Research ArticleExperimental Studies
Open Access

Significant Contribution of Interleukin-18 Genotypes to Childhood Acute Lymphocytic Leukemia Risk in Taiwanese

CHAO-CHUN CHEN, HUEY-EN TZENG, CHIEN-CHUNG KUO, S. NGERN SAE LIM, PEI-CHEN HSU, YUAN-NIAN HSU, YU-TING CHIN, WEN-SHIN CHANG, CHUNG-HSING WANG, CHIA-WEN TSAI, JEN-SHENG PEI and DA-TIAN BAU
Anticancer Research November 2022, 42 (11) 5283-5290; DOI: https://doi.org/10.21873/anticanres.16035

Abstract

Background/Aim: Evidence has shown that interleukin-18 (IL-18) has both antitumor and pro-tumor effects in various types of leukemia. The current study aimed at investigating the contribution of IL-18 polymorphisms to the risk of childhood acute lymphocytic leukemia (ALL) in Taiwan. Materials and Methods: IL-18 promoter −656 (rs1946519), −607 (rs1946518), and −137 (rs187238) genotypes of 266 childhood ALL cases and 266 controls were determined by polymerase chain reaction-restriction fragment length polymorphism methodology. Results: The distributions of genotypic and allelic frequencies of IL-18 rs1946519, rs1946518 or rs187238, were not significantly different between childhood ALL cases and controls (all p>0.05). However, in the stratification analysis among the cases, IL-18 rs187238 GC and CC genotypes were associated with increased childhood ALL risk and shorter survival (OR=4.19 and 2.93, 95%CI=2.04-8.64 and 1.19-7.23, p=0.0001 and 0.0250, respectively). No association was found with rs1946519 and rs1946518 (all p>0.05). Conclusion: IL-18 rs187238 GC and CC genotypes can serve as predictors for childhood ALL prognosis among Taiwanese. Validation in larger and various populations can greatly extend the feasibility of this novel predictor.

Key Words:

Acute lymphoblastic leukemia (ALL) is a disease that arises from the uncontrolled proliferation of lymphoid progenitors (1, 2). Typically, ALL is the most prevailing pediatric hematologic malignancy and mainly attacks children aged 2–5 years old (3-5). Although the pathogenesis and etiology of childhood ALL remain largely unknown, it is widely believed that childhood ALL is caused by genetic variations and environmental factors (6, 7). Recently, lots of studies reported that subtle alterations in the inherited genome, single nucleotide polymorphisms (SNPs), may play a critical role in determining the personal susceptibility to childhood ALL (8-13). The genetic factors associated with childhood ALL are largely undefined, and further explorations of the roles of these factors in relation to childhood ALL are beneficial for early detection and prediction of the disease. Interleukin-18 (IL-18) was originally found in 1999 as a member of IL-1 cytokine family (14). It is secreted by various cells including T and B lymphocytes, monocytes, macrophages, natural killer cells, and Langerhans cells (15-17). In literature, IL-18 is a double-edged knife, carrying both anti-tumor and pro-tumor effects (18, 19). On the anti-tumor side, IL-18 can activate natural killer cells, promoting primarily Th1 responses, resulting in the elimination of tumor cells (20-23). On the opposite side, IL-18 is capable of activating lots of behaviors of tumor cells, including angiogenesis, proliferation, migration, and immune escape ability (24). Higher expression levels of IL-18 have been reported in different solid cancer types, such as gastric, lung, and breast cancer (25-27). There is still no conclusive finding regarding IL-18 expression levels in childhood ALL.

