Hoefnagel Sanne J M, Li Shulin, Timmer Eva M, Meijer Sybren L, Krishnadath Kausilia K
Center for Experimental and Molecular Medicine, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Department of Gastroenterology and Hepatology, Amsterdam UMC, Location Academic Medical Center, Amsterdam, the Netherlands.
Gastro Hep Adv. 2022 Aug 24;2(1):63-71. doi: 10.1016/j.gastha.2022.08.005. eCollection 2023.
Barrett's esophagus (BE) is the precursor lesion for esophageal adenocarcinoma (EAC). To detect EAC in early stage, patients with BE undergo endoscopic surveillance. Surveillance cohorts largely consist of nondysplastic BE (NDBE) patients with a low annual progression risk (<0.5%). Predictive biomarkers for malignant progression of NDBE could improve efficacy of surveillance. Biomarker research has mostly focused on aberrant protein expression on BE epithelial cells. Moreover, insight in cell signaling driving malignant transformation is unknown. This study uses a data-driven approach to analyze tumor-stroma interaction in NDBE which progressed to high-grade dysplasia or EAC.
In this case-control study, we performed RNA sequencing analysis on index NDBE biopsies from 6 patients who, during long-term follow-up, progressed and 7 who did not progress to high-grade dysplasia/EAC. For control samples, squamous and duodenum tissues from BE patients were analyzed. For validation, we used quantitative PCR.
Significant differences in BE transcriptomic profiles between progressors and nonprogressors were found by principal component and differential expression analyses. Ingenuity pathway analysis indicated that 8 cell signaling pathways were significantly upregulated in the progressors, and 14 pathways were significantly downregulated. The most interesting finding was the upregulation of the xenobiotic metabolism pregnane X receptor signaling pathway in the progressor cohort, while of the downregulated pathways in progressors, several were related to the immune system.
These novel transcriptomic insights are fundamental for developing (chemo-)preventive therapies. These could be therapies, which protect against toxins, including biles, responsible for pregnane X receptor activation or which enhance protective immune mechanisms. The identified RNA markers are promising biomarkers for improving risk stratification in surveillance programs.
巴雷特食管（BE）是食管腺癌（EAC）的前驱病变。为了早期检测EAC，BE患者需接受内镜监测。监测队列主要由年度进展风险较低（<0.5%）的非异型增生性BE（NDBE）患者组成。NDBE恶性进展的预测生物标志物可提高监测的有效性。生物标志物研究大多集中在BE上皮细胞的异常蛋白表达上。此外，驱动恶性转化的细胞信号传导机制尚不清楚。本研究采用数据驱动的方法分析进展为高级别异型增生或EAC的NDBE中的肿瘤-基质相互作用。
在这项病例对照研究中，我们对6例在长期随访中进展为高级别异型增生/EAC的患者和7例未进展的患者的索引NDBE活检样本进行了RNA测序分析。对于对照样本，分析了BE患者的鳞状组织和十二指肠组织。为进行验证，我们使用了定量PCR。
通过主成分分析和差异表达分析，发现进展者和未进展者的BE转录组谱存在显著差异。通路分析表明，8条细胞信号通路在进展者中显著上调，14条通路显著下调。最有趣的发现是进展者队列中异源物质代谢孕烷X受体信号通路的上调，而进展者中下调的通路中有几条与免疫系统有关。
这些新的转录组学见解对于开发（化学）预防疗法至关重要。这些疗法可以是防止包括胆汁在内的毒素激活孕烷X受体的疗法，或者是增强保护性免疫机制的疗法。所鉴定的RNA标志物是改善监测计划中风险分层的有前景的生物标志物。
