Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria.
Lab Invest. 2024 Sep;104(9):102108. doi: 10.1016/j.labinv.2024.102108. Epub 2024 Jul 6.
Full-thickness high-grade squamous intraepithelial lesions (HSIL) are precursors of invasive cervical squamous cell carcinoma (SCC). The World Health Organization and Lower Anogenital Squamous Terminology Standardization Project for human papilloma virus (HPV)-associated lesions divide full-thickness HSIL of the cervix into thin HSIL with thickness of 1 to 9 cell layers and the typical full-thickness HSIL of >10 cell layers. Although HPV oncogene transcripts and p16ink4a overexpression, as markers of transforming HPV infection, are detectable in thin HSIL, the biological significance of thin HSIL in cervical carcinogenesis remains poorly understood. To further characterize thin HSIL, we performed a comparative study of chromosomal copy number variations (CNV), an analysis of dysregulated genes present in the segments with CNV, and a generalized genetic complexity calculation for 31 thin HSIL, 31 thick HSIL, 24 microinvasive SCC (pT1a SCC), and 22 highly invasive SCC samples. Thin HSIL share various CNV and specific dysregulated gene pathways with thick HSIL and invasive SCC. Thin HSIL exhibited an average CNV of 11.6% compared with 14.1% for thick HSIL, 15.5% for pT1a SCC, and 26.6% for highly invasive SCC. The CNV included gains at 1q and 3q (40% and 43%, respectively), partial loss of 3p, and loss of chromosomes 11 (18%), 16 (50%), 20 (35%), and 22 (40%). Pathways affected solely in thin HSIL were those enhancing immune evasion and primarily involved the (interleukin) IL6, IL21, and IL23 genes. ILs are transiently upregulated in response to infection and play a crucial role in mounting antitumor T-cell activity. Deregulation reflects an attempt by the HPV to evade the initial immune response of the host. The primary pathways shared by thick HSIL and invasive SCC were interactions between lymphoid and nonlymphoid cells, NOTCH2 signaling, tight junction interactions (primarily of the claudin family), and FGR2 alternative splicing. Our results show that thin HSIL carry similar genetic changes as thick HSIL and SCC, indicating that thin HSIL are true precursor lesions that can progress to thick HSIL and SCC.
全层高级别鳞状上皮内病变（HSIL）是浸润性宫颈鳞状细胞癌（SCC）的前驱病变。世界卫生组织和人乳头瘤病毒（HPV）相关病变的下生殖道低级别鳞状上皮内病变术语标准化项目将宫颈全层 HSIL 分为厚度为 1 至 9 个细胞层的薄 HSIL 和典型的> 10 个细胞层的全层 HSIL。虽然 HPV 癌基因转录物和 p16ink4a 过表达可作为转化 HPV 感染的标志物在薄 HSIL 中检测到，但薄 HSIL 在宫颈癌变中的生物学意义仍知之甚少。为了进一步描述薄 HSIL，我们对 31 例薄 HSIL、31 例厚 HSIL、24 例微浸润 SCC（pT1a SCC）和 22 例高侵袭性 SCC 样本进行了染色体拷贝数变异（CNV）的比较研究，分析了存在 CNV 片段中的失调基因，并进行了广义遗传复杂性计算。薄 HSIL 与厚 HSIL 和浸润性 SCC 具有各种 CNV 和特定的失调基因途径。与厚 HSIL（14.1%）、pT1a SCC（15.5%）和高侵袭性 SCC（26.6%）相比，薄 HSIL 的平均 CNV 为 11.6%。CNV 包括 1q 和 3q 的增益（分别为 40%和 43%）、3p 的部分缺失以及染色体 11（18%）、16（50%）、20（35%）和 22（40%）的缺失。仅在薄 HSIL 中受影响的途径是增强免疫逃逸的途径，主要涉及（白细胞介素）IL6、IL21 和 IL23 基因。ILs 是感染后短暂上调的，在启动抗肿瘤 T 细胞活性中起关键作用。失调反映了 HPV 试图逃避宿主的初始免疫反应。厚 HSIL 和浸润性 SCC 共同的主要途径是淋巴样细胞和非淋巴样细胞之间的相互作用、NOTCH2 信号转导、紧密连接相互作用（主要是 Claudin 家族）和 FGR2 可变剪接。我们的结果表明，薄 HSIL 具有与厚 HSIL 和 SCC 相似的遗传变化，表明薄 HSIL 是真正的前驱病变，可以进展为厚 HSIL 和 SCC。
