Menoufia Medical Journal

: 2018  |  Volume : 31  |  Issue : 3  |  Page : 730--734

TRAIL receptor 1 polymorphism and cancer risk: a systematic review

Amr A.F Mohamed1, Samia H Kandeel1, Hassan E Zaghlaa2, Nahla F Osman1, Mohamed A Helwa1, Hanan M.I Bedier2,  
1 Department of Clinical Pathology, Faculty of Medicine, National Liver Institute, Menoufia University, Menoufia, Egypt
2 Department of Hepatology, National Liver Institute, Menoufia University, Menoufia, Egypt

Correspondence Address:
Hanan M.I Bedier
5 Taiseer Street, Shebein El-Kom, Menoufia Governorate


The aim of this study was to perform systematic review to summarize the association of TRAIL receptor 1 polymorphism at codon A683C and C626G with cancer risk. Medline, articles in Medscape, AAFP, and PubMed were searched. The search was performed on 1 August 2016, and included all articles with no language restrictions. The initial search presented 219 articles. A total of 16 research studies met the inclusion criteria for the two DR4 polymorphisms; the articles included TRAIL receptor 1 polymorphism and increased cancer risk. Data from each eligible study were independently abstracted in duplicate using a data collection form to capture information on study characteristics, interventions, and quantitative results reported for each outcome of interest. There was heterogeneity in the collected data. It was not possible to perform meta-analysis. Significant data were collected. Thus, a structured review was performed. TRAIL receptor 1 polymorphism at codon A683C and C626G increases the risk of different types of malignancy such as hepatocellular carcinoma (HCC), gall bladder cancer, ovarian cancer, hematological system cancer, and bladder cancer, but without significant increase in the risk of other malignancies such as lung and breast cancers. A total of 14 articles were reviewed summarize the TRAIL receptor 1 polymorphism and cancer risk. Genotyping of this polymorphism at codon A683C and C626G can be used to assess patients' risk of developing cancer, which would allow early diagnosis with subsequent improvement in patient survival. Furthermore, TRAIL- directed therapy is likely to be beneficial in these cases.

How to cite this article:
Mohamed AA, Kandeel SH, Zaghlaa HE, Osman NF, Helwa MA, Bedier HM. TRAIL receptor 1 polymorphism and cancer risk: a systematic review.Menoufia Med J 2018;31:730-734

How to cite this URL:
Mohamed AA, Kandeel SH, Zaghlaa HE, Osman NF, Helwa MA, Bedier HM. TRAIL receptor 1 polymorphism and cancer risk: a systematic review. Menoufia Med J [serial online] 2018 [cited 2019 Jan 24 ];31:730-734
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Full Text


Apoptosis is a complex process with numerous activators and inhibitors acting in an orchestrated manner. Changes at any of the steps of the pathway can lead to resistance in cancer cells to apoptosis. Apoptosis is triggered by two major signaling routes, namely, the extrinsic death receptor and the intrinsic mitochondrial pathway[1],[2].

The extrinsic apoptosis pathway is dependent on death ligands binding to the cell receptors. With ligand engagement to the transmembrane receptors, a death signal is transmitted from the outside to the inside of cells[3].

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of tumor necrosis factor superfamily, selectively kills cancer cells but not normal cells; thus, it is considered as a promising candidate for cancer therapy[4]. TRAIL induces apoptosis through its binding to death receptors including DR4 with subsequent activation of the apoptotic pathway[5].

TRAIL receptor (TRAIL-R) family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 (DR4) initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of the death-inducing signaling complex, caspase activation, and ultimately apoptosis[6].

DR4 consists of two extracellular cysteine-rich, ligand-binding pseudorepeats (50 and 90 s loops), one single transmembrane helix as well as the apoptosis-triggering cytoplasmic death domain[7],[8],[9],[10].

Genetic alterations in death receptors might compromise apoptotic cell signaling and therefore contribute to the development of tumor cells. Several studies suggested an increased risk for cancer associated with single nucleotide polymorphisms (SNPs) in the DR4 gene[11].


The guideline for conducting this review was according to guidance developed by the center for review and dissemination. It was used to assess the methodology and outcome of the studies.

Search strategy

Search was performed in several databases. It included Medline, articles in Medscape, AAFP, and PubMed. The search was performed on 1 August 2016, and included all published articles. There were no restriction according to language.

Study selection

All researches were assessed to be include in the review by three researchers. They were included if they fulfilled the following criteria: apoptosis, pathways and role in cancer, physiology of TRAIL-R1, TRAIL-R1 polymorphism at codon A683C and C626G, and cancer risk.

Participants included were patients with ovary cancer, lung cancer, bladder cancer, breast cancer, or hepatocellular carcinoma (HCC).

Intervention included early detection and proper management by genotyping to DR4 polymorphism.

Comparative analysis was done for frequency of polymorphism in general population. Outcome was improving patient survival.

