PO.MCB08.03 · 分子与细胞生物学
流行病学与新型转录组学在低分化子宫内膜癌中的结合
Epidemiology meets novel transcriptomics in poorly differentiated endometrial carcinomas
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：子宫内膜癌（EC）是高收入地区最常见的妇科恶性肿瘤，传统上分为雌激素相关的I型和非雌激素性的II型疾病。II型组织学类型预后较差，且在非洲人群中分子层面的表征不足。南非的EC数据稀少，且大多从国际队列外推而来。本研究通过对患有上皮性EC的南非女性的临床结局和RNA水平改变进行分析，弥补了流行病学和转录组学方面的空白，重点关注黑人女性并与非洲裔美国人数据集进行比较。
材料与方法：回顾性审阅来自Inkosi Albert Luthuli中心医院的290份电子健康记录（2009-2019年），以确定上皮性EC的发病率、FIGO分期分布和生存情况。对76份低分化FFPE肿瘤标本进行分子分析：总RNA提取、短读长RNA测序、使用STAR进行比对、使用featureCounts/StringTie进行定量。分析包括差异基因表达（|log2FC|≥1.0）、可变剪接（ΔPSI）、新型异构体发现，以及Reactome通路富集，以确定失调的通路。使用公开可得的非洲裔美国人数据集进行跨人群比较。
结果：II型组织学类型占病例的47.9%，与晚期FIGO分期相符，中位总生存期为3.7个月。转录组分析揭示出一种双重特征：MAPK/ERK和视黄酸通路上调（如MKNK2 +2.03 log₂FC，RARA +2.14），同时RNA-Pol II转录和细胞周期调控因子受到抑制（如ZNF793 −5.26，MYC −4.50）。GJA1中的外显子跳跃和广泛的内含子保留标志着剪接重编程。StringTie发现了新型lncRNA和锌指异构体（如LINC01605），这两个层面在现有注释中均缺失。跨人群分析证实了拷贝数高/p53异常亚型的关键共有驱动因素，同时新型剪接变异体则表现为人群特异性。
结论：这些发现验证了II型子宫内膜癌在南非女性中的主导地位和侵袭性。本研究揭示了黑人女性中独特的转录组和剪接格局，扩展了TCGA的亚型分类。新型激酶和lncRNA靶点（MKNK2、SRPK1、LINC01605）为量身定制的治疗提供了希望。将分子分类纳入国家指南、加强诊断基础设施并启动精准医学试验，将是缩小生存差异并提供公平、生物标志物驱动诊疗的关键。
查看英文原文 English abstract
Background: Endometrial cancer (EC) is the commonest gynecological malignancy in high‑income settings and is traditionally divided into estrogen‑related Type I and non‑estrogenic Type II diseases. Type II histologies carry a poorer prognosis and have been under‑characterized molecularly in African populations. South African EC data are sparse and largely extrapolated from international cohorts. This study addresses epidemiologic and transcriptomic gaps by profiling clinical outcomes and RNA‑level alterations in South African women with epithelial EC, with emphasis on Black females and comparison to African American datasets.
Materials and Methods: Retrospective review of 290 electronic health records (2009-2019) from Inkosi Albert Luthuli Central Hospital to determine incidence, FIGO stage distribution, and survival for epithelial EC. Molecular profiling of 76 poorly differentiated FFPE tumor specimens: total RNA extraction, short‑read RNA sequencing, alignment with STAR, quantification with featureCounts/StringTie. Analyses included differential gene expression (|log2FC| ≥ 1.0), alternative‑splicing (ΔPSI), novel‑isoform discovery, and Reactome pathway enrichment to define dysregulated pathways. Publicly available African American datasets were used for cross‑population comparisons.
Results: Type II histologies comprised 47.9% of cases and aligned with advanced FIGO stage and median overall survival of 3.7 months. Transcriptome analysis revealed a dual signature: upregulation of MAPK/ERK and retinoic‐acid pathways (e.g., MKNK2 +2.03 log₂FC, RARA +2.14) alongside repression of RNA‐Pol II transcription and cell‐cycle regulators (e.g., ZNF793 −5.26, MYC −4.50). Exon‐skipping in GJA1 and widespread intron retention marked splicing rewiring. StringTie uncovered novel lncRNA and zinc‐finger isoforms (e.g., LINC01605), two layers absent from existing annotations. Cross‐population analysis confirmed key shared drivers of the copy‐number‐high/p53‐abnormal subtype, while novel splicing variants emerged as population‐specific.
Conclusion: These findings validate the predominance and aggressiveness of Type II endometrial carcinoma in South African women. The study reveals unique transcriptomic and splicing landscapes in Black females that extend TCGA subtyping. Novel kinase and lncRNA targets (MKNK2, SRPK1, LINC01605) hold promise for tailored therapeutics. Integrating molecular classification into national guidelines, bolstering diagnostic infrastructure, and launching precision‐medicine trials will be essential to narrow survival disparities and deliver equitable, biomarker‐driven care.
利益披露 Disclosure
T. Molefi, None..
M. Sebitloane, None..
Z. Dlamini, None.