(RP)is the most common dose-limiting complicationin lungcancer patients
treated with radiotherapy. Accumulating evidence indicates that P53 and the ataxia telangiectasia-mutated protein
(ATM)—dependent signaling response cascade play a crucial role in radiation-induced diseases. Consistent with
this, our previous study showed that a functional genetic ATM polymorphism was associated with increased RP risk.
Methods and Materials: To evaluate the role of genetic P53 polymorphism in RP, we analyzed the P53 Arg72Pro
polymorphism in a cohort including 253 lung cancer patients receiving thoracic irradiation.
Results: We found that the P53 72Arg/Arg genotype was associated with increased RP risk compared with the
72Pro/Pro genotype. Furthermore, the P53 Arg72Pro and ATM –111G>A polymorphisms display an additive com-
bination effect in intensifying the risk of developing RP. The cross-validation test showed that 63.2% of RP cases
can be identiﬁed by P53 and ATM genotypes.
Conclusions: These results indicate that genetic polymorphisms in the ATM-P53 pathway inﬂuence susceptibility
to RP and genotyping P53 and ATM polymorphisms might help to identify patients susceptible to developing RP
when receiving radiotherapy. Ó 2011 Elsevier Inc.
Radiation-induced pneumonitis, Genetic polymorphism, P53, Ataxia telangiectasia mutated protein, Lung cancer.
Radiation-induced pneumonitis (RP), one of the most common
and dose-limiting toxicities of radiotherapy, might compromise
the success of current efforts regarding lung cancer treatment
intensiﬁcation (1, 2). The characteristic symptoms of RP
include shortness of breath, cough, fever, and death resulting
from respiratory failure (3). After thoracic irradiation,
approximately 10–20% of lung cancer patients develop severe
RP, and almost half of these patients die of it (4–6). It has been
shown that genetic susceptibility factors play a role in
individual response to radiotherapy and RP development
(7, 8). Therefore, the discovery and application of biomarkers
that incorporate with traditional dosimetric and clinical
determinants of RP could largely help to tailor radiotherapy
treatment to maximize efﬁcacy and minimize toxicity.
In response to cellular stress response, such as irradiation
during radiotherapy, the tumor suppressor P53 can lead
to cell cycle arrest and apoptosis (9). During this process,
P53 protein is phosphorylated and activated by a variety
of DNA damage–induced kinases, including ataxia
telangiectasia-mutated (ATM) and DNA-dependent protein
kinases (10). Activated P53 protein induces expression of
various downstream targets, including genes involved in
cell-cycle regulation, apoptosis, and DNA repair. Regulation
of these processes by P53 controls cellular response to
irradiation-induced damage. In addition, P53 also directly
regulates the expression and activation of some cytokines,
such as interleukin-6 (11), transforming growth factor-
b (12, 13), and intercellular adhesion molecule-1 (13), which
are all involved in the complex inﬂammation process induced
Reprint requests to: Dongxin Lin, M.D., Department of Etiology
and Carcinogenesis, Cancer Institute and Hospital, Chinese Acad-
emy of Medical Sciences, Beijing 100021, China. Fax: (+86) 10-
67722460; E-mail: firstname.lastname@example.org
Ming Yang , Li Zhang, Luhua Wang, and Dongxin Lin contrib-
uted equally to this study.
Supported by National High Technology Project Grant (no.
2006AA02A401 to D. Lin), State Key Basic Research Program
(no. 2004CB518701 to D. Lin), and National Natural Science Foun-
dation (no. 30740024 to L. Wang).
Conﬂict of interest: none.
Received Oct 5, 2009, and in revised form Dec 12, 2009.
Accepted for publication Dec 23, 2009.
Int. J. Radiation Oncology Biol. Phys., Vol. 79, No. 5, pp. 1402–1407, 2011
Copyright Ó 2011 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/$–see front matter