Research ArticleArticle

Novel Contribution of Long Non-coding RNA MEG3 Genotype to Prediction of Childhood Leukemia Risk

JEN-SHENG PEI, WEN-SHIN CHANG, CHAO-CHUN CHEN, MEI-CHIN MONG, SHIH-WEI HSU, PEI-CHEN HSU, YUAN-NIAN HSU, YUN-CHI WANG, CHIA-WEN TSAI and DA-TIAN BAU
Cancer Genomics & Proteomics January 2022, 19 (1) 27-34; DOI: https://doi.org/10.21873/cgp.20301

Abstract

Background/Aim: Acute lymphoblastic leukemia (ALL) is frequent among children. Few studies have researched the relationship between maternally expressed gene 3 (MEG3) and cancer risk. We hypothesized long non-coding RNA MEG3 polymorphisms might influence the risk of childhood ALL. Materials and Methods: In a total of 266 patients with childhood ALL and 266 healthy controls, genotypes of MEG3 rs7158663, rs3087918, rs11160608 and rs4081134 single nucleotide polymorphisms were investigated for their associations with childhood ALL. Results: MEG3 rs7158663 AG and AA genotypes were significantly associated with ALL [odds ratio=1.61 (95% confidence interval=1.12-2.31) and 2.21 (1.16-4.22), respectively]. The A allele also exhibited a statistical association with higher risk of ALL (p=0.0015). There was no positive association as for rs3087918, rs11160608 or rs4081134. Interestingly, a significant interaction between MEG3 rs7158663 and age (≥3.5 years) and gender (male) was found. Conclusion: MEG3 rs7158663 AG/AA genotypes were associated with higher susceptibility to childhood ALL. These novel findings should be validated in larger populations and different ethnicities.

Key Words:

Childhood acute lymphoblastic leukemia (ALL) is a malignant disorder commonly found among children and frequently in children less than 15 years of age. The peak ages of early onset are 2-5 years old (1, 2), accounting for approximately one-third of childhood tumors (3). The etiology and pathogenesis remain unclear, and it is believed that childhood ALL is the consequence of a combinative influence of genetic variations and lifestyle/environmental factors (4, 5). In recent years, there is mounting evidence that single nucleotide polymorphisms (SNPs) may play an important role in determining the risk for childhood ALL (6-11). However, the role of many genetic factors is unclear, and further exploration of the complex genomic understanding about childhood ALL is urgently needed.

Long non-coding RNAs (lncRNA) are defined as RNAs longer than 200 nucleotides and form a novel group of non-coding RNAs, with microRNA-like features, which are not translated into functional proteins (12). Mounting evidence has shown that lncRNAs play a critical role in controlling a variety of biological processes, including leukemia progression, immune regulation, carcinogenesis, tumor metastasis and drug resistance (13-15). The maternally expressed gene 3 (MEG3) encodes a myelocyte-related lncRNA and is believed to be involved in the process of carcinogenesis and responsiveness to chemotherapy (16, 17). MEG3 is considered a tumor suppressor (15). It has been reported to play a role in several types of cancer, including bladder (18), gastric (19), and lung (20), as well as hepatocellular carcinoma (21). Accumulating evidence has suggested that genetic variants in the MEG3 gene predispose to cancer. However, the impacts of MEG3 polymorphisms in childhood ALL remain unclear. According to the information above, we were interested in investigating the contribution of MEG3 genotypes to childhood ALL. We also summarize the literature on the associations of MEG3 genotypes with various types of cancer to provide the reader with a better understanding of the contribution of MEG3 genotype to cancer risk.

Materials and Methods

Recruitment of childhood leukemia cases and healthy controls. Childhood ALL cases were ascertained by pediatric oncologists with pathological confirmation. All the recruited cases completed a questionnaire with help from their parents or guardians, and donated blood samples. Healthy controls without prior history of any tumor were recruited in the same period. Healthy controls were matched to each case by age (±2 years) and gender. All the participants were Taiwanese. This study was approved by the Institutional Review Board of China Medical University Hospital (DMR103-IRB-153).

