Integrated Transcriptomic Analysis Reveals Distinct Molecular and Immune Microenvironment Features of Peutz–Jeghers Syndrome-Associated Lobular Endocervical Glandular Hyperplasia and Gastric-Type Endocervical Adenocarcinoma

Background: Gastric-type endocervical adenocarcinoma (GAS) is an aggressive, human papillomavirus-independent cervical adenocarcinoma, whereas lobular endocervical glandular hyperplasia (LEGH) is considered a potential precursor. Molecular and immune microenvironment differences between Peutz–Jeghers syndrome-associated LEGH (PJS-LEGH) and GAS (PJS-GAS) remain poorly characterized. This study aimed to characterize these differences through integrated transcriptomic analysis. Methods: Bulk RNA sequencing was performed on tissues from 7 PJS-LEGH and 8 PJS-GAS cases. Differential expression and functional enrichment analyses were integrated with weighted gene co-expression network analysis (WGCNA), molecular interaction network analysis, and machine learning. Immune-related transcriptional patterns were assessed using single-sample gene set enrichment analysis (ssGSEA) and xCell, with CD45/CD4 multiplex immunofluorescence for preliminary tissue-level assessment. Results: We identified 1794 differentially expressed genes, including 976 upregulated and 818 downregulated genes in PJS-GAS. Functional and network analyses highlighted differences involving ciliary biology, epithelial differentiation, chemokine signaling, and immune regulation. ssGSEA revealed higher scores for selected T-cell, dendritic-cell, monocyte, and myeloid-derived suppressor cell signatures in PJS-GAS. xCell provided complementary evidence of higher scores for selected immune-cell populations, together with activation- and inhibition-associated transcriptional signatures. Integrated analyses converged on PTPRC, encoding the pan-leukocyte marker CD45, as a prominent leukocyte-associated feature of PJS-GAS. Multiplex immunofluorescence showed higher CD45+ and CD4+ cell densities in the sampled PJS-GAS tissues. Conclusions: This study provides the first transcriptomic comparison of PJS-LEGH and PJS-GAS and identifies distinct molecular features and increased immune-cell-associated transcriptional signatures with coexisting activation- and inhibition-associated expression patterns in PJS-GAS.