Radiation pneumonitis (RP) is the inflammation of the normal lung tissue within the radiation field following radiation therapy. RP is one of the most common complications and one of the most important dose-limiting toxicities in the treatment of thoracic tumors by radiotherapy (1). Although significant progress has been made in the treatment technologies, a considerable number of patients experience RP following thoracic irradiation. Studies have demonstrated that ~10–20% of lung cancer patients develop severe RP (grade ≥3) following radiotherapy, of whom 50% succumb to this complication (2). The main risk factors of RP include patient-related factors, such as gender, smoking and pulmonary function, and treatment-related factors, such as radiation dose, irradiated lung volume, surgery and chemotherapy (3–7). However, it remains difficult to predict the occurrence of RP for any individual patient. Based on the development of the human genome project and pharmacogenomics, it is reported that single-nucleotide polymorphisms (SNPs) in inflammation-related, DNA repair-related, stress response-related and angiogenesis-related genes, may be used as biomarkers to predict the development of RP.

Inflammation is a defensive reaction that results from tissue damage or cellular injury, and is also a key process underlying radiation-induced toxicity (8,9). Several studies have been conducted to evaluate inflammation-related biomarkers, focusing mostly on genes as described below.

Ionizing radiation may cause DNA damage, including DNA strand breaks, base change, ribose destruction and dimer formation. Radiotherapy-induced DNA damage mainly consists of strand breaks and base alterations; therefore, the repair pathways involved in DNA damage are DNA double-strand break repair (DSBR) and base excision repair (BER) (25). The genetic variants of DNA repair-related genes may affect the capacity of the DNA repair pathways. Insufficient DNA repair capacity leads to increased DNA damage and high tissue radiosensitivity, resulting in severe radiation-related complications (26,27).

At the molecular level, reactive oxygen species induced by ionizing radiation exert a direct damaging effect on DNA and tissue, leading to DNA DSBs and production of cytokines or growth factors, which may cause pulmonary hypoxia, inflammation, chronic oxidative stress and, eventually, damage repair delay (44–46). In addition to inflammation and DNA repair-related genes, stress response-related genes may also be involved in the regulation of the effect of radiation on lung tissue.

5,10-Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism, thymidine synthesis, homocysteine processing and other important metabolic pathways (47). Folate metabolism is closely related to DNA synthesis and repair and MTHFR is the key enzyme of redox reaction in cellular metabolic activity, which may irreversibly convert MTHFR to 5-methyltetrahydrofolate. Mak et al (48) investigated the correlation between the SNPs of MTHFR and superoxide dismutase (SOD) 2 genes and the risk of RP, and demonstrated that the MTHFR rs1801131 (A>C) AC/CC genotypes decreased the risk of grade ≥2 RP (HR=0.37, 95% CI: 0.18–0.76, P=0.006) and grade ≥3 RP (HR=0.21, 95% CI: 0.06–0.70, P=0.01). No SOD2 gene polymorphisms were found to be associated with RP risk in this study. Since the number of candidate SNPs is limited, this study was unable to fully analyze the correlation between these two genes and RP risk.

Heat shock proteins (HSPs) may be stimulated by several stressors, such as drugs or ionizing radiation, and protect the body from the injury caused by these stressors. The HSP27 protein is widely expressed in the human body at a low level. HSP27 strengthens the cells' ability of resistance when they are exposed to oxidative stress, cytotoxic agents, thermal shock and apoptosis (49–51). Furthermore, HSP27 chaperone may also enhance the antioxidant capacity of the cell by increasing glutathione and decreasing the toxicity of oxidizing reactions (52). The plasma HSP27 levels are regulated by the HSPB1 gene; thus, HSPB1 was considered to modulate cell radiosensitivity. Pang et al (53) demonstrated that the HSPB1 rs2868371 (C>G) CC genotype was associated with a higher risk of grade ≥3 RP compared with the CG/GG genotype (P=0.02).

