Polymorphisms in METTL3 gene and hepatoblastoma risk in Chinese children: A seven-center case-control study

Chen, Huitong; Duan, Fei; Wang, Mi; Zhu, Jinhong; Zhang, Jiao; Cheng, Jiwen; Li, Li; Li, Suhong; Li, Yong; Yang, Zhonghua; Xia, Huimin; Niu, Huizhong; He, Jing

doi:10.1016/j.gene.2021.145834

Cited by 8 publications

(16 citation statements)

References 47 publications

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“…After have being engaged in genetic association studies in pediatric cancers for over a decade, our team has found a number of hepatoblastoma susceptibility genes with 313 cases and 1446 controls, including LINC00673 [29], NRAS [30], KRAS [30], TP53 [31], HMGA2 [32], miR-34b/c [31], as well as DNA repair genes [6,7]. Moreover, we also identified genetic variants in RNA m6A-mediated genes (i.e., METTL3 [33], METTL14 [34], WTAP [9], YTHDF1 [11], YTHDC1 [10], and ALKBH5 [35]) associated with hepatoblastoma susceptibility. Over the past years, research gradually realized that, like RNA m6A modification, the abundant RNA m7G modifications also have fundamental importance to cellular homeostasis.…”

Section: Discussionmentioning

confidence: 92%

WDR4 gene polymorphisms increase hepatoblastoma susceptibility in girls

He¹,

Zhu²,

Xiao³

et al. 2022

J. Cancer

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Hepatoblastoma, originating from hepatoblasts, is the most common hepatic malignancy. WD repeat domain 4 (WDR4) is a subunit of RNA N(7)-methylguanine (m7G) methyltransferase complex. Recently, WDR4 has shown oncogenic potential in various adult cancers, but its roles in pediatric cancers have not been reported. We performed a case-control study (313 cases vs. 1446 controls) to investigate whether genetic variants in the WDR4 gene influence hepatoblastoma susceptibility in the Chinese Han nationality. We first determine the genotypes of five WDR4 gene polymorphisms (rs2156315 C>T, rs2156316 C>G, rs6586250 C>T, rs15736 G>A, rs2248490 C>G) in participants, using the Taqman assay. And then, an unconditional logistic regression analysis was performed to assess the association between WDR4 gene polymorphisms and hepatoblastoma risk. Overall, we did not find any polymorphism significantly associated with the risk of developing hepatoblastoma. Instead, the stratified analysis revealed that the co-existence of 2-5 risk genotypes increased hepatoblastoma risk by 2.23 folds in girls (adjusted odds ratio=2.23, 95% confidence interval=1.17-4.23, P=0.014). In conclusion, our results demonstrate that single selected polymorphisms were too weak to exert a significant effect on the whole study population. However, in combination, two or more WDR4 gene polymorphisms significantly conferred increased hepatoblastoma risk in girls. Our findings may encourage more genetic association studies to discover significant polymorphisms in the WDR4 gene for hepatoblastoma.

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Section: Discussionmentioning

confidence: 92%

WDR4 gene polymorphisms increase hepatoblastoma susceptibility in girls

He¹,

Zhu²,

Xiao³

et al. 2022

J. Cancer

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“…We have previously shown that several RNA m6A-mediated genes (i.e., METTL3, METTL14, WTAP, YTHD1, YTHDC1, and ALKBH5) are associated with hepatoblastoma susceptibility [11,12,22,[31][32][33]. YTHDF1 gene rs6090311 was associated with decreased hepatoblastoma risk [11], whereas rs7766006 in the WTAP gene was associated with an increased risk of hepatoblastoma [22].…”

Section: Discussionmentioning

confidence: 99%

“…Currently, there are no genome-wide association studies (GWASs) examining hepatoblastoma. Several groups, including ours, have demonstrated that some genetic variants in the LINC00673 , NRAS , KRAS , TP53 , HMGA2 , miR-34b/c , YTHDF1 , and WTAP genes were associated with hepatoblastoma susceptibility [ 7 – 12 ]. However, given the limited number of susceptibility genes and small sample size, many more functional genetic variants in essential genes should be investigated in large cohorts.…”

