Association of P53 and ATM Polymorphisms With Risk of Radiation-Induced Pneumonitis in Lung Cancer Patients Treated With Radiotherapy

doi:10.1016/j.ijrobp.2009.12.042

International Journal of Radiation OncologyBiologyPhysics

Volume 79, Issue 5, 1 April 2011, Pages 1402-1407

https://doi.org/10.1016/j.ijrobp.2009.12.042 Get rights and content

Purpose

Radiation-induced pneumonitis (RP) is the most common dose-limiting complication in lung cancer 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 combination 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.

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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Cited by (47)

Somatic and germline ATM variants in non-small-cell lung cancer: Therapeutic implications
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ATM is an apical kinase of the DNA damage response involved in the repair of DNA double-strand breaks. Germline ATM variants (gATM) have been associated with an increased risk of developing lung adenocarcinoma (LUAD), and approximately 9% of LUAD tumors harbor somatic ATM mutations (sATM). Biallelic carriers of pathogenic gATM exhibit a plethora of immunological abnormalities, but few studies have evaluated the contribution of immune dysfunction to lung cancer susceptibility. Indeed, little is known about the clinicopathological characteristics of lung cancer patients with sATM or gATM alterations. The introduction of targeted therapies and immunotherapies, and the increasing number of clinical trials evaluating treatment combinations, warrants a careful reexamination of the benefits and harms that different therapeutic approaches have had in lung cancer patients with sATM or gATM. This review will discuss the role of ATM in the pathogenesis of lung cancer, highlighting potential therapeutic approaches to manage ATM-deficient lung cancers.
Radiogenomics in lung cancer: Where are we?
2023, Lung Cancer
Huge technological and biomedical advances have improved the survival and quality of life of lung cancer patients treated with radiotherapy. However, during treatment planning, a probability that the patient will experience adverse effects is assumed. Radiotoxicity is a complex entity that is largely dose-dependent but also has important intrinsic factors. One of the most studied is the genetic variants that may be associated with susceptibility to the development of adverse effects of radiotherapy. This review aims to present the current status of radiogenomics in lung cancer, integrating results obtained in association studies of SNPs (single nucleotide polymorphisms) related to radiotherapy toxicities. We conclude that despite numerous publications in this field, methodologies and endpoints vary greatly, making comparisons between studies difficult. Analyzing SNPs from the candidate gene approach, together with the study in cohorts limited by the sample size, has complicated the possibility of having validated results. All this delays the incorporation of genetic biomarkers in predictive models for clinical application. Thus, from all analysed SNPs, only 12 have great potential as esophagitis genetic risk factors and deserve further exploration. This review highlights the efforts that have been made to date in the radiogenomic study of radiotoxicity in lung cancer.
Low dose ionizing radiation effects on the immune system
2021, Environment International
Ionizing radiation interacts with the immune system in many ways with a multiplicity that mirrors the complexity of the immune system itself: namely the need to maintain a delicate balance between different compartments, cells and soluble factors that work collectively to protect, maintain, and restore tissue function in the face of severe challenges including radiation damage. The cytotoxic effects of high dose radiation are less relevant after low dose exposure, where subtle quantitative and functional effects predominate that may go unnoticed until late after exposure or after a second challenge reveals or exacerbates the effects. For example, low doses may permanently alter immune fitness and therefore accelerate immune senescence and pave the way for a wide spectrum of possible pathophysiological events, including early-onset of age-related degenerative disorders and cancer. By contrast, the so called low dose radiation therapy displays beneficial, anti-inflammatory and pain relieving properties in chronic inflammatory and degenerative diseases. In this review, epidemiological, clinical and experimental data regarding the effects of low-dose radiation on the homeostasis and functional integrity of immune cells will be discussed, as will be the role of immune-mediated mechanisms in the systemic manifestation of localized exposures such as inflammatory reactions. The central conclusion is that ionizing radiation fundamentally and durably reshapes the immune system. Further, the importance of discovery of immunological pathways for modifying radiation resilience amongst other research directions in this field is implied.
Functional 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 Medicine
Single-nucleotide polymorphisms (SNPs) in the ataxia telangiectasia–mutated gene ATM have been linked with pneumonitis after radiotherapy for lung cancer but have not been evaluated in terms of pulmonary function impairment. Here we investigated potential associations between SNPs in ATM and changes in diffusing capacity of the lung for carbon monoxide (DLCO) in patients with non–small-cell lung cancer (NSCLC) after radiotherapy.
