Research ArticleExperimental Studies
Open Access

The Contribution of DNA Ligase 4 Genetic Variations to Taiwanese Lung Cancer

YEN-HSIEN LEE, SHOU-CHENG WANG, CHIA-HSIANG LI, LI-HSIOU CHEN, TE-CHUN SHEN, YEN-FENG LIU, YUN-CHI WANG, CHIA-WEN TSAI, TE-CHUN HSIA, DA-TIAN BAU and WEN-SHIN CHANG
Anticancer Research August 2023, 43 (8) 3447-3453; DOI: https://doi.org/10.21873/anticanres.16520

Abstract

Background/Aim: Impaired non-homologous end-joining DNA repair capacity may have a significant role in maintaining genome integrity and triggering carcinogenesis. However, the specific impact of DNA ligase 4 (Lig4) genotypes remains unclear. This study aimed to assess the contribution of Lig4 genotypes to the risk of developing lung cancer. Materials and Methods: Polymerase chain reaction-restriction fragment length polymorphism analysis was used to examine the genotypes of Lig4 rs1805388, and their association with lung cancer risk was evaluated in a case-control study consisting of 358 lung cancer cases and 716 age- and sex-matched cancer-free control subjects. Results: The distribution of CC, CT, and TT genotypes for Lig4 rs1805388 among the cases was 45.0%, 41.6%, and 13.4%, respectively, compared to 58.0%, 36.3%, and 5.7% among the controls (p for trend=1.98×10−6). Allelic analysis indicated that individuals carrying the T-allele for Lig4 rs1805388 had a 1.66-fold higher risk of developing lung cancer compared to those carrying the wild-type C-allele [95% confidence interval (CI)=1.36-2.02, p=4.04×10−7]. Moreover, a significant interaction was observed between the Lig4 rs1805388 genotype and smoking status (p=1.32×10−7). Conclusion: These findings suggest that the CT and TT variant genotypes of Lig4 rs1805388, combined with cigarette smoking, may contribute to a higher risk of developing lung cancer.

Key Words:

Lung cancer is a prevalent cancer type worldwide, accounting for over 11% of all neoplasms and causing 18% of cancer-related deaths (1). In 2018, there were an estimated 2.1 million new cases and 1.8 million deaths related to lung cancer globally (2). The increasing number of cases and high mortality rates have prompted the search for reliable markers to predict lung cancer risk, prognosis, and drug treatment response. Multiple factors, including behavioral, environmental, and genetic factors, contribute to initiation and development of lung cancer. Among these factors, cigarette smoking is the most significant risk factor for lung cancer (3). However, the fact that 10% to 25% of lung cancer patients worldwide are non-smokers indicates that genetic influences also play a crucial role in personal lung cancer etiology (4). In Taiwan, lung cancer is ranked third in incidence and first in mortality among different types of cancer (5). Although several biomarkers have been examined for early lung cancer detection in recent years, there is still an urgent need to find clinically practical markers for early detection of lung cancer (6-10).

The human genome is frequently damaged by both endogenous and exogenous mutagens, and DNA repair systems are essential in preventing irreversible mutations that can cause carcinogenesis (11, 12). In the case of non-small cell lung cancer, patients over the age of 50 and those with adenocarcinoma exhibit significantly higher genomic instability compared to those with squamous-cell carcinoma. Additionally, genomic instability is negatively correlated with tumor grade (12). Double-strand breaks (DSBs) are a severe type of DNA damage resulting from both exogenous and endogenous factors such as ionizing radiation, free radicals, replication errors, and telomere dysfunction (13, 14). DSBs should be promptly repaired, as failure to do so can result in irreversible consequences.

The Lig4 gene, located on the 13q33 chromosome, encodes a nuclear protein that is homologous to other ligases in the N-terminal region but not in the C-terminal region (15, 16). The importance of the Lig4 protein in maintaining genomic stability is underscored by the fact that mutations in this gene are associated with a rare autosomal syndrome (OMIM 606593), characterized by microcephaly, immunodeficiency, spontaneous genomic instability, and a higher susceptibility to various human diseases, including cancer (17-20). Cells from LIG4-deficient patients display increased radio-sensitivity and are defective in non-homologous end joining (NHEJ) repair capacity (18, 20, 21). In mice, knockout of Lig4 resulted in late embryonic lethality with massive neuronal apoptosis and lymphocyte development arrest due to the lack of V(D)J recombination (22-24). Taken together, these findings emphasize the crucial role of Lig4 in maintaining normal DNA repair capacity and cellular viability.