Genotyping methodology for MEG3 genotype. Peripheral blood was collected from each participant and the genomic DNA was extracted within 24 h (22). The genotypes at MEG3 SNP rs7158663, rs3087918, rs11160608 and rs4081134 were determined using a TaqMan assay with an ABI 7500 Real-Time PCR System (Applied Biosystems, Foster City, CA, USA). For quality control, two negative controls (distilled water without DNA sample) were included in each 96-well plate. Furthermore, genotyping of about 3% of randomly selected samples was repeated in a blind fashion to confirm the genotyping results.

Statistical methodology. The good-of-fit chi-square test was used to tests for deviation from Hardy–Weinberg equilibrium of the selected polymorphic sites. Student’s t-test was used to check the distributions of ages. Pearson’s chi-square methodology was used in checking the distribution pattern of MEG3 genotypes and the interaction of MEG3 genotype with age and gender. The contribution of MEG3 genotypes to childhood ALL were also validated with the corresponding odds ratios (ORs) and 95% confidence intervals (CIs). Any association with a p-value less than 0.05 was considered statistically significant

Results

Comparison of basic and clinical demographics. The distributions of age of ALL onset, gender and white blood cell counts of childhood ALL cases and matched healthy controls are shown in Table I. In addition, the immunophenotype, risk classification and survival time of the childhood leukemia cases are also shown. There was no difference in distributions of age and gender between the cases and controls (p>0.05) since the two groups were matched for these indices (Table I). The mean white blood cell count of childhood ALL cases was significantly higher than those of healthy controls (p<0.0001). Among the patients, 48.9% (130 in number) were at standard risk, 25.2% (67 in number) were at high risk, and 25.9% (69 in number) were at very high risk. Lastly, 25.9% of the patients survived less than 5 years (Table I).

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Table I.

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

Significant association between MEG3 rs7158663 genotypes and childhood ALL. The genotypic distributions of MEG3 rs7158663 among the controls and the childhood ALL patients are presented and analyzed in Table II. Firstly, the genotypic frequencies of MEG3 rs7158663 among the control individuals were in Hardy–Weinberg equilibrium (p=0.7108). Secondly, the genotypes of MEG3 rs7158663 were differently distributed between the childhood ALL and healthy control groups (p for trend=0.0064) (Table II). Carrying MEG3 rs7158663 heterozygous AG or homozygous AA genotype was associated with an increased childhood ALL risk, compared with the wild-type GG genotype (OR=1.61 and 2.21, 95% CI=1.12-2.31 and 1.16-4.22; p=0.0097 and 0.0142, respectively). Thirdly, in the recessive model, compared with those carrying GG and AG genotypes, risk of ALL for homozygous variant AA genotype carriers at MEG3 rs7158663 did not reach a significant level (OR=1.79, 95% CI=0.96-3.35; p=0.0641). Fourthly, in the dominant model, there was an increased risk of childhood ALL for those carrying an A allele at MEG3 rs7158663, compared with those with homozygous GG genotype (OR=1.70, 95% CI=1.21-2.39, p=0.0024). These results showed that AG and AA genotype carriers at MEG3 rs7158663 had a significantly elevated risk for childhood ALL.

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Table II.

Maternally expressed gene 3 (MEG3) rs7158663 genotypes among the 266 patients with childhood acute lymphoblastic leukemia and 266 healthy controls.

Non-significant association for other MEG3 SNPs examined. The genotypic distributions of MEG rs3087918, rs11160608, and rs4081134 are presented and analyzed in Table III, Table IV and Table V, respectively. The genotypic frequencies of MEG3 rs3087918, rs11160608, and rs4081134 among the control individuals all fit the Hardy–Weinberg equilibrium (all p>0.05). However, none of these SNPs seemed to be significantly associated with ALL in any model analyzed (all p>0.05).

