DataSheet8_Association Between the TP53 Polymorphisms and Breast Cancer Risk: An Updated Meta-Analysis.DOCX

Background: The relationship of TP53 codons 72, IVS3 16 bp, and IVS6+62A > G polymorphisms with breast cancer (BC) risk has been analyzed in seventeen published meta-analyses. However, the credibility of statistically significant associations was ignored and many new studies have been reported on these themes.
Objectives: To explore whether TP53 codons 72, IVS3 16 bp, and IVS6+62A > G polymorphisms are associated with BC risk and the clinical phenomena.
Methods: To comprehensively search the data (through October 25, 2021), we provided a clear search strategy and reviewed the references of published meta-analyses. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were used.
Results: The current meta-analysis had a larger sample size than the previous ones: 99 studies with 43,951 BC and 48,479 controls for TP53 codon 72 polymorphism, 35 studies with 8,705 BC and 7,516 controls for IVS3 16 bp polymorphism, and 25 studies with 12,222 BC and 12,895 controls for IVS6+62A > G polymorphism. Five gene models were used to explore the association between the three polymorphisms and BC risk, and partial positive results were similar to published meta-analyses results. However, a large number of significant results were considered to be unreliable after correcting with Bayesian false-discovery probability (BFDP), except for the association between TP53 IVS3 16 bp polymorphism and BC risk in overall analysis (GG vs. CC: BFDP = 0.738), matched studies (GG vs. CC: BFDP = 0.173; GG vs. CC + CG: BFDP = 0.447), and tumor size below 2 cm (GG vs. CC: BFDP = 0.088; GG + CG vs. CC: BFDP = 0.730; GG vs. CC + CG: BFDP = 0.311). These unreliable results were confirmed again without new solid results emerging in further sensitivity analysis (only studies in compliance with the quality assessment standard).
Conclusion: After considering the quality of the included studies and the reliability of the results, the present meta-analysis suggested that TP53 codons 72, IVS3 16 bp, and IVS6+62A > G polymorphisms were not significantly associated with the BC risk. Those results which prove that these three polymorphisms increase BC risk are more likely to be false-positive results due to various confounding factors.

背景：已有17项已发表的荟萃分析探讨了TP53密码子72、IVS3 16bp以及IVS6+62A>G多态性与乳腺癌（breast cancer, BC）风险的关联。然而，既往研究未关注统计学显著关联的可信度，且当前已有大量相关新研究发表。
目的：探讨TP53密码子72、IVS3 16bp及IVS6+62A>G多态性与乳腺癌风险及临床表型的关联。
方法：为全面检索截至2021年10月25日的相关数据，本研究制定了明确的检索策略，并对已发表荟萃分析的参考文献进行了回溯审查。本研究遵循系统评价与荟萃分析首选报告条目（Preferred Reporting Items for Systematic Reviews and Meta-Analyses, PRISMA）规范开展研究。
结果：本荟萃分析的样本量大于既往同类研究：针对TP53密码子72多态性，共纳入99项研究，包含43951例乳腺癌患者与48479例对照；针对IVS3 16bp多态性，纳入35项研究，包含8705例乳腺癌患者与7516例对照；针对IVS6+62A>G多态性，纳入25项研究，包含12222例乳腺癌患者与12895例对照。本研究采用5种基因模型探讨上述3种多态性与乳腺癌风险的关联，部分阳性结果与已发表荟萃分析的结果一致。然而，经贝叶斯错误发现概率（Bayesian false-discovery probability, BFDP）校正后，绝大多数显著关联结果被认为不可靠，仅TP53 IVS3 16bp多态性与乳腺癌风险的关联在全人群分析（GG vs. CC：BFDP=0.738）、匹配研究（GG vs. CC：BFDP=0.173；GG vs. CC+CG：BFDP=0.447）以及肿瘤大小低于2cm亚组（GG vs. CC：BFDP=0.088；GG+CG vs. CC：BFDP=0.730；GG vs. CC+CG：BFDP=0.311）中仍具有统计学意义。进一步的敏感性分析（仅纳入符合质量评价标准的研究）未发现新的可靠结果，再次证实了上述不可靠的关联结论。
结论：综合纳入研究的质量与结果可靠性后，本荟萃分析显示，TP53密码子72、IVS3 16bp及IVS6+62A>G多态性与乳腺癌风险无显著关联。既往认为这3种多态性会增加乳腺癌风险的研究结果，更可能是因各类混杂因素导致的假阳性结果。