In humans, IL-18 gene is located on chromosome 11q22.2-q22.23 (28). In literature, IL-18 expression levels have been shown to be regulated by at least IL-18, −607 (A/C, rs1946518) and −137 (G/C, rs187238) (29). For instance, the IL-18 gene promoter −137 (G/C, rs187238) polymorphism may change the binding site of histone 4 transcription factor-1 nuclear factor, thus altering IL-18 expression levels (29). Human hematopoietic cell lines, including U937, HL-60, KG-1, K562, J6-1, Jurkat, and HEL, express IL-18 and its receptor (30). In addition, although there is no evidence of IL-18 over-expression in childhood ALL patients, elevated levels of IL-18 have been reported in several types of leukemia patients, such as ALL, chronic myelogenous leukemia (CML) (31), T-cell large granular lymphocytic leukemia (32), and acute mixed lineage leukemia (33). However, IL-18 receptor expression has been mainly reported in CD19+ B cells and some CD8+ T cells (34). In 2005, Wu et al. examined the expression levels of cytokines and their receptors in childhood ALL (35), but no difference was found regarding IL-18.

In 2022, high circulating levels of IL-18 were suggested as a potential predictor for decreased risk of acute myeloid leukemia (AML) (36). In 2017, IL-18 rs1946518 genotypes were reported to associate with prognosis and survival of AML (37), but to the best of our knowledge, there has been no study on IL-18 genotypes in association with ALL. Based on these findings, the aim of this study was to investigate the potential association between IL-18 −656 (rs1946519), −607 (rs1946518), −137 (rs187238) genotypes and susceptibility to ALL in the Taiwanese population. The genomic map of IL-18 rs1946519, rs1946518, and rs187238 is shown in Figure 1.

Figure 1.
Figure 1.

The polymorphic sites of interleukin-18 (IL-18) rs1946519, rs1946518, and rs187238 on chromosome 11.

Materials and Methods

Childhood leukemia cases and healthy controls. Childhood ALL cases were identified by expert pediatric oncologists. All the recruited 266 controls and 266 cases have completed a questionnaire with the help of their parents or guardians and donated their blood sample. Non-cancer healthy controls were matched to each case by age (within 2 years) and sex. The participants are all Taiwanese. This study was approved by the Institutional Review Board of China Medical University Hospital (CMUH111-REC1-038).

IL-18 genotyping design and settings. IL-18 rs1946519, rs1946518, and rs187238 genotyping was conducted as previously published (38-41). Briefly, IL-18 rs1946518 and rs187238 genotyping was carried out using Real-Time PCR (Applied Biosystems, Foster City, CA, USA). As for IL-18 rs1946519, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology was adapted (41). The restriction enzymes have been purchased from New England Biolabs (Ipswich, MA, USA).

Statistical analysis. Genotyping results from 266 childhood ALL patients and 266 healthy controls were finally analyzed. Student’s t-test was adopted to evaluate the differential distribution of age in case and control groups. Pearson’s Chi-square test was used to evaluate the possible differential distributions of various IL-18 genotypes. The associations between specific IL-18 genotypes and childhood ALL cancer risk were estimated by odds ratios (ORs) and corresponding 95% confidence intervals (CIs). A p-value less than 0.05 was considered statistically significant.

Results

Comparison of basic and clinical demographics. There was no difference in age and sex between the ALL case and control groups (p>0.05) since the two groups were well matched for these indices (Table I). As for white blood cell counts, childhood ALL cases had significantly higher levels compared to those of healthy controls (p<0.0001). Among childhood ALL patients, 85.3% (227) of them were of B subtype and 14.7% (39) were of T subtype. Furthermore, 48.9% (130) had standard risk for childhood ALL, 25.2% (67) had high risk for childhood ALL, and 25.9% (69) had very high risk for childhood ALL. Regarding survival, 25.9% of the patients survived for less than 5 years, whereas 74.1% survived for longer than 5 years (Table I).

View this table:
Table I.

Distribution of some basic and clinical demographics of the 266 patients with childhood acute lymphoblastic leukemia and 266 matched controls.