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Table III.

Maternally expressed gene 3 (MEG3) rs3087918 genotypes among the 266 patients with childhood acute lymphoblastic leukemia and 266 healthy controls.

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Table IV.

Maternally expressed gene 3 (MEG3) rs11160608 genotypes among the 266 patients with childhood acute lymphoblastic leukemia and 266 healthy controls.

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Table V.

Maternally expressed gene 3 (MEG3) rs4081134 genotypes among the 266 patients with childhood acute lymphoblastic leukemia and 266 healthy controls.

Allelic frequency distribution analysis supported the findings. To validate the results shown in Table II to Table V, analysis of the allelic frequency distribution for MEG3 rs7158663, rs3087918, rs11160608, and rs4081134 SNPs were conducted, and the results are shown in Table VI. Most importantly, the variant A allele at MEG3 rs7158663 was found in 33.3% in the childhood ALL group and in 24.4% in the control group (OR=1.54, 95% CI=1.18-2.01, p=0.0015, Table VI). This supports the finding that the A allele was associated with an increased risk of childhood ALL in Taiwanese. For other SNPs, including rs3087918, rs11160608, and rs4081134, none of the variant alleles seemed to be significantly associated with childhood ALL risk.

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Table VI.

Distribution of allelic frequencies for rs7158663, rs3087918, rs11160608 and rs4081134 single nucleotide polymorphisms (SNPs) of maternally expressed gene 3 (MEG3) among the 266 patients with childhood acute lymphoblastic leukemia and 266 healthy controls.

Interaction of MEG3 rs7158663 genotypes with age and gender. We were interested in examining whether there was any difference of MEG3 rs7158663 genotypes according to age and gender. Table VII shows that among children aged less than 3.5 years, those with MEG3 rs7158663 AG and AA variant genotypes had non-significant odds of having childhood ALL (95% CI=0.97-2.70 and 0.54-3.43, p=0.0627 and 0.5048, respectively). Even after adjustment for gender, the level was similar and did not reach the significance level (adjusted OR=1.78 and 1.43, 95% CI=0.92-2.62 and 0.52-3.34, respectively) (Table VII). Among children aged 3.5 years and over, those with MEG3 rs7158663 AA genotype were at 3.49-fold odds of having childhood ALL (95% CI=1.36-8.92, p=0.0066). The difference was even more significant after adjusting for gender (adjusted OR=3.52, 95% CI=1.42-8.75, 0.0066; Table VII).

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Table VII.

Maternally expressed gene 3 (MEG3) rs7158663 genotype in childhood acute lymphoblastic leukemia risk after stratification by age.

Table VIII shows that among boys, those with MEG3 rs7158663 AG and AA genotypes had 1.75- and 3.11-fold of odds of having childhood ALL (95% CI=1.08-2.83 and 1.27-7.59, p=0.0238 and 0.0101), respectively. Even after adjustment for age, the significance remained (adjusted OR=1.63 and 2.59, 95% CI=1.02-2.07 and 1.34-4.49, respectively) (Table VIII). Among girls, these differences were not as obvious as for the boys, no matter their genotype, nor before and after adjusting for their age (Table VIII).

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Table VIII.

Maternally expressed gene 3 (MEG3) rs7158663 genotype in childhood acute lymphoblastic leukemia risk after stratification by gender.

Discussion

lncRNAs play a critical role in leukemia development and scientists are devoted to elucidating their various biological functions involved in leukemia carcinogenesis (15). Among these, MEG3 is a tumor suppressor, and via various signaling pathways, it is highly involved in the regulation of the p53 expression and p53-dependent transcription (23). In a panel of cancer types, protein expression of lncRNA MEG3 was found to be down-regulated in gastric, liver, colorectal, breast and ovarian cancer (24). However, (childhood) leukemia is not in this list. SNPs of MEG3 have been associated with cell phenotype alteration, cancer susceptibility, and chemotherapy toxicity in patients with solid tumors (24, 25). To our knowledge, the current study is the first to investigate the association of MEG3 genotypes with childhood leukemia.