Articles not in English language were translated. The article title and abstract were initially screened. Then the selected articles were read in full and further assessed for eligibility. All references from the eligible articles were reviewed to identify additional studies.

Data extraction

Data from each eligible study were independently abstracted in duplicate using a data collection form to capture information on study characteristics, interventions, and quantitative results reported for each outcome of interest. Conclusion and comments on each study were stated.

There was heterogeneity in the collected data. It was not possible to perform meta-analysis. Significant data were collected. Thus, a structured review was performed with the result tabulated.


A total of 14 studies were selected. The studies were deemed eligible by fulfilling the inclusion criteria. Among the 14 eligible studies, 11 and eight presented data on C626G and A683C, respectively. Of the 16 studies, two applied on lung cancer, three on bladder cancer, four on breast cancer, two on ovarian cancer, two on hematological cancer, and three on gastrointestinal cancer. There was a high degree of heterogeneity regarding defective apoptotic pathway because of DR4 polymorphism at both codons; they are summarized in [Table 1].{Table 1}


Defective apoptosis is a leading cause of cancer development and progression. Death receptors (DR4 and FAS) and their ligands (TRAIL and FASL) are thought to mediate the major extrinsic apoptotic pathway in the cell[12].

TRAIL signaling pathway starts by TRAIL binding to the proapoptotic receptors TRAIL-R1 and TRAIL-R2, which promotes recruitment of Fas-associated protein with death domain and assembles the death-inducing signaling complex, leading to pro-caspase-8 activation and initiation of apoptosis[26]. TRAIL can selectively kill cancer cells but not normal cells, making it an attractive agent for cancer therapy[27]. Changes at any of the steps of the TRAIL pathway can lead to resistance in cancer cells to apoptosis[2].

TRAIL-R11 (DR4) polymorphisms at codon increase the risk of cancer; DR4 C626G polymorphism that occurs in the ectodomain region changes a cytosine to a guanine at nucleotide 626 and substitutes an arginine for a threonine whereas A683C polymorphism present in extracellular cysteine-rich domain changes an adenine to a cytosine and substitutes an alanine for a glutamate, and this substitution alters the TRAIL-binding domain of DR4 and thus alters DR4 affinity for TRAIL and increases the frequency of primary tumors of different origin as compared with matched controls[11],[13],[28],[29].

In total, four articled discuss the effect of polymorphism and the risk of breast cancer. Frank et al.[14] evaluated the role of SNPS at codon A683C and C626G by Taqman assay in breast cancer in their case–control study performed in German BRCA1 and BRCA2 mutation–negative breast cancer cases. They found that neither variants showed a significant association with breast cancer risk even after stratification according to age at diagnosis (>50; <50 years). However, regarding haplotype frequency, they found that the rare haplotype 626C–683C revealed a significant difference in frequency resulting in an increased risk of breast cancer. As the haplotype 626C–683C is very rare, it represents a moderate amount of risk regarding familial breast cancer. Martinez-Ferrandis et al.[15] performed a case–control study on large number of Spanish women by Taqman assay; they reported no differences in genotype or haplotype distribution for C626G polymorphism between patients with breast cancer and controls in Spain.

Another study was performed by Dick et al.[16], and it included 557 female carriers of BRCA1 and 283 female carriers of BRCA2 mutations. All mutations carriers were younger than 18 years and were genotyped for DR4 A683C and C626G polymorphism by the Taqman allelic discrimination assay. They found no evidence for a significant association with breast cancer risk regarding C626G polymorphism. In contrast to Elubina et al.[17] and Frank et al.[18] they found that carriers of BRCA2 mutations alone showed a decreased risk of developing breast cancer in homozygous of the 683C allele.

Ulybina et al.[17] used PCR-RFLP to study C626G polymorphism; they found no association between C626G polymorphism and the risk for breast cancer in their study carried on 121 patients with breast cancer with clinical features of hereditary predisposition (family history and/or early onset and/or bilaterality) and 142 elderly tumor-free women.

The role of A683C and C626G polymorphisms at DR4 gene and risk for tumors of gastrointestinal tract such as HCC, gall bladder cancer, and colorectal cancer were studied. Regarding the relation between A683C and C626G polymorphism and risk for colorectal cancer, Frank et al.[18] conducted a large population case–control based study in Germany. They used a Taqman assay to study 659 unrelated male and female subjects (33-91 years of age; median: 68); they found a significant association of the DR4 C626G variant with a decreased colorectal cancer risk for heterozygotes and 626G carriers greater than or equal to 65 years of age. Female carriers of 683C variant exhibited a significantly enhanced risk dependent on allele dose. In addition, the DR4 626C–683C haplotype conferred a higher colorectal cancer risk, suggesting its relevance in human cancer.

