PO.BCS01.05 · 生物信息与计算

食管鳞状细胞癌中的转录本异构体多样性：对非洲肿瘤异质性和治疗靶点的见解

Transcript isoform diversity in esophageal squamous cell carcinoma: Insights into tumor heterogeneity and therapeutic targets in Africa

编号 5438 展板 5 时间 4/21 02:00–05:00 区域 Section 1 主讲 Zodwa Dlamini, PhD

分会场 Application of Bioinformatics to Cancer Biology 5

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作者与单位 Authors & Affiliations

Sikhumbuzo Z. Mbatha¹, Mohammed Alaouna², Botle Precious Damane¹, Tebogo Marutha², Rodney Hulll², Jonathan Featherston³, Aristotelis Chatziioannou⁴, Zodwa Dlamini²

¹Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa,²Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria, South Africa,³Division of National Health Laboratory Service, The National Institute For Communicable Diseases Of South Africa, Sandringham, South Africa,⁴Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Kallithea, Greece

摘要 Abstract

中文摘要

背景：食管鳞状细胞癌（ESCC）是撒哈拉以南非洲，尤其是非洲ESCC走廊地区癌症死亡的主要原因。该地区复杂的病因，包括病毒感染，可能影响RNA加工过程，如可变剪接（AS）——这是ESCC生物学中一个关键但研究不足的机制。本研究表征了非洲ESCC中全转录组范围的AS格局，并评估了HPV和HIV感染是否促成剪接失调和结构蛋白改变。方法：于2024年2月至12月开展了一项横断面研究，纳入29例经组织学确诊ESCC且HIV状态明确的患者。采集配对的肿瘤/邻近正常内镜活检组织，进行组织学评估、HPV基因分型和RNA测序。研究了可变剪接谱，重点关注其与病毒状态的关联。采用计算结构建模和分子对接来预测肿瘤特异性剪接变异体的功能影响。结果与讨论：外显子跳跃是主要的AS事件，其次是可变5′和3′剪接位点。出现了显著的患者特异性异质性，其中原钙黏蛋白基因家族受影响最大，提示细胞黏附和侵袭的破坏。失调的非编码RNA（DGCR5、LINC00641）进一步反映了肿瘤抑制性控制的丧失。预测CXADR中一个肿瘤富集的3′剪接位点变异体会改变连接处信号传导。按病毒状态（HIV+/HPV+、HIV+/HPV-、HIV-/HPV+、HIV-/HPV-）分层显示，对总体剪接负荷无显著影响。结论：非洲ESCC表现出一种独特的、以外显子跳跃为主的AS特征，其驱动的分子多样性独立于HIV/HPV状态，突显了AS作为非洲精准肿瘤学中一个有前景的诊断和治疗轴心的地位。

查看英文原文 English abstract

Background: Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer mortality in sub-Saharan Africa, particularly African ESCC corridor. The region's complex etiology, including viral infections, may influence RNA processing such as alternative splicing (AS), a critical but understudied mechanism in ESCC biology. This study characterized the transcriptome wide AS landscape in African ESCC and assessed whether HPV and HIV infections contribute to splicing dysregulation and structural protein alterations. Methods: A cross-sectional study was conducted between February to December 2024 involving 29 patients with histologically confirmed ESCC and verified HIV status. Paired tumor/ adjacent normal endoscopic biopsies were collected and subjected to histological evaluation, HPV genotyping, and RNA sequencing. Alternative splicing profiles were investigated, with a focus on their association with viral status. Computational structural modeling and molecular docking was used to predict the functional impact of tumor-specific splice variant. Results and Discussion: Skipped exons were the predominant AS event, followed by alternative 5′ and 3′ splice sites. Substantial patient-specific heterogeneity emerged, with the protocadherin gene family most affected, implicating disrupted cellular adhesion and invasion. Dysregulated non-coding RNAs (DGCR5, LINC00641) further reflected loss of tumor-suppressive control. A tumor-enriched 3′ splice-site variant in CXADR was predicted to alter junctional signaling. Stratification by viral status (HIV+/HPV+, HIV+/HPV-, HIV-/HPV+, HIV-/HPV-) revealed no significant effect on overall splicing burden. Conclusion: African ESCC exhibits a distinct, skipped-exon-dominated AS signature that drives molecular diversity independent of HIV/HPV status, highlighting AS as a promising diagnostic and therapeutic axis for precision oncology in Africa.

利益披露 Disclosure

S. Mbatha, None.. M. Alaouna, None.. B. P. Damane, None.. T. Marutha, None.. R. Hulll, None.. J. Featherston, None.. A. Chatziioannou, None.. Z. Dlamini, None.

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