In the current study, we revealed that the frequencies of GG, AG, and AA genotypes at MEG3 rs7158663 were 57.5%, 36.1%, and 6.4% in healthy Taiwanese controls (Table II). Among the childhood ALL cases, MEG3 rs7158663 variants AG and AA were both statistically significantly more frequent (44.7% and 10.9%) than in the corresponding controls (Table II). We confirmed the findings via carrier comparisons and allelic frequency analysis, revealing that variant AA genotype and A allele contribute to elevated childhood ALL risk (Table II and Table VI). On the contrary, no positive association was found for MEG3 rs3087918, rs11160608, or rs4081134 (Table III, Table IV, Table V and Table VI). In addition, the present study is the first to reveal a significant interaction of MEG3 rs7158663 genotypes with age and gender for childhood ALL risk (Table VII and Table VIII). Our studies demonstrated that older children (≥3.5 years old) with AA genotype at MEG3 rs7158663 and boys carrying one or more A alleles tended to be more likely to have childhood ALL (Table VII and Table VIII). The detailed mechanisms of how MEG3 genotype contributes to age and gender differences in the etiology of childhood ALL need further investigation.

In literature, there are very few articles reporting the association of MEG3 genotypes with cancer risk, not to mention (childhood) leukemia. This does not mean the MEG3 genotype is irrelevant to cancer development, on the contrary, it means that genotyping investigations focusing on MEG3 genotypes and their contribution to all types of cancer are urgently needed. To provide a clearer picture of how important MEG3 genotypes are in determining and predicting cancer risk, we summarize the contribution of MEG3 genotypes to cancer risk as given in literature.

In 2016, Cao et al. explored the contributions of five MEG3 polymorphic variants, rs3087918, rs11160608, rs7158663, rs4081134 and rs10144253, to colorectal cancer risk. They found that only the AA genotype of MEG3 rs7158663 significantly increased colorectal cancer risk, especially in those aged less than 60 years and with a family history of cancer (26). In 2018, Yang et aI. examined the associations of MEG3 rs7158663 and rs4081134 with lung cancer risk with a 526-case and 526-control Han population. They found that the AA genotype of MEG3 rs4081134 may be associated with a reduced lung cancer risk, while no association between the MEG3 rs7158663 genotype and lung cancer risk was found (27). In the same year, Zhuo and colleagues explored the role of MEG3 rs7158663 and rs4081134 in childhood neuroblastoma. Theirs was a very valuable in case–control study since the research in childhood neuroblastoma are quite rare, and the sample size was relatively large, with 392 cases and 783 controls. They found AG and AA genotypes of MEG3 rs4081134 tended to develop neuroblastoma among subgroups aged >18 months and with clinical stage III/IV disease. No association of MEG3 rs7158663 with childhood neuroblastoma was found (28). In 2019, Hou and colleagues investigated the contributions of the genotypes of seven polymorphic sites on MEG3, rs4378559, rs3783355, rs11160608, rs4906024, rs4081134, rs2281511 and rs12431658, to oral cancer risk. The polymorphic sites are all intronic sites, while they omitted MEG3 rs7158663. They found a critical role of MEG3 rs11160608 in oral carcinogenesis within a Han population of 984 controls and 444 cases. They also conducted a phenotypic luciferase assay, reporting that the activity of MEG3 rs11160608 A allele was lower than that of the rs11160608 C allele (29). In 2020, Ali et al. attempted to determine the influence of MEG3 rs7158663 on the serum MEG3 level and breast cancer risk in an Egyptian population of 154 controls and 150 patients with breast cancer. They found the AA genotype at MEG3 rs7158663 not only correlated with a lower level expression of MEG3 in serum, but also with an elevated breast cancer risk (24). In 2020, Zheng and colleagues examined the contribution of MEG3 rs3087918, rs7158663 and rs11160608 to breast cancer risk with 434 cases and 700 controls. They found the GG genotype of MEG3 rs3087918 was associated with a reduced risk of breast cancer (25). In 2021, Xu et al. explored the association of MEG3 rs11627993 and rs7158663 with prostate cancer risk in a Han population of 165 cases and 200 controls. They had no positive finding (30). Recently, Shaker and colleagues investigated the impact of genotypes of MEG3 rs7158663 on the expression levels of microRNA-182 and microRNA-29, and on breast cancer risk in a moderate Egyptian population of 150 controls, 120 fibroadenoma and 180 breast cancer cases. The AG and AA genotypes contributed to a higher risk of breast cancer. Moreover, the A allele of MEG3 rs7158663 was associated with a significantly lower serum level of MEG3, which correlated with higher TMN staging and larger tumor size among the breast cancer cases (31) (Table IX).