The first report of an association between Lig4 rs1805388 CT and TT genotypes and increased lung cancer risk among 152 non-small cell lung cancer patients in Taiwan was published in 2009 (25). Subsequently, in 2012, it was reported that these genotypes were associated with severe radiation pneumonitis in 195 non-small cell lung cancer patients in the USA (26). In 2015, Xu and his colleagues attempted to validate whether Lig4 rs1805388 could serve as a practical marker for severe radiation pneumonitis in an Asian population of 160 non-small cell lung cancer patients but in vain (27). Although the association was not statistically significant, their findings, along with those of the previous studies, suggest that Lig4 rs1805388 genotypes may be critical in determining phenotypes and may be of clinical significance in lung cancer therapy. However, the latter two reports (Yin’s and Xu’s) do not provide evidence for Lig4 rs1805388 genotypes as predictive diagnostic markers. Moreover, the investigated populations in all three studies were not large enough and require further validation. Therefore, in this study, we aim to conduct a hospital-based case-control study in a representative population (control:case=716:358), validate the contribution of Lig4 rs1805388, examine the interaction of Lig4 genotypes with smoking status on lung cancer risk.

Materials and Methods

Lung cancer case and age- and sex-matched control population. A total of 358 patients with histologically confirmed lung cancer were recruited from the China Medical University Hospital, as described previously (28, 29). Exclusion criteria included a history of malignancy or other pulmonary diseases such as chronic obstructive pulmonary disease (COPD), pneumothorax, and asthma. Two healthy volunteers were selected as controls for each lung cancer patient, matched for age (within 5 years), sex, and smoking behavior to minimize the influence of smoking. Controls were selected from the Health Examination Cohort database of the China Medical University Hospital, which contained over 15,000 individuals. Exclusion criteria for controls included a history of malignancy or metastasized cancer, and any genetic or familial diseases. Both cases and controls were Taiwanese, and Table I summarizes several population characteristics.

View this table:
Table I.

Distribution of demographic data of 358 lung cancer patients and 716 matched non-cancer. controls.

Genotyping conditions for Lig4 rs1805388. Genomic DNA was extracted from the peripheral blood leukocytes of each participant within 24 h of blood collection using the QIAamp Blood Mini Kit (Blossom, Taipei, Taiwan, ROC), as previously described (30). The extracted DNA was quantified, stored long-term at −80°C, and aliquoted for genotyping as a working stock at −20°C. The genotyping methodology for Lig4 rs1805388 was designed by the Terry Fox Cancer Research Lab. The forward and reverse primer sequences were 5′-TCTGTATTCGTTCTAAAGTT-3′ and 5′-TGCTTTACTAGTTAAA CGAG-3′, respectively. Polymerase chain reaction (PCR) cycling conditions were as follows: one cycle at 94°C for 5 min, 35 cycles of 94°C for 30 s, 52°C for 30 s, and 72°C for 30 s and a final extension step at 72°C for 10 min. After PCR amplification, the products were digested with the HpyCH4 III restriction endonuclease and separated via 3% agarose gel electrophoresis for 25 min. The Lig4 rs1805388 genotypes were identified as wild-type C/C with a 121-bp product, heterozygous variant C/T with 121-, 65-, and 56-bp products, and homozygous variant T/T with 65- and 56-bp products. Genotyping was repeated independently by two researchers in a blind manner, and all genotyping results were 100% successful and concordant.

Statistical analysis. The distribution of ages between the case and control groups was compared using the Student’s t-test. The goodness-of-fit chi-square test was utilized to assess the Hardy-Weinberg equilibrium among the different Lig4 rs1805388 genotypes in 716 non-cancer controls. Pearson’s Chi-square methodology was used to compare the distributions of Lig4 rs1805388 genotypes among subgroups, as well as to perform stratification analysis for the interaction between Lig4 rs1805388 genotypes and smoking status. Logistic regression analysis was used to estimate the odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) to determine the associations between Lig4 rs1805388 genotypes and lung cancer risk. A p-value less than 0.05 was considered significant in any comparison.

Results

Table I presents the frequency distributions of age, sex, and smoking status for 358 lung cancer patients and their 716 matched non-cancer healthy controls. Additionally, the histology of lung cancer patients is shown. Frequency matching was performed on age, sex, and smoking status to recruit the healthy controls, and the data demonstrated no significant differences in the distribution of age, sex, or smoking behavior between the two groups (all p>0.05). It is important to note that the high percentage of smokers (78.6%) in the control group is due to the frequency matching strategy and may not represent the entire Taiwanese population. Adenocarcinoma was the most common histological type, accounting for 60.9% (218/358) of lung cancer cases, followed by squamous cell carcinoma (29.6%, 106/358) and other types (9.5%, 34/358).