From November 1998 through June 2009, 448 consecutive patients with inoperable primary NSCLC underwent definitive (≥60 Gy) radiotherapy, with or without chemotherapy. After excluding patients with a history of thoracic surgery, radiation, or lung cancer; without DNA samples available for analysis; or without pulmonary function testing within the 12 months before and the 12 months after radiotherapy, 100 patients were identified who are the subjects of this study. We genotyped two SNPs of ATM previously found to be associated with radiation-induced pneumonitis (rs189037 and rs228590) and evaluated potential correlations between these SNPs and impairment (decreases) in DLCO by using logistic regression analysis.
Univariate and multivariate analyses showed that the AA genotype of ATM rs189037 was associated with decreased DLCO after definitive radiotherapy than the GG/AG genotypes [univariate coefficient, −0.122; 95% confidence interval (CI), −0.236 to −0.008; P = 0.037; and multivariate coefficient, −0.102; 95% CI, −0.198 to −0.005; P = 0.038]. No such correlations were found for rs228590 (univariate coefficient, −0.096; 95% CI, −0.208 to 0.017; P = 0.096).
The AA genotype of ATM rs189037 was associated with higher risk of lung injury than were the GG/AG genotypes in patients with NSCLC treated with radiotherapy. This finding should be validated prospectively with other patient populations.
Molecular determinants of radiosensitivity in normal and tumor tissue: A bioinformatic approach
2017, Cancer Letters
Although radiation therapy is a treatment of choice for cancer, a high percentage of patients develop adverse effects in normal tissue following radiotherapy, mainly, due to genetic factors. Notably, although it is established that a lower dose of ionizing radiation can minimize the tumor cell population in radiosensitive cancer patients, the sensitivity of tumor cells to radiation has not gained enough attention. In this mini-review, the molecular pathways/mechanisms and the related molecules involved in clinically relevant radiotoxicity, as well as normal and tumor cell radiosensitivity, were investigated for various types of cancers employing bioinformatics approaches. A total of 255 genes/gene products were retrieved and investigated in this study, which are implicated in pathways related mainly to DNA damage repair, oxidative stress, apoptosis and fibrosis. Furthermore, a novel molecular gene signature of normal tissue radiotoxicity was identified. The findings of our study could be utilized by healthcare professionals in personalized clinical decision-making, in order to efficiently sensitize tumor cells to radiation and yet minimize adverse effects in the adjacent normal tissues as well as to improve the quality of life in cancer patients undergoing radiotherapy.
A meta-analysis of the relationship between ataxia-telangiectasia mutated gene polymorphisms and lung cancer susceptibility
2017, Pathology Research and Practice
Citation 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].
This study aimed to analyze the relationship between ataxia-telangiectasia mutated (ATM) gene polymorphisms and lung cancer susceptibility using a meta-analysis.
A literature search of the PubMed and EMBASE databases was performed using keywords such as “ATM gene” and “lung cancer,” and the deadline “October 15 (th), 2016.” After extracting relevant details, each selected literature was evaluated for quality according to the Newcastle–Ottawa Scale (NOS) scores, and Hardy–Weinberg equilibrium and heterogeneity tests were performed. Odds ratios (ORs) and 95% confidence interval (CI) were evaluated using R 3.12 software.
Eight eligible studies, published from 2004 to 2013, were identified. The NOS scores of these ranged from 5 to 7. The allele genetic model (OR = 1.15; 95% CI, 1.01–1.31); additive genetic model (OR = 1.44; 95% CI, 1.09–1.90); recessive genetic model (OR = 1.48; 95% CI, 1.16–1.88); and dominant genetic model (OR = 1.50; 95% CI, 1.16–1.93) of rs664143 (A > G) were found to be significantly different. For rs664677 (C > T), significant differences were found in the additive genetic model (OR = 1.26, 95% CI, 1.01–1.55) and recessive genetic model (OR = 1.31; 95% CI, 1.09–1.57). However, the other 2 genetic models (rs609429, rs664982) did not show significant differences.
The polymorphisms rs664143 and rs664677 of ATM are associated with lung cancer occurrence.

View all citing articles on Scopus

: 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.

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Clinical InvestigationAssociation of P53 and ATM Polymorphisms With Risk of Radiation-Induced Pneumonitis in Lung Cancer Patients Treated With Radiotherapy

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patients

Patient characteristics and clinical outcome

Association between P53 SNP and RP risk

Discussion

Int J Radiat Oncol Biol Phys

J Thorac Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Cell

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiation pneumonitis following combined modality therapy for lung cancer: Analysis of prognostic factors

J Clin Oncol

Single nucleotide polymorphism at rs1982073:T869C of the TGFβ1 gene is associated with the risk of radiation pneumonitis in patients with non–small-cell lung cancer treated with definitive radiotherapy

J Clin Oncol

Surfing the p53 network

Nature

Enhanced phosphorylation of p53 by ATM in response to DNA damage

Science

Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product

Proc Natl Acad Sci USA

Clinical Investigation
Association of P53 and ATM Polymorphisms With Risk of Radiation-Induced Pneumonitis in Lung Cancer Patients Treated With Radiotherapy