PO.CL01.20 · 临床研究
IGF 系统基因作为波多黎各结直肠癌的生物标志物
IGF system genes as colorectal cancer biomarkers in Puerto Rico
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：结直肠癌（CRC）对西班牙裔/拉丁裔（H/L）人群的影响尤为严重；然而分子生物标志物在该人群中仍然研究不足。虽然单个 IGF 轴已被作为 CRC 生物标志物进行探索，但对整个 IGF 系统（包括 IGF、受体和结合蛋白）进行全面的转录组学评估以用于分期特异性检测仍然有限，尤其是对生活在波多黎各的 H/L 人群而言。本研究旨在表征 CRC 中 IGF 系统的转录组失调，并评估单个基因和多基因特征作为诊断性生物标志物，以区分肿瘤组织与正常组织，以及区分早期与晚期疾病。
方法：使用 QIAGEN RNeasy 试剂盒从波多黎各家族性结直肠癌登记处（PURIFICAR）的 28 例组织样本（15 例 CRC 病例，13 例对照）中提取 RNA。在 Illumina NextSeq 550 上进行 RNA 测序。使用 DESeq2 分析差异基因表达（校正后 p<0.05，log2FC>1）。使用 Reactome 数据库分析通路富集。逻辑回归模型（粗模型及年龄和 BMI 校正模型）估算了基因关联的比值比，包括总体及按 CRC 分期。ROC 分析确定诊断性能：AUC、灵敏度和特异性。使用不相关的差异表达 IGF 基因（IGF1、IGF2、IGFL2、IGFL4）开发了一个 IGF 系统多基因特征评分。显著性设定为 p<0.05。
结果：我们的结果显示 IGF 系统在各 CRC 分期中均存在失调，其中 IGF2 和 IGF1R 持续上调，并呈现分期特异性的 IGFBP 表达模式。该多基因特征显示出良好的 CRC 区分能力（AUC：0.831，p=0.002），在晚期疾病中表现更优（AUC：0.894，p=0.002）。在单个基因中，IGFBP5 显示出最高的粗准确性（AUC：0.856，p=0.020），在按年龄和 BMI 校正后有所改善（AUC：0.964，灵敏度/特异性 92.3%，p<0.001）。IGFL4 在晚期模型中显示出极佳的区分能力（校正后 AUC：1.00，OR：6.03，p<0.001）。IGFBP5 和 IGFL2 对早期检测尤为强大（校正后 AUC>0.94）。富集的通路包括晚期疾病中的 IGF1R-SHC 信号传导和血小板活化。
结论：这项转录组学分析确定 IGFBP5 和一个多基因 IGF 特征作为波多黎各 H/L 人群 CRC 的潜在分期特异性生物标志物候选。有必要在更大的队列中进一步验证，以确定 IGF 系统基因是否能够改善 CRC 检测。
查看英文原文 English abstract
Introduction: Colorectal cancer (CRC) disproportionately affects Hispanic/Latino (H/L) populations; however molecular biomarkers remain understudied in this population. While individual IGF-axis have been explored as CRC biomarkers, comprehensive transcriptomic evaluation of the complete IGF system, including IGFs, receptors, and binding proteins, for stage-specific detection remains limited, particularly for H/L living in Puerto Rico. This study aimed to characterize transcriptomic dysregulation of the IGF system in CRC and evaluate individual genes and multi-gene signatures as diagnostic biomarkers to discriminate tumor from normal tissue and differentiate early-stage from advanced-stage disease.
Methods: RNA was extracted from 28 tissue samples (15 CRC cases, 13 controls) from the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR) using QIAGEN RNeasy Kit. RNA sequencing was performed on Illumina NextSeq 550. Differential gene expressions were analyzed using DESeq2 (adjusted p<0.05, log2FC>1). Pathway enrichment was analyzed using the Reactome database. Logistic regression models (crude and age and BMI-adjusted) estimated odds ratios for gene associations, overall and by CRC stage. ROC analysis determined diagnostic performance: AUC, sensitivity, and specificity. An IGF system multi-gene signature score was developed using the uncorrelated differentially expressed IGF genes (IGF1, IGF2, IGFL2, IGFL4). Significance was set at p<0.05.
Results: Our results show dysregulation of the IGF system across CRC stages, with IGF2 and IGF1R consistently upregulated and stage-specific IGFBP expression patterns. The multi-gene signature demonstrated good CRC discrimination (AUC: 0.831, p=0.002), with superior performance in advanced disease (AUC: 0.894, p=0.002). Among individual genes, IGFBP5 showed highest crude accuracy (AUC: 0.856, p=0.020), which improved when adjusted for age and BMI (AUC: 0.964, 92.3% sensitivity/specificity, p<0.001). IGFL4 showed excellent discrimination in advanced-stage models (adjusted AUC: 1.00, OR: 6.03, p<0.001). Early-stage detection was particularly strong for IGFBP5 and IGFL2 (adjusted AUC>0.94). Enriched pathways included IGF1R-SHC signaling and platelet activation in advanced disease.
Conclusion: This transcriptomic analysis identifies IGFBP5 and a multi-gene IGF signature as potential stage-specific biomarker candidates for CRC in H/L in Puerto Rico. Further validation in larger cohorts is warranted to determine whether IGF system genes can improve CRC detection.
利益披露 Disclosure
H. Centeno-Girona, None..
C. Zenon-Melendez, None..
S. N. Lopez Acevedo, None..
I. Montes-Rodriguez, None..
E. V. Caraballo-Rivera, None.