Supplementary Material for: Association Between Hypoxia-Inducible Factor-2α (HIF-2α) Expression and Colorectal Cancer and Its Prognostic Role: a Systematic Analysis

<b><i>Background/Aims:</i></b> Although some studies showed that HIF-2α expression was correlated with an unfavorable prognosis in colorectal cancer (CRC), the prognostic results remain conflicting in CRC. The present study was performed to evaluate the association between HIF-2α expression and the clinicopathological features of this disease and to examine the potential prognostic role of HIF-2α expression in CRC. <b><i>Methods:</i></b> Pooled odds ratios (ORs) or hazard ratios (HRs) were calculated from available publications, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets. Trial sequential analysis (TSA) was used to estimate the required sample information. <b><i>Results:</i></b> HIF-2α protein expression was more frequent in CRC than in normal colonic tissues (OR = 150.49, <i>P</i> &lt; 0.001), higher in male than female CRC patients (OR = 1.47, <i>P</i> = 0.008), and lower in high-grade than low-grade CRC (OR = 0.49, <i>P</i> = 0.029). TSA verified the reliability of the above results. HIF-2α expression was not linked to the prognosis of CRC in overall survival (OS), disease-specific survival (DSS), metastasis-free survival, and relapse-free survival, and no significant correlation was found between HIF-2α alteration and OS or disease-free survival (DFS) of CRC. Expression of both HIF-2α and vascular endothelial growth factor (VEGFA, VEGFB, or VEGFC) was associated with a poor metastasis-free survival of CRC (HR = 6.95, HR = 113.51, and HR = 8.11, respectively). No association was observed between HIF-2α expression and DFS in other cancers, but HIF-2α expression was correlated with a worse DFS of CRC (HR = 1.23, <i>P</i> = 0.037). Moreover, HIF-2α expression was linked to a good survival benefit in some cancers (B-cell lymphoma and lung adenocarcinoma: OS, multiple myeloma: DSS, breast cancer: distant metastasis-free survival, liposarcoma: distant recurrence-free survival) (all HRs &lt; 1, <i>Ps</i> &lt; 0.05). <b><i>Conclusions:</i></b> HIF-2α expression may be associated with the carcinogenesis of CRC, which is higher in males than in females, negatively linked to tumor differentiation, and correlated with a worse DFS of CRC. Additional prospective studies are needed.

背景与目的：尽管已有研究表明缺氧诱导因子-2α（HIF-2α）在结直肠癌（CRC）中的表达与不良预后相关，但目前关于结直肠癌的相关预后研究结论仍存在分歧。本研究旨在探讨HIF-2α表达与结直肠癌临床病理特征的关联，并分析其在结直肠癌中的潜在预后价值。方法：本研究从已发表文献、癌症基因组图谱（The Cancer Genome Atlas, TCGA）及基因表达综合数据库（Gene Expression Omnibus, GEO）的数据集中提取数据，计算合并比值比（odds ratios, OR）或风险比（hazard ratios, HR）。采用试验序贯分析（trial sequential analysis, TSA）评估所需的样本信息量。结果：结直肠癌组织中的HIF-2α蛋白表达率显著高于正常结肠组织（OR=150.49，P<0.001）；男性结直肠癌患者的HIF-2α表达率高于女性患者（OR=1.47，P=0.008）；高级别结直肠癌的HIF-2α表达率低于低级别结直肠癌（OR=0.49，P=0.029）。试验序贯分析验证了上述结果的可靠性。在总生存期（overall survival, OS）、疾病特异性生存期（disease-specific survival, DSS）、无转移生存期及无复发生存期方面，HIF-2α表达与结直肠癌患者的预后无显著关联；HIF-2α基因变异与结直肠癌的总生存期或无病生存期（disease-free survival, DFS）亦无显著相关性。HIF-2α与血管内皮生长因子（vascular endothelial growth factor, VEGFA、VEGFB或VEGFC）共表达时，与结直肠癌患者较差的无转移生存期相关（分别对应HR=6.95、HR=113.51及HR=8.11）。在其他癌种中，未观察到HIF-2α表达与无病生存期的关联，但在结直肠癌中，HIF-2α高表达与较差的无病生存期相关（HR=1.23，P=0.037）。此外，在部分癌种中，HIF-2α高表达与更优的生存获益相关：B细胞淋巴瘤、肺腺癌的总生存期，多发性骨髓瘤的疾病特异性生存期，乳腺癌的无远处转移生存期，脂肪肉瘤的无远处复发生存期（所有HR<1，P均<0.05）。结论：HIF-2α表达可能与结直肠癌的发生发展相关，其在男性患者中的表达水平高于女性，与肿瘤分化程度呈负相关，且与结直肠癌患者较差的无病生存期相关。该研究结论尚需更多前瞻性研究进一步验证。