HCC is the sixth most common cancer worldwide and the third most common cause of cancer death[30], and its outcome can benefit from a surveillance program[31]. Körner et al.[13] studied the risk of TRAIL-R1 in the development of HCC. They genotyped A683C and C626G polymorphism through PCR-RFLP analysis; their study was done on 393 patients with chronic hepatitis C virus genotype 1, including 159 patients with HCV-associated HCC and 234 patients without HCC. In addition, 359 HCV-negative healthy individuals and 56 patients with HCC caused by chronic hepatitis B served as control groups. They found that the distribution of C626G and A683C genotypes was not significantly different between healthy controls and HCV-positive patients without HCC. DR4 variants 626C and 683A occurred at increased frequencies in patients with HCC. The risk of HCC was linked to carriage of the 626C allele and the homozygous 683AA genotype, and the simultaneous presence of the two risk variants was confirmed as independent HCC risk factor. Furthermore, HCV viral loads were significantly increased in patients who simultaneously carried both genetic risk factors.

According to Rai et al.[12], a case–control study included 400 gall bladder cancer and 246 healthy controls. Genotyping was carried out by Taqman genotyping assays and found that the DR4 626C has no effect on risk of gall bladder carcinogenesis; controversially they found that the presence of A allele at position 683 increases the risk of gall bladder cancer at allele, heterogenotype, and in dominant model as detected by allele-specific PCR performed on 400 patients with gall bladder cancer compared with 246 healthy age-matched and sex-matched controls.

The relation of TRAIL DR4 C626G SNP and risk of bladder carcinoma was studied by Wolf et al.[19], who found that the rare allele 683C is more frequent in patients with bladder cancer.

Mittal et al.[20] found a significant association between DR4 A683C and smoking observed in patients with bladder cancer. The study included 200 patients with cancer bladder in addition to 225 healthy controls, and they were analyzed by allele-specific PCR, Another study was conducted by Timirci-Kahraman et al.[21]. They performed a hospital-based prospective case-control study that included 91 Turkish patients with bladder cancer. All patients were newly diagnosed with histopathologically confirmed transitional cell carcinoma of the bladder. Patients who had previously received radiotherapy and chemotherapy were not included in the study. They found that the frequency of DR4 C626G GG genotype increased risk of high-grade bladder cancer when compared with low-grade tumor.

In relation to hematological malignancies, Fernàndez et al.[22] studied 114 patients with non-Hodgkin's lymphoid neoplasms such as Mantle cell lymphoma (MCL), Chronic lymphocytic leukemia (CLL), follicular lymphoma, and diffuse large B-cell lymphomas. They found that the DR4 C626G polymorphism was associated with a significant overall decreased risk for MCL.

Wolf et al.[19] examined the allele distribution of the 683A>C-SNP among samples of mantle cell lymphoma and chronic lymphocytic leukemia. They recognized that the rare allele 683C is more frequent in all of these tumors. Thus, screening for 683A to C nucleotide exchanges may become important in diagnosis and/or treatment of these malignancies.

The role of TRAIL-R1 polymorphism in ovary cancer was discussed by Dick et al.[16] regarding A683C polymorphism, they documented a significant association between the DR4 683A>C-SNP and an increased risk of developing ovarian cancer in carriers of BRCA1 mutations and showed no evidence of association between DR4 626C>G and the risk of ovarian cancer.

Horak et al.[23] also reported no differences in genotype or haplotype distribution for C626G polymorphism in DR4 gene and excluded its role in the carcinogenesis of ovarian cancer in their study by PCR-RFLP that performed in germline DNA of 97 patients with ovarian cancer and controls as well as in established ovarian cancer cell lines.

Regarding TRAIL-R1 polymorphism and lung cancer, Van Dyke et al.[24] found that presence of the minor allele in C626G SNPs associated with a decreased risk of non-small-cell lung carcinoma among never smokers but not among smokers, whereas presence of the minor allele was associated with an increased risk of lung cancer among white women with chronic obstructive pulmonary disease but not among those without a history of chronic obstructive pulmonary disease using PCR-RFLP analysis.

Taştemir-Korkmaz et al.[25] found no difference in frequency in these alleles between 60 patients with lung cancer and 20 healthy sex-matched and age-matched random selected volunteers with DR4 genetic heterogeneity in lung cancer susceptibility.


Defective apoptosis is a hallmark of cancer development and progression. Death receptors (DR4) and their ligands (TRAIL) are thought to mediate the major extrinsic apoptotic pathway in the cell. SNPs in these genes may lead to defective apoptosis and increase the risk of different type of malignancy such HCC, gall bladder cancer, ovarian cancer, hematological system cancer, and bladder cancer, but without significantly increasing the risk of some type of malignancies such as lung and breast cancers.

The wide heterogeneity of results may be because of variations in the activity of TRAIL pathway in different tissues. Variations in inclusion and exclusion criteria of patients in different studies may lead to heterogeneous results owing to variable ethnic, demographic, environmental, or hereditary predisposition or may be related to the sample size or method used in genotyping.

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Conflicts of interest

There are no conflicts of interest.


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