Table II displays the genotypic distributions of Lig4 rs1805388 among the 716 non-cancer controls and the 358 lung cancer patients. The genotypic frequencies of Lig4 rs1805388 among control subjects were found to be in Hardy-Weinberg equilibrium (p=0.9737, Table II). Furthermore, the genotypic frequencies of Lig4 rs1805388 were observed to be differently distributed between the lung cancer and healthy control groups (p for trend=1.98E-6, Table II). Specifically, both the heterozygous CT and homozygous variant TT genotypes of Lig4 rs1805388 were associated with increased lung cancer risks (OR=1.48 and 3.02, 95%CI=1.13-1.94 and 1.91-4.76, p=0.0059 and 0.0001, respectively; Table II). The recessive model showed a significant 2.55-fold increase in lung cancer risk for carriers of the Lig4 rs1805388 TT genotype compared to those with CC+CT genotypes (95%CI=1.65-3.95, p=0.0001, Table II). In the dominant model, there was a significant 1.69-fold increase in lung cancer risk for carriers of the CT+TT genotypes of Lig4 rs1805388 compared to those carrying CC genotypes (95%CI=1.31-2.18, p=0.0001, Table II).

View this table:
Table II.

Distribution of Lig4 rs1805388 genotypes among the 358 lung cancer and non-cancer 716 controls.

To validate the findings in Table II, an analysis of allelic frequency distribution for Lig4 rs1805388 was performed, and the results are presented in Table III. The results further support the notion that the Lig4 rs1805388 genotype is associated with lung cancer risk, as the proportion of the risk T allele was found to be 34.2% among the lung cancer cases, which is significantly higher than the 23.9% observed among the cancer-free controls (OR=1.66, 95%CI=1.36-2.02, p=4.04×10−7).

View this table:
Table III.

Distribution of Lig4 rs1805388 allelic frequencies among the 358 lung cancer and the non-cancer 716 controls.

We further performed a stratification analysis to investigate the interaction between the inherited Lig4 rs1805388 genotype and personal cigarette smoking habits, as cigarette smoking is a well-known risk factor for lung cancer. Interestingly, no significant interaction was found among non-smokers (p>0.05) (Table IV). However, among smokers, those with Lig4 rs1805388 CT and TT genotypes had 1.61- and 3.92-fold higher odds of having lung cancer, respectively (95%CI=1.19-2.18 and 2.33-6.59, p=0.0026 and 0.0001, respectively). The statistical significance persisted at a similar level after adjusting for age, sex, and alcohol drinking status (OR=1.58 and 3.79, 95%CI=1.12-2.26 and 2.21-5.84, respectively, Table IV).

View this table:
Table IV.

Distribution of Lig4 rs1805388 genotypes among 358 lung cancer and 716 controls after stratification by smoking status.

Discussion

The DNA repair system is a crucial mechanism that evolved to maintain genomic stability and prevent cells from mutating into tumors. The primary pathways of the DNA repair system include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double-strand break repair (DSBR). Inter-individual variations in DNA repair capacity may contribute to differences in susceptibility to various types of cancer (31). Among these pathways, Lig4 plays a pivotal role in the joining of DSBs through the NHEJ pathway. Existing literature has demonstrated that LIG4 interacts with XRCC4, which is critical to stabilize LIG4 protein in cells (32, 33). Cells deficient in XRCC4, such as XR-1 cells, exhibit reduced levels of LIG4 (34). Although the interaction between XRCC4 and DNA Lig4 remains unresolved, subtle alterations in DSB repair genes may contribute to the development and progression of all types of cancer, including lung cancer.

In recent years, several studies have reported associations between SNPs in genes involved in the DSB repair pathway and lung cancer, including Nijmegen breakage syndrome 1 (NBS1), X-ray repair cross-complementing group 3 (XRCC3), and ataxia telangiectasia mutated (ATM) (35-37). However, studies on the association between NHEJ pathway gene SNPs and lung cancer risk are limited and not well characterized. Interestingly, studies have shown that genotypes of XRCC4, XRCC6, and XRCC7 are associated with lung cancer risk (38-40).

