Table_1_IGFLR1 as a Novel Prognostic Biomarker in Clear Cell Renal Cell Cancer Correlating With Immune Infiltrates.DOCX

ObjectiveInsulin Growth Factor-Like receptor 1 (IGFLR1) reflects progressive disease and confers a poor prognosis in clear cell renal cell cancer (ccRCC). However, extensive studies highlighting the mechanisms involved in how IGFLR1 triggers the progression of ccRCC remain lacking.
MethodsIn the present study, the expression level of IGFLR1 mRNA and correlation between IGFLR1 expression and prognosis of ccRCC were analyzed based on The Cancer Genome Atlas (TCGA) ccRCC cohort. Further, we analyzed methylation and copy number variation to try to explain the difference in IGFLR1 expression. Subsequently, we investigated the correlation between IGFLR1 and tumor-infiltrating immune cells with the aid of TIMER (Tumor Immune Estimation Resource). The potential candidates’ genes associated with IGFLR1 were screened by variation analysis, which were used for further enrichment analysis of signaling pathways and immune gene sets to infer the certain function and corresponding mechanisms in which IGFLR1 was involved in ccRCC. Finally, we establish prognostic risk models using multivariate Cox regression analysis and analyzed the possible involvement of IGFLR1 in chemotherapeutic drug resistance.
ResultsThe results showed that upregulated IGFLR1 was detected in ccRCC compared with para-cancer tissues and significantly affected the prognosis of ccRCC (overall survival: Logrank p < 0.0001; disease free survival: Logrank p = 0.022). Univariate and multivariate analyses indicated that IGFLR1 was an independent prognostic factor for ccRCC (HR = 2.064, p = 0.006) and the risk prognostic model based on age, M, level of platelet and calcium and IGFLR1 expression had satisfying predictive ability. The correlation analysis showed that the expression level of IGFLR1 was positively correlated with the abundance of myeloid derived suppressor cell and their marker genes in ccRCC significantly. IGFLR1 may be related to the regulatory activation, intercellular adhesion of lymphocytes and drug resistance in cancer.
ConclusionThese findings suggested that IGFLR1 was significantly associated with the prognosis in a variety of cancers, particularly ccRCC. IGFLR1 may play an important role in tumor related immune infiltration and showed potential diagnostic, therapeutic and prognostic value in ccRCC.

研究背景：胰岛素样生长因子样受体1（Insulin Growth Factor-Like receptor 1, IGFLR1）在透明细胞肾细胞癌（clear cell renal cell cancer, ccRCC）中可反映疾病进展状态，并提示患者预后不良。然而，目前针对IGFLR1如何驱动ccRCC进展的具体分子机制的深入研究仍较为匮乏。
研究方法：本研究基于癌症基因组图谱（The Cancer Genome Atlas, TCGA）ccRCC队列，分析了IGFLR1 mRNA的表达水平及其与ccRCC患者预后的相关性。进一步通过甲基化与拷贝数变异分析，尝试阐释IGFLR1表达差异的潜在机制。随后，借助肿瘤免疫评估资源（Tumor Immune Estimation Resource, TIMER）探究IGFLR1表达与肿瘤浸润免疫细胞的相关性。通过变异分析筛选与IGFLR1相关的潜在候选基因，随后对这些基因进行信号通路与免疫基因集富集分析，以推断IGFLR1在ccRCC中参与的生物学功能及潜在作用机制。最后，采用多因素Cox回归分析构建预后风险模型，并探讨IGFLR1可能参与的化疗药物耐药机制。
研究结果：结果显示，相较于癌旁组织，ccRCC组织中IGFLR1的表达显著上调，且该表达水平显著影响ccRCC患者的预后（总生存期：Log-rank检验p < 0.0001；无病生存期：Log-rank检验p = 0.022）。单因素及多因素分析结果表明，IGFLR1是ccRCC的独立预后危险因素（风险比HR=2.064，p=0.006）；基于年龄、远处转移分期（M分期）、血小板计数与血钙水平联合IGFLR1表达构建的预后风险模型具有良好的预测效能。相关性分析显示，ccRCC组织中IGFLR1的表达水平与髓系来源抑制性细胞及其标记基因的浸润丰度呈显著正相关。IGFLR1可能与淋巴细胞的调控活化、细胞间黏附及肿瘤耐药性密切相关。
研究结论：本研究结果表明，IGFLR1与多种癌症的预后显著相关，尤其在ccRCC中表现突出。IGFLR1可能在肿瘤相关免疫浸润过程中发挥重要调控作用，并在ccRCC中展现出潜在的诊断、治疗及预后评估价值。