Association between IL-18 genotypes and childhood ALL risk. The distributions of genotype frequencies of IL-18 rs1946519, rs1946518, and rs187238 were 0.4521, 0.7066, and 0.2825, respectively, and fitted well with the Hardy-Weinberg equilibrium. There was no significant difference in the distribution of IL-18 rs1946519, rs1946518, or rs187238 between childhood ALL and control groups (p for trend=0.8495, 0.7860, 0.8438, respectively) (Table II). In detail, variant GT and TT genotypes at IL-18 rs1946519 did not associate with altered childhood ALL risk (OR=1.10 and 1.13, 95%CI=0.75-1.61 and 0.70-1.84, p=0.7114 and 0.7003, respectively). Variant AC and CC genotypes at IL-18 rs1946518 did not associate with altered childhood ALL risk either (OR=0.89 and 1.01, 95%CI=0.59-1.34 and 0.62-1.62, p=0.6465 and 0.9825, respectively). Variant GC and CC genotypes at IL-18 rs187238 also did not associate with altered childhood ALL risk (OR=0.90 and 0.78, 95%CI=0.57-1.40 and 0.21-2.95, p=0.7173 and 0.7494, respectively). We also conducted recessive and dominant model analysis, but no significant association was found (data not shown).

View this table:
Table II.

Distribution of interleukin-18 (IL-18) genotypes among the 266 patients with childhood acute lymphoblastic leukemia and 266 healthy controls.

Association between IL-18 rs1946519, rs1946518, and rs187238 alleles and childhood ALL risk. To further validate the findings shown in Table III, we performed statistical analysis on the allelic frequency distributions of the IL-18 rs1946519, rs1946518, and rs187238, and the results showed that neither the T allele at IL-18 rs1946519, nor the C allele at IL-18 rs1946518 and the C allele at IL-18 rs187238 was associated with a significantly altered risk of childhood ALL (OR=1.07, 1.00 and 0.89, 95%CI=0.84-1.37, 0.79-1.27 and 0.60-1.31, p=0.6206, 1.0000 and 0.6174) (Table III).

View this table:
Table III.

Distribution of interleukin-18 (IL-18) allelic frequencies among the 266 patients with childhood acute lymphoblastic leukemia and 266 healthy controls.

Association between IL-18 rs1946519, rs1946518, and rs187238 genotypes and childhood ALL immunophenotype, risk classification, and survival. We analyzed the potential contribution of IL-18 rs1946519, rs1946518, and rs187238 genotypes to childhood ALL immunophenotype, risk classification, and survival, and no association with IL-18 rs1946519 or rs1946518 was found (p>0.05) (Table IV and Table V). However, we found that IL-18 rs187238 variant genotypes (GC+CC) were associated with higher (high or very high) childhood ALL risk, and shorter survival (OR=4.19 and 2.93, 95%CI=2.04-8.64 and 1.19-7.23, p=0.0001 and 0.0250, respectively) (Table VI).

View this table:
Table IV.

Distribution of interleukin-18 (IL-18) rs1946519 genotypes among the 266 patients with childhood acute lymphoblastic leukemia stratified by immunophenotype, risk classification, and survival.

View this table:
Table V.

Distribution of interleukin-18 (IL-18) rs1946518 genotypes among the 266 patients with childhood acute lymphoblastic leukemia stratified by immunophenotype, risk classification, and survival.

View this table:
Table VI.

Distribution of interleukin-18 (IL-18) rs187238 genotypes among the 266 patients with childhood acute lymphoblastic leukemia stratified by immunophenotype, risk classification, and survival.

Discussion

In this study, we evaluated the contribution of IL-18 genotypes to ALL risk in a representative Taiwanese population, consisting of 266 childhood ALL patients and the same number of healthy controls (Table I). The data showed that IL-18 rs1946519, rs1946518, and rs187238 genotypes were not associated with childhood ALL risk (Table II and Table III). Thus, these IL-18 SNPs may not serve as useful biomarkers for early detection of childhood ALL in Taiwan. Noticeably, we have found that IL-18 rs187238 GC+CC genotypes were associated with higher risk for childhood ALL, and shorter survival (Table VI). This is a novel finding and will be quite useful for prognosis prediction. The findings also support the concept that IL-18 somehow plays a critical role in the etiology of ALL, although the detail mechanisms need further investigation.