In this study, we investigated the genotypes of Lig4 rs1805388 in Taiwan and assessed the reliability of our sampling and genotyping data. We compared the percentages of Lig4 rs1805388 genotypic distribution in our cancer-free control group with those on the National Center for Biotechnology Information (NCBI) website for East Asian populations. Towards this aim, the percentages of Lig4 rs1805388 genotypic distribution among the cancer-free controls were compared to those on National Center for Biotechnology Information (NCBI) websites (41). According to the 1,170 and 3,128 subjects of East Asians genotyped and analyzed, the minor allelic frequencies at Lig4 rs1805388 are 0.2205 and 0.2430, respectively (updated on 2023/05/07). In our data, the variant T allele has the frequency of 0.2390 and can represent the Taiwan population which located in East Asia. We then examined the association between the Lig4 rs1805388 genotypes and lung cancer risk in a genetically homogeneous population in Taiwan consisting of 716 healthy subjects and 358 lung cancer cases. Our findings revealed that the CT and TT genotypes of Lig4 rs1805388 were associated with an increased risk of lung cancer (Table II and Table III), and this genetic factor had a joint effect with cigarette smoking on determining lung cancer susceptibility (Table IV). Cigarette smoke contains compounds that induce DNA DSBs and promote lung carcinogenesis (42, 43). Lig4 rs1805388 genotypes may influence protein function, resulting in differential capacity to repair DSB damage in lung cells. It has been reported in the literature that the T allele at Lig4 rs1805388 is associated with reduced adenylation and ligation activities of the enzyme (44), which may result in a lower capacity for DSB removal and a higher risk of lung cancer. Further investigations are required to validate the genotype-phenotype correlation.

In the scientific literature, other Lig4 polymorphisms have been investigated for their potential associations with various human diseases. For example, Lig4 rs1805386 genotypes were initially linked to ovarian cancer risk (45), However, subsequent replication studies failed to confirm this association (46). Additionally, the genotypes of Lig4 rs1805386 were not associated with either breast cancer risk (46, 47), or lung cancer risk (48), except for a borderline significant association with a decreased risk of breast cancer reported by Kuschel and colleagues (p=0.04) (49). Another Lig4 polymorphic site, rs2232641, was not associated with breast cancer risk (50), but was linked to a reduced risk of developing lung cancer in Japanese individuals (p=0.03) (51).

There are several limitations of this study that should be acknowledged. First, the lack of recorded follow-up data restricted the analysis of the correlation between Lig4 rs1805388 genotypes and prognosis indices, such as survival time. Second, the use of tumor and non-tumor samples restricted the investigation of differential expression of Lig4 mRNA and protein levels in lung cancer patients. Third, the relatively small sample size, particularly for subgroup analyses such as those shown in Table IV (especially the 6 TT carriers in non-smoker case group), may have caused in some sampling bias and reduced statistical power for further annotations. The findings of subgroup stratification should be further validated with larger samples in the future.

In summary, the present study demonstrated a correlation between the T allele at Lig4 rs1805388 and increased lung cancer susceptibility, particularly in the context of smoking. Future research should investigate the impact of Lig4 genotypes on mRNA and protein expression levels, as well as NHEJ capacity, to better understand the underlying mechanisms driving this association.

Acknowledgements

The Authors appreciate the team under Hsia TC in collection of the blood and clinical data from all the participants. The perfect PCR-RFLP technology and efforts from Wang YC, Chang WS, Chin YT, Huang YR, and Lin YH are also appreciated. This study is supported by the grant from China Medical University and Asia University (CMU111-ASIA-03), Taichung Armed Forces General Hospital (TCAFGH-E-110041) and Taichung Tzu Chi Hospital (TTCRD111-18).

Footnotes

  • Authors’ Contributions

    Research design: Chang WS, Bau DT and Hsia TC; Patient and questionnaire summary: Lee YH, Wang SC, Li CH, Chen LH, Shen TC, Liu YF, and Hsia TC; Experiment data clearing and checking: Lee YH, Wang YC and Chang WS; Statistical analysis: Chen LH, Wang SC and Chen LH; Literature review: Lee YH, Wang YC, and Tsai CW; Manuscript writing: Lee YH, Tsai CW, Hsia TC, Chang WS and Bau DT; Review and revision: Bau DT, Chang WS and Hsia TC.

  • Conflicts of Interest

    The Authors declare no conflicts of interest regarding this study.

  • Received May 8, 2023.
  • Revision received May 30, 2023.
  • Accepted June 19, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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The Contribution of DNA Ligase 4 Genetic Variations to Taiwanese Lung Cancer
YEN-HSIEN LEE, SHOU-CHENG WANG, CHIA-HSIANG LI, LI-HSIOU CHEN, TE-CHUN SHEN, YEN-FENG LIU, YUN-CHI WANG, CHIA-WEN TSAI, TE-CHUN HSIA, DA-TIAN BAU, WEN-SHIN CHANG
Anticancer Research Aug 2023, 43 (8) 3447-3453; DOI: 10.21873/anticanres.16520
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