Research paperThe contribution of WTAP gene variants to Wilms tumor susceptibility
Introduction
Wilms tumor (nephroblastoma) is the most common embryonal kidney cancer in the pediatric population (Aldrink et al., 2019). It usually derives from abnormal fetal nephrogenesis (Phelps et al., 2018). The prevalence of Wilms tumor is about 7 new cases in a million children in the United States, while 3.3 in a million in China (Breslow et al., 1993, Bao et al., 2013). Nearly 80% of cases are less than 5 years old at diagnosis, with a peak incidence at 2–3 years of age (Hohenstein et al., 2015). Due to large-scale cooperative trials conducted over the last decades, survival rates of Wilms tumor have increased to over 90% in Western countries (Dome et al., 2015). However, patients with unfavorable histology, relapsed disease, or bilateral Wilms tumor still have suboptimal outcomes (Sonn and Shortliffe, 2008, Saltzman et al., 2020, Spiegl et al., 2020). More disappointingly, intensified therapeutic regimens often bring about late severe side-effects.
The etiology of Wilms tumor tumorigenesis is complex with numerous gene mutations identified over the past decades. The first identified Wilms tumor suppressor gene, the Wilms tumor 1 (WT1) gene, was cloned in 1990 (Haber et al., 1990). Subsequently, mutations in CTNNB1, AMER1, and TP53 genes, as well as an abnormality of 11p15 methylation, have been identified as oncogenic drivers of Wilms tumor (Pelletier et al., 1991, Ruteshouser et al., 2008, Turnbull et al., 2012, Treger et al., 2019). Apart from these, genetic association analyses in case-control studies have also mapped further Wilms tumor risk loci (Ferrara et al., 2009, Zhu et al., 2018a, Zhu et al., 2018b, Fu et al., 2019, Zhuo et al., 2019). However, all of the identified genetic alterations account for less than 50% of Wilms tumor by far. Thus, it is indispensable to identify more variants in better unraveling the genetic susceptibility to Wilms tumor. Moreover, detailed genetic information often leads to new druggable targets, a starting point for developing more effective treatments.
N6-methyladenosine (m6A) modification is ranked as the most frequently distributed methylations in eukaryotic mRNA, amounting to over 80% of all RNA base methylations (Balacco and Soller, 2019). m6A modifications are seen in approximately 0.1–0.4% of adenosines in total RNA (Wei et al., 1975). The entire process of m6A is dynamically orchestrated by methyltransferases (“writers”), demethylases (“erasers”), and m6A associated RNA binding proteins (“readers”) (Lan et al., 2019). “Writers” install a methyl group to adenine nucleotides in acceptor RNA substrates, whereas “erasers” reversibly demethylate m6A. And “readers” specifically recognize the m6A in mRNAs eventually (Chen et al., 2019b). The core m6A “writers” are composed of methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), and Wilms tumor 1-associated protein (WTAP). METTL3 acts as an S-adenosylmethionine (SAM)-binding subunit with methyltransferases activity, while METTL14 is critical for substrate RNA binding without methyltransferases activity [10]. WTAP itself cannot catalyze m6A modification due to its lack of a conserved catalytic methylation domain. However, it coordinates the localization of the METTL3-METTL14 heterodimer into nuclear speckles, thereby facilitating m6A deposition (Ping et al., 2014). m6A modification is involved in a diverse set of biological processes, such as mRNA transcription, splicing, translation, nuclear export, localization, and stability (Lan et al., 2019). Growing evidence has pointed to the involvement of METTL3, METTL14, ALKBH5, FTO, and YTHDF2 in the carcinogenesis and progression of cancers (Cai et al., 2019, Chen et al., 2019a, Cheng et al., 2019, Dahal et al., 2019, Hou et al., 2019, Li et al., 2019a, Chao et al., 2020, Cui et al., 2020).
The contribution of the WTAP gene to oncogenesis has been partly clarified whereas genetic variants in the WTAP gene and their roles in the risk of cancer are hardly known (Jo et al., 2013, Chen et al., 2019c). To gain a more comprehensive insight into Wilms tumor etiology, we conducted a multi-center epidemiological study in Wilms tumor among children of Chinese ancestry.
Section snippets
Sample selection
We included a total of 414 diagnosed with Wilms tumor and 1199 hospital-based controls (Supplemental Table 1), recruited from five hospitals (Guangzhou Women and Children’s Medical Center, The First Affiliated Hospital of Zhengzhou University, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, and Second Affiliated Hospital of Xi’an Jiao Tong University, Shanxi Provincial Children’s Hospital) in five different cities of China (Li et al., 2019b, Hua et
Association between the WTAP gene SNPs and Wilms tumor risk
Among the selected subjects, nine cases and two controls failed to be genotyped. Association analysis results of WTAP gene SNPs and Wilms tumor risk are shown in Table 1. P value of the χ2 test for HWE was 0.326, 0.166, and 0.730 for the rs9457712 G > A, rs1853259 A > G, and rs7766006 G > T in controls, respectively. These results indicated no deviation from HWE. In the single locus analysis, we found that carriers of the WTAP gene rs1853259 AG genotype showed significantly decreased
Discussion
Previous studies have shown significant contributions of m6A-related genes SNPs to cancer susceptibility. With this in mind, we investigated the effects of SNPs in these genes on the risk of Wilms tumor. This is the first study that identifies a weak case-control significant association between WTAP genetic variants and Wilms tumor risk.
WTAP partners with the WT1 (Little et al., 2000). WTAP is a conserved nuclear protein co-localized with splicing factors. Unlike the tissue-specific expression
Conclusion
In summary, our study illustrates the impact of the WTAP gene SNPs on Wilms tumor risk. Expanded studies, comprehensively evaluate the underlying role of the WTAP gene SNPs in Wilms tumor risk are ongoing.
CRediT authorship contribution statement
Li Ma: Investigation, Writing - original draft. Rui-Xi Hua: Investigation, Writing - original draft. Huiran Lin: Investigation, Writing - original draft. Jinhong Zhu: Investigation, Writing - review & editing. Wen Fu: Funding acquisition, Investigation, Resources. Ao Lin: Investigation, Methodology. Jiao Zhang: Investigation, Resources. Jiwen Cheng: Investigation, Resources. Haixia Zhou: Investigation, Resources. Suhong Li: Investigation, Resources. Zhenjian Zhuo: Conceptualization, Data
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This study was funded by grants from the Natural Science Foundation of Guangdong Province (No: 2019A1515010360), National Natural Science Foundation of China (No: 81803320), Science and Technology Project of Guangzhou (No: 201804010037), and Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease (No: 2019B030301004).
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These authors contributed equally to this work.