To the best of our knowledge, there is no report on the role of IL-18 genotypes in ALL. In 2015, for a study was conducted on the role of IL-18 genotypes in chronic lymphocytic leukemias (CLL) and CML among Turkish patients (42). However, the sample sizes for CLL, CML and healthy controls were only 20, 30, and 30, respectively. Although they provided promising data showing that IL-18 rs187238 was associated with chronic leukemia in the Turkish population, large-scale studies are required to validate their findings. In 2017, Wang et al. reported that IL-18 rs1946518 was not associated with the risk of AML, but the GT genotype of IL-18 rs1946518 led to significantly poorer survival rates (37). The case and control sample sizes of their study were 383 and 300, which were more representative and reliable.

The genotypes of IL-18 rs1946518 and rs187238 have been investigated for their association with the risk of various types of solid cancers. In esophageal, colorectal, ovarian, bladder, prostate, breast and lung cancer, positive associations have been reported (27, 41, 43-48). However, there also studies reporting no association (49-52). Data have also shown that IL-18 rs1946518/rs187238 haplotype was associated with an elevated nasopharyngeal carcinoma risk (53). These inconsistent conclusions might be explained not only by ethnic differences, but also by the type of cancer. These findings should be validated in various populations with large sample sizes.

Over-expression of IL-18 in serum has been reported to serve as a good marker for solid cancers, such as lung cancer (27); however, whether the serum level of IL-18 is a good marker for ALL is still unknow. There is evidence that high circulating levels of IL-18 associate with a decreased risk of AML (36). Dynamic alterations of IL-18 protein make it difficult to conclude whether IL-18 protein can serve as a good marker for ALL. However, the current results showed that the GG genotype of IL-18 rs187238 can be a predictor of childhood ALL survival, although the detail mechanism needs more investigations (Table VI).

In conclusion, our pilot study showed that IL-18 rs1946519, rs1946518, and rs187238 genotypes cannot serve as prognostic predictors for childhood ALL risk, as shown in other solid tumors. However, the variant GC and CC genotypes of IL-18 rs187238 may serve as a predictor of higher risk and shorter survival.

Acknowledgements

The Authors are grateful to the Tissue-bank of China Medical University Hospital and doctors/nurses for their blood sample and questionnaire collection. This study was supported by research grants from China Medical University Hospital, Taichung, Taiwan (DMR-111-160), and Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan (PTH110039).

Footnotes

  • ↵*,† These Authors contributed equally to this study.

  • Authors’ Contributions

    Research design: Chen CC, Tzeng HE, Kuo CC; patient and questionnaire summaries: Wang CH, Kuo CC, Lim SNS, Hsu PC; experimental work: Chang WS, Chin YT, Tsai CW; statistical analysis: Hsu YN, Chen CC; manuscript writing: Tsai CW, Pei JS, Bau DT; manuscript checking and discussing: Chen CC, Tzeng HE, Kuo CC, Lim SNS, Hsu PC, Chang WS, Chin YT, Tsai CW, Hsu YN, Pei JS, Bau DT.

  • Conflicts of Interest

    All the Authors declare no conflicts of interest regarding this study.

  • Received August 12, 2022.
  • Revision received September 6, 2022.
  • Accepted September 7, 2022.

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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Significant Contribution of Interleukin-18 Genotypes to Childhood Acute Lymphocytic Leukemia Risk in Taiwanese
CHAO-CHUN CHEN, HUEY-EN TZENG, CHIEN-CHUNG KUO, S. NGERN SAE LIM, PEI-CHEN HSU, YUAN-NIAN HSU, YU-TING CHIN, WEN-SHIN CHANG, CHUNG-HSING WANG, CHIA-WEN TSAI, JEN-SHENG PEI, DA-TIAN BAU
Anticancer Research Nov 2022, 42 (11) 5283-5290; DOI: 10.21873/anticanres.16035
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