The role of common variants of non-homologous end-joining repair genes XRCC4, LIG4 and Ku80 in thyroid cancer risk

Abstract

Abstract. Variations, such as single nucleotide polymorphisms (SNPs) in DNA damage repair genes have been pointed out as possible factors to cancer predisposition. Ionizing radiation (IR) induces DNA double strand breaks (DSBs) and is the main recognized risk factor for thyroid cancer. However, most of the patients do not show chronic contact with IR and the other factors have non-concordant data. Thus, thyroid cancer could be due to gene variations in association with certain exogenous factors. One of the pathways that repair DSBs is DNA non-homologous end-joining (NHEJ) that comprises several polymorphic genes. We intend to study the role of polymorphic variants in XRCC4, LIG4 and Ku80 genes, since there is scarcity of data on the role of these genes in thyroid cancer susceptibility. We carried out a hospital-based case-control study in a Caucasian Portuguese population (109 patients and 217 controls) to estimate the potential role of the XRCC4 (N298S and T134I), LIG4 (T9I) and Ku80 (Ex21-238G➝A, Ex21+338T➝C, Ex21-352C➝A, Ex21+466A➝G) polymorphisms in the individual susceptibility for this disease. The results here reported do not associate these polymorphisms with susceptibility for non-familial thyroid cancer. However, when the data were analyzed according to the type of tumour, significant results for Ku80Ex21-238G➝A and Ex21+466A➝G were found for papillary tumours (adjusted OR = 2.281; 95% CI = 1.063-4.894; P=0.034). Taken together these results suggest that some of these variants in NHEJ genes can contribute to thyroid cancer susceptibility. However, further studies with a larger sample size will be needed to support our results.

The XRCC4 rs1805377 polymorphism is not associated with the risk of cancer: An updated meta-analysis

“…Twenty-four publications were included according to the established inclusion criteria. 13,32–54 A flow diagram of this process is shown in Figure 1. Subjects involved in the studies are not overlapping.…”

Selective inhibition of DNA ligase IV provides additional efficacy to the treatment of anaplastic thyroid cancer

“…However, the use of DNA ligase IV inhibitors for cancer sensitization to DNA damaging agents is poorly exploited (53). It has been shown that patients with homozygous mutations in DNA ligase IV are characterized by hyper-radiosensitivity (62)(63)(64). scRNAseq analysis showed reduced expression of the LIG4 gene at the mRNA level in normal follicular thyroid cells and thyroid cancer cells, but its activity is tightly regulated at the protein level by XRCC4 and DNA-PKcs (65).…”

Polymorphisms of DNA Repair Genes in Thyroid Cancer

“…No study showed a significant association between the tested polymorphisms and the risk of thyroid cancer. Gomes et al examined the rs1805377 (Asn298Ser) and rs28360135 (Thr134Ile) polymorphisms of XRCC4 and their interactions with LIG4 ; however, no significant gene-gene interaction was demonstrated, and the analysis of the polymorphisms did not indicate a relationship with the risk of cancer in the study population [ 53 ]. In the Arab population, the analysis of XRCC4 rs1805377 also did not show a significant statistical correlation with the risk of thyroid cancer compared to the control groups [ 29 ].…”

“…XRCC5 / Ku80 gene polymorphisms have been investigated in the context of thyroid cancer. In the study by Gomes et al, the rs2440 polymorphism was not found to be significant in the overall Portuguese (Caucasian) population, but the logistic regression test showed significance for PTC but not for FTC (adjusted OR = 2.28; 95% CI = 1.06–4.89; p = 0.03) [ 53 ]. The remaining polymorphisms, that is, rs1051677, rs6941, and rs1051685, did not show statistically significant genotype differences between the study and control populations.…”