病毒相关的宫颈癌的分子多样性仍然是一个相对未开发的问题，而在特定的宫颈癌微环境形成过程中，免疫学和血管生成特征之间的相互关系尚未充分表征，尤其是对其早期临床阶段，尽管这可能揭示出肿瘤侵袭性、治疗反应性和预后差异背后的机制。在这项研究中，我们旨在识别在免疫相关特征、信号通路模式和微环境组成方面与其直接前体（上皮内）病变存在显著差异的早期宫颈癌的转录组景观。我们使用含人乳头状瘤病毒阳性宫颈上皮内瘤变（CIN）、FIGO IA1-IIB阶段的侵袭性宫颈鳞状癌以及形态正常的上皮组织样本的面板进行了Illumina平台基于RNA测序。推导的转录组文件通过信号通路激活模式、肿瘤浸润细胞种群分布和参与的基因组区域进行了生物信息学分析和比较。根据整体转录组景观的分层集群分析，组织样本分布在三个组或基因表达模式之间（其中包括大部分癌前病例的一组，以及主要包含早期侵袭性癌症病例的另外两组）。检索了每个组间成对比较中的差异表达基因，随后进行了Gene Ontology分析。与CIN组相比，对两组肿瘤样本的基因集富集分析确定了肿瘤组之间的免疫和血管生成特性的显著差异，说明了不同分子表型的发展。细胞组成分析证实了免疫和非免疫种群丰度的不同变化，并相应地显示了与这两组肿瘤相比的CIN在肿瘤微环境中免疫和间质组分的不同作用。位置基因表达分析表明，鉴定到的转录组差异与不同染色体区域关联，并在免疫调节、炎症、细胞分化和肿瘤侵袭中涉及的特定基因家族共定位。总体而言，在其最早阶段发现不同的侵袭性宫颈癌转录组模式支持了免疫应答和血管生成相关机制对肿瘤侵袭和发展的多样影响。这可能为扩大靶向抗血管生成和免疫治疗适用性并提高效率提供了新的选择。版权©2023年Kurmyshkina, Dobrynin, Kovchur和Volkova。

Molecular diversity of virus-associated cervical cancer remains a relatively underexplored issue, and interrelations of immunologic and angiogenic features during the establishment of a particular landscape of the cervical cancer microenvironment are not well-characterized, especially for its earliest clinical stages, although this may provide insight into the mechanisms behind the differences in tumor aggressiveness, treatment responsiveness and prognosis. In this research, we were aimed at identifying transcriptomic landscapes of early-stage cervical carcinoma that differ substantially in their immune-related characteristics, patterns of signaling pathways and composition of the microenvironment in comparison with immediate precursor (intraepithelial) lesions.We performed the Illumina platform-based RNA sequencing using a panel of fresh tissue samples that included human papillomavirus-positive cervical intraepithelial neoplastic lesions (CIN), invasive squamous carcinoma of the cervix of FIGO IA1-IIB stages, and morphologically normal epithelium. The derived transcriptomic profiles were bioinformatically analyzed and compared by patterns of signaling pathway activation, distribution of tumor-infiltrating cell populations, and genomic regions involved.According to hierarchical cluster analysis of the whole-transcriptome profiles, tissue samples were distributed between three groups, or gene expression patterns (the one comprising most pre-cancer cases and the other two encompassing mostly early-stage invasive cancer cases). Differentially expressed genes were retrieved in each intergroup pairwise comparison followed by Gene Ontology analysis. Gene set enrichment analysis of the two groups of tumor samples in comparison with the CIN group identified substantial differences in immunological and angiogenic properties between tumorous groups suggesting the development of different molecular phenotypes. Cell composition analysis confirmed the diverse changes in the abundancies of immune and non-immune populations and, accordingly, different impacts of the immune and stromal compartments on the tumor microenvironment in these two groups of tumors compared to CIN. Positional gene expression analysis demonstrated that the identified transcriptomic differences were linked to different chromosomal regions and co-localized with particular gene families implicated in immune regulation, inflammation, cell differentiation, and tumor invasion.Overall, detection of different transcriptomic patterns of invasive cervical carcinoma at its earliest stages supports the diverse impacts of immune response- and angiogenesis-related mechanisms on the onset of tumor invasion and progression. This may provide new options for broadening the applicability and increasing the efficiency of target anti-angiogenic and immune-based therapy of virus-associated cervical carcinoma.Copyright © 2023 Kurmyshkina, Dobrynin, Kovchur and Volkova.