International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationAssociation of P53 and ATM Polymorphisms With Risk of Radiation-Induced Pneumonitis in Lung Cancer Patients Treated With Radiotherapy
Introduction
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, 5, 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-β 12, 13, and intercellular adhesion molecule-1 (13), which are all involved in the complex inflammation process induced by RP. Therefore, aberrant function of P53 is expected to be one of the essential events in the pathogenesis of radiation-induced lung injuries, including pneumonitis.
Previous studies in our laboratory and others have demonstrated that single-nucleotide polymorphisms (SNPs) in some genes may be associated with the risk of RP 8, 14. For example, we have shown that an SNP in the ATM promoter (–111G>A), which significantly reduces the gene expression, was associated with increased risk of RP in lung cancer patients treated with radiotherapy (14). As the main downstream effecter of ATM in response to irradiation the P53 protein is also polymorphic. A functional polymorphism, the G>C change at codon 72, which results in Arg>Pro amino acid substitution, exists in exon 4 of P53 gene. It has been shown that the Arg/Arg genotype induces apoptosis with faster kinetics and suppresses transformation more efficiently than the Pro/Pro genotype 15, 16. However, the P53 72Pro allele seems to be better at initiating senescence and cell cycle arrest than the 72Arg allele 17, 18. It has been reported that the P53 Arg72Pro polymorphism has an impact on radiotherapy-induced skin side effects in breast cancer patients (19); however, little or nothing is known about its role in radiation lung toxicity. Here we report a prospective study showing that the P53 Arg72Pro polymorphism is associated with increased risk of RP in lung cancer patients treated with radiotherapy. Additionally, we examined whether P53 Arg72Pro polymorphism might have an impact on the risk of RP in combination with the ATM –111G>A polymorphism.
Section snippets
Patients
This prospective study, which has been described in a previous report (14), included 253 patients with lung cancer (188 non–small-cell lung cancer and 65 small-cell lung cancer). Briefly, patients were recruited between January 2004 and August 2006 at the Cancer Hospital, Chinese Academy of Medical Sciences (Beijing). The eligible patients were those with histologically or cytologically confirmed lung cancer, inoperable tumor, Karnofsky performance status (KPS) >60, and an expected survival of
Patient characteristics and clinical outcome
This perspective study recruited 253 patients with lung cancer. The baseline clinical characteristics of patients are summarized in Table 1. By the time of the final analysis (August 2007), the median follow-up time had been 22 months. After treatment with radiotherapy, 44 patients (17.4%) had ≥Grade 2 RP (Grades 2, 3, and 5 were observed in 30, 11 and 3 patients, respectively). The median occurrence time of RP was 59 days from the first day of irradiation.
Association between P53 SNP and RP risk
Cox regression analysis revealed that
Discussion
In this present study, we examined the hypothesis that functional P53 Arg72Pro and ATM –111G>A polymorphisms might have an impact on the RP risk in lung cancer patients treated with radiotherapy, separately or synergistically. We found that a ∼4.5-fold increased risk of RP was associated with the P53 72Arg/Arg genotype compared with the P53 72Pro/Pro genotype. Additionally, the P53 72Arg/Arg genotype displayed an additive gene–gene joint effect with the ATM –111A allele in intensifying the RP
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Somatic and germline ATM variants in non-small-cell lung cancer: Therapeutic implications
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2023, Lung CancerLow dose ionizing radiation effects on the immune system
2021, Environment InternationalFunctional promoter rs189037 variant of ATM is associated with decrease in lung diffusing capacity after irradiation for non–small-cell lung cancer
2018, Chronic Diseases and Translational MedicineA meta-analysis of the relationship between ataxia-telangiectasia mutated gene polymorphisms and lung cancer susceptibility
2017, Pathology Research and PracticeCitation Excerpt :During cellular senescence, ATM combines replication stress with metabolic reprograming [31]. ATM mediates the proliferation and apoptosis of non-small cell lung cancer (NSCLC) via the AMPK pathway [3] and the genetic polymorphisms in ATM influence radiation-induced pneumonitis susceptibility by p53 pathway [32]. ATM gene polymorphisms are associated with risk of lung cancer, for example, rs189037 is positively correlated with risk of lung cancer in the Chinese Han population [33].
Ming Yang , Li Zhang, Luhua Wang, and Dongxin Lin contributed 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 Foundation (no. 30740024 to L. Wang).
Conflict of interest: none.