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Table IX.

Summary of findings from literature (until 31/10/2021) on the association of single nucleotide polymorphisms of maternally expressed gene 3 (MEG3) genotype among different types of cancer.

Several limitations and potential improvements of the present study should be noted. Firstly, these findings were based on genomic analysis of a single gene with a relatively moderate sample size of childhood ALL cases which need to be validated using more independent and larger investigations. Secondly, our study was a hospital-based study, although two well-known and outstanding medical centers were involved. Therefore, potential sources of selection bias may exist. Thirdly, the current study had incomplete information on lifestyle, environmental and familial factors which may contribute to childhood ALL. Further studies are needed to reveal the correlation of lifestyle/environmental information and family history with genetic variants such as MEG3 in childhood ALL. The mRNA level of MEG3 was reported to be lower in patients with breast cancer than in healthy controls, and those with MEG3 rs7158663 AA genotype had the lowest level among the various genotypes (24). Therefore, the phenotype of MEG3 rs7158663 AA genotype should be validated among patients with childhood ALL, and the consequences of a lower serum MEG3 level should be further investigated.

In conclusion, this study provides first-hand evidence that the A allele at MEG3 rs7158663 may serve as a predictor for childhood ALL. Moreover, there was an obvious interaction of age (≥3.5 years) and gender (boys) with MEG3 rs7158663 genotype on personal susceptibility to childhood ALL. Further studies are needed to validate the clinical practicability of this novel biomarker.

Acknowledgements

The expert DNA extraction technology and statistical analysis from Yu-Chen Hsiau, Tzu-Yu Wang and Tzu-Hsuan Wang are appreciated. This study was supported by the grant from Taoyuan General Hospital, Ministry of Health and Welfare (PTH109032) and China Medical University Hospital and Asia University (CMU110-ASIA-05).

Footnotes

  • ↵* These Authors contributed equally to this study.

  • Authors’ Contributions

    Research Design: Pei JS, Chang WS, Bau DT and Tsai CW; Patient and Questionnaire Summarize: Chen CC, Pei JS and Hsu PC; Experiment Data Clearing and Checking: Mong MC and Hsu SW; Statistical Analysis: Hsu YN and Wang YC Manuscript Writing: Chang WS, Tsai CW and Bau DT; Reviewing and Revising: Bau DT.

  • Conflicts of Interest

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

  • Received November 3, 2021.
  • Revision received December 1, 2021.
  • Accepted December 3, 2021.

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Novel Contribution of Long Non-coding RNA MEG3 Genotype to Prediction of Childhood Leukemia Risk
JEN-SHENG PEI, WEN-SHIN CHANG, CHAO-CHUN CHEN, MEI-CHIN MONG, SHIH-WEI HSU, PEI-CHEN HSU, YUAN-NIAN HSU, YUN-CHI WANG, CHIA-WEN TSAI, DA-TIAN BAU
Cancer Genomics & Proteomics Jan 2022, 19 (1) 27-34; DOI: 10.21873/cgp.20301
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