Transcriptome profiling identifies RET activation as a therapeutic target in gastric-type endocervical adenocarcinoma

OBJECTIVE: Gastric-type endocervical adenocarcinoma (GAS) is a human papillomavirus (HPV)-independent cervical adenocarcinoma characterized by resistance to standard treatments and aggressive clinical behavior. This study aimed to clarify the molecular basis and developmental trajectory of GAS. METHODS: We performed transcriptomic profiling of GAS, usual-type endocervical adenocarcinoma (UEA), and the precursor lesion lobular endocervical glandular hyperplasia (LEGH). Clustering, correlation, and differential expression analyses were conducted to identify GAS-associated genes. Pathway and upstream regulator analyses were also performed. Immunohistochemistry was used to validate candidate markers. The therapeutic potential of RET inhibition was evaluated using vandetanib in vitro and in vivo. RESULTS: GAS exhibited a transcriptional profile distinct from UEA, indicating that it represents a separate subtype. Clustering and correlation analyses revealed that LEGH aligned closely with GAS, supporting a shared lineage. Differential expression analysis identified 90 genes specific to GAS and 12 genes that increased progressively from LEGH to GAS. Among these, PGC showed clear stepwise upregulation, which was confirmed by immunohistochemistry, demonstrating its value as a diagnostic marker. Pathway analyses revealed activation of proliferative signaling pathways, including RTK-RAS-PI3K-MAPK and FGF-FGFR-ERK, as well as metabolic and cytoskeletal remodeling programs. Upstream regulator analysis predicted RET activation, and RET inhibition with vandetanib markedly suppressed GAS cell growth in vitro and in vivo. CONCLUSIONS: These findings support a shared cellular lineage between LEGH and GAS, indicate that PGC is a useful diagnostic marker, and suggest that RET inhibition may represent a therapeutic strategy for GAS.