Angiogenesis is not only an important physiological process in normal tissues, but also a necessary step in carcinogenesis, cancer development and metastasis (54–56). Pro-angiogenic substances excreted by tumor cells and tumor stromal cells may promote tumor revascularization. Reactive oxygen species generated by radiation therapy result in vascular endothelial cell damage in normal lung tissues and lead to early inflammation and high vascular permeability (45,57,58). Subsequently, white blood cells migrate to the sites of inflammation, a series of inflammatory reactions occur and lead to increased radiation toxicity in the surrounding normal tissues. Vascular endothelial growth factor (VEGF) exerts a dual effect on the occurrence of RP: High VEGF levels stimulate the growth of endothelial cells and maintain the integrity of vascular endothelium, which may enhance the resistance to RP; on the other hand, VEGF may increase the synthesis of inflammatory cytokines through NF-κB in the damaged endothelial cells, leading to RP (59). VEGF SNPs were analyzed by Yin et al (60), who observed that the rs2010963 (G>C) CC and rs3025039 (C>T) TT genotypes were associated with a high risk of RP in 195 NSCLC patients.

The recent studies on the effects of gene polymorphisms on RP risk are summarized in Table I and Fig. 1 outlines the mechanisms, pathways and genes involved. These studies, however, had certain limitations: First, they were all retrospective studies based on recorded information; thus, it was difficult to accurately classify the severity of the RP. Second, the diagnosis of RP was subjective, whereas RP should be differentially diagnosed from chronic obstructive pulmonary disease, infectious pneumonia and heart disease, taking into consideration the patients' overall condition. Therefore, the diagnosis of RP requires experienced physicians. The standard used for RP grading in the abovementioned articles was the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 or 4.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf or http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf). However, other researchers raised the viewpoint that the use of an objective evaluation method may more accurately determine the degree of radiation-induced toxicity, as it may avoid subjective confounders (61,62). Third, the majority of the studies adopted the candidate gene approach, with which was easy to overlook the crucial but rare SNPs. In addition, the sample size was relatively small, which may may have led to a high false-positive rate. Finally, some independent factors, which were shown in previous articles, should be kept consistent in the study to avoid adversely affecting the results, including smoking, MLD, and volume of normal lung receiving ≥20Gy radiation.

Radiogenomics analyzes the differences in radiosensitivity caused by gene sequence variations (63). Radiogenomics has two objectives: The first is to determine a way of predicting the risk of radiation injuries in patients following radiotherapy, and the second is to investigate the molecular mechanisms underlying normal tissue toxicity induced by radiation (64). Thus, radiogenomics may help achieve treatment individualization for patients treated with radiotherapy. In 2006, the RAPPER study (Radiogenomics Assessment of Polymorphisms for Predicting the Effects of Radiotherapy), which was the first nationwide radiation genomics program worldwide, was launched in UK (65). In 2009, the International Radiogenomics Consortium was founded, dedicated to the study of genetic predictors of adverse reactions following radiotherapy in various types of tumors (66).

Genome-wide association study (GWAS) is an approach to radiogenomics research. GWASs do not miss important SNPs, as they analyze SNPs with a minor allele frequency of ≥1% over the entire gene (64). Due to the large number of SNPs, it is necessary to enlarge the sample size or validate in replication studies to obtain a higher statistical power (67). Several SNPs identified in GWASs are located in non-coding regions with unknown functions (68,69), which may broaden our understanding of the mechanisms underlying normal tissue toxicity caused by radiation. Despite GWASs being effective in SNP genotyping, they are less efficient in distinguishing changes in DNA structure, such as inversions, deletions and insertions, which may exert an effect on the response to radiation (70,71). Currently available published GWAS studies mainly investigate the complications following radiotherapy in breast and prostate cancer patients, with only few studies on lung cancer.

Through accurately evaluating the patients' sensitivity to radiation and effectively predicting the occurrence of RP, we may determine an optimal individualized treatment plan for each patient. For patients at high risk of developing RP, non-radiotherapy or low-dose radiation therapy may be applied to achieve a relatively high radiation dose based on the low risk of RP. For low-risk patients, the radiation dose may be increased to achieve the best therapeutic effect. At present, preliminary studies have demonstrated that genetic polymorphisms are closely associated with RP and radiation sensitivity, but the specific molecular mechanisms remain unclear. With the development of radiogenomics and the promotion of GWAS, the molecular mechanisms of gene polymorphisms and radiosensitivity are major issues that must be addressed in the future, as they may provide a reliable molecular basis for the personalized therapy of malignant tumors.