Section: Introductionmentioning

confidence: 99%

METTL1 gene polymorphisms synergistically confer hepatoblastoma susceptibility

Zhu

Liu

et al. 2022

Discov Onc

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Introduction Hepatoblastoma is a rare but devastating pediatric liver malignancy. Overexpressed methyltransferase-like 1 (METTL1) is a methyltransferase that catalyzes essential N7-methylguanosine (m7G) modification of eukaryotic mRNA. Accumulating evidence has revealed the oncogenic potential of METTL1. However, whether METTL1 gene polymorphisms confer susceptibility to hepatoblastoma has not been reported. This study aimed to identify causal relationships between genetic variants of this gene and susceptibility to hepatoblastoma. Materials and methods Using the TaqMan assay, we genotyped three METTL1 polymorphisms (rs2291617 G > T, rs10877013 T > C, rs10877012 T > G) in germline DNA samples from 1759 Chinese children of Han ethnicity (313 cases vs. 1446 controls). Results None of these polymorphisms were associated with hepatoblastoma risk. However, combination analysis showed that children with 1 to 3 risk genotypes were associated with increased hepatoblastoma risk (adjusted odds ratio = 1.47, 95% confidence interval 1.07–2.02; P = 0.018). Stratified analyses revealed significant effects of combined polymorphisms mainly among young children (< 17 months of age), boys, and those with advanced hepatoblastoma. Conclusion We identified some potential functional METTL1 gene polymorphisms that work together to increase the risk of hepatoblastoma among Chinese Han children; single polymorphism showed only weak effects. These METTL1 polymorphisms may be promising biomarkers for screening high-risk individuals for hepatoblastoma. These findings are inspiring and deserve to be validated among individuals of different ethnicities. Graphical Abstract

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“…METTL3 plays a dual role as either an oncogene or a tumor suppressor gene in various types of cancers, including hepatocellular carcinoma (HCC) [ 60 , 61 ], hepatoblastoma [ 62 ], gastric cancer (GC) [ 63 ], colorectal cancer (CRC) [ 64 ], non-small cell lung cancer (NSCLC) [ 65 , 66 ], and bladder cancer (BLC) [ 67 , 68 ]. Abnormal expression of METTL3 in tumor cells affects the infiltration of immune cells.…”

Section: Role Of M 6 a Modification In Remodeling ...mentioning

confidence: 99%

Targeting the RNA m6A modification for cancer immunotherapy

et al. 2022

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N6-methyladenosine (m6A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription and translation programs that promote cancer occurrence and progression. Although defective gene regulation resulting from m6A often affects oncogenic and tumor-suppressing networks, m6A can also modulate tumor immunogenicity and immune cells involved in anti-tumor responses. Understanding this counterintuitive concept can aid the design of new drugs that target m6A to potentially improve the outcomes of cancer immunotherapies. Here, we provide an up-to-date and comprehensive overview of how m6A modifications intrinsically affect immune cells and how alterations in tumor cell m6A modifications extrinsically affect immune cell responses in the tumor microenvironment (TME). We also review strategies for modulating endogenous anti-tumor immunity and discuss the challenge of reshaping the TME. Strategies include: combining specific and efficient inhibitors against m6A regulators with immune checkpoint blockers; generating an effective programmable m6A gene-editing system that enables efficient manipulation of individual m6A sites; establishing an effective m6A modification system to enhance anti-tumor immune responses in T cells or natural killer cells; and using nanoparticles that specifically target tumor-associated macrophages (TAMs) to deliver messenger RNA or small interfering RNA of m6A-related molecules that repolarize TAMs, enabling them to remodel the TME. The goal of this review is to help the field understand how m6A modifications intrinsically and extrinsically shape immune responses in the TME so that better cancer immunotherapy can be designed and developed.

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Polymorphisms in METTL3 gene and hepatoblastoma risk in Chinese children: A seven-center case-control study

Cited by 8 publications

References 47 publications

WDR4 gene polymorphisms increase hepatoblastoma susceptibility in girls

WDR4 gene polymorphisms increase hepatoblastoma susceptibility in girls

METTL1 gene polymorphisms synergistically confer hepatoblastoma susceptibility

Targeting the RNA m6A modification for cancer immunotherapy

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