Supplementary Material for: Prognostic effects of RASSF1A, BRCA1, APC, and p16 promoter methylation in ovarian cancer: a meta-analysis

Introduction: DNA methylation plays an important role in the carcinogenesis, progression, and prognosis of various human cancers. RASSF1A, BRCA1, APC, and p16 are the frequently methylated genes among patients with ovarian cancer. Therefore, our study aimed to better determine the prognostic and cancer characteristics effects of RASSF1A, BRCA1, APC, and p16 promoter methylation in ovarian cancer patients.
Methods: Databases such as PubMed, Web of Science, EMBASE, CNKI, and WanFang were searched for published studies up to March 4, 2024. The outcomes are shown as OR and HR with their 95% CIs. Then, the random or fixed effect model was performed to evaluate the effect sizes.
Results: Finally, 27 articles were included in this meta-analysis. No significant relationships were observed between RASSF1A, BRCA1, and APC promoter methylation and the clinical prognostic (including overall survival and progression-free survival) and cancer characteristics (including ascites, lymph node metastasis, and pelvic peritoneal metastasis) in ovarian cancer. p16 promoter methylation was significantly related to poor PFS (HR=1.52, 95% CI=1.14 to 2.04) and OS (HR=1.39, 95% CI=1.06, to 1.83) in univariate, and poor PFS in multivariate Cox regression models (HR =1.42, 95% CI=1.05 to1.92). Besides, our results indicated that the clinical stage was associated with inferior OS while there was no significant association between tumor grade and OS.
Conclusion: RASSF1A, BRCA1, and APC promoter methylation were not significantly associated with clinical prognostic and cancer characteristics. P16 may be a useful biomarker for predicting PFS in ovarian cancer. Furthermore, the clinical stage was significantly associated with OS. In further research, more prospective and multicenter validation studies remain needed.

引言：DNA甲基化在多种人类癌症的发生、进展及预后中发挥重要作用。RASSF1A、BRCA1、APC及p16是卵巢癌患者中常见的甲基化基因。因此，本研究旨在明确RASSF1A、BRCA1、APC及p16启动子甲基化对卵巢癌患者的预后及肿瘤特征的影响。方法：检索截至2024年3月4日发表于PubMed、Web of Science、EMBASE、中国知网（CNKI）及万方（WanFang）的相关研究。研究结局以比值比（OR）、风险比（HR）及其95%置信区间（95% CI）表示，并采用随机或固定效应模型评估效应量。结果：最终本荟萃分析共纳入27篇文献。RASSF1A、BRCA1及APC启动子甲基化与卵巢癌患者的临床预后指标（包括总生存期（Overall Survival, OS）及无进展生存期（Progression-Free Survival, PFS））及肿瘤特征（包括腹水、淋巴结转移及盆腔腹膜转移）均无显著相关性。p16启动子甲基化在单因素分析中与较差的PFS（HR=1.52，95% CI=1.14~2.04）及OS（HR=1.39，95% CI=1.06~1.83）显著相关，且在多因素Cox回归分析中仍与较差的PFS相关（HR=1.42，95% CI=1.05~1.92）。此外，本研究结果显示临床分期与较差的OS显著相关，而肿瘤分级与OS无明显关联。结论：RASSF1A、BRCA1及APC启动子甲基化与卵巢癌患者的临床预后及肿瘤特征无显著相关性。p16启动子甲基化或可作为预测卵巢癌患者PFS的有效生物标志物。此外，临床分期与OS显著相关。未来仍需开展更多前瞻性、多中心的验证研究以进一步验证本研究结论。