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Updated: Jun 28, 2026
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Transcriptome profiling identifies RET activation as a therapeutic target in gastric-type endocervical adenocarcinoma
Hiroaki Yamada1, Akira Yokoi2, Kazuhiro Suzuki3
1Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Japan.
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.
Insights
Gastric-type endocervical adenocarcinoma (GAS) shares a lineage with its precursor lesion, lobular endocervical glandular hyperplasia (LEGH). PGC is a diagnostic marker, and RET inhibition shows therapeutic potential for GAS.
Area of Science:
- Gynecologic Oncology
- Molecular Pathology
- Cancer Genomics
Background:
- Gastric-type adenocarcinoma (GAS) is an aggressive, human papillomavirus (HPV)-independent cervical cancer subtype.
- GAS exhibits resistance to conventional therapies, necessitating novel treatment strategies.
- Understanding the molecular underpinnings of GAS is crucial for developing targeted therapies.
Purpose of the Study:
- To elucidate the molecular basis of GAS.
- To investigate the developmental trajectory of GAS from precursor lesions.
- To identify potential therapeutic targets for GAS.
Main Methods:
- Transcriptomic profiling of GAS, usual-type endocervical adenocarcinoma (UEA), and lobular endocervical glandular hyperplasia (LEGH).
- Bioinformatic analyses including clustering, differential gene expression, and pathway analysis.
- Immunohistochemistry for marker validation and in vitro/in vivo evaluation of RET inhibition using vandetanib.
Main Results:
- GAS demonstrated a distinct transcriptional profile, supporting its classification as a separate subtype.
- LEGH and GAS shared a common cellular lineage, evidenced by clustering and correlation analyses.
- PGC was identified as a progressively upregulated gene and validated as a diagnostic marker; RET pathway activation was predicted and targeted successfully with vandetanib.
Conclusions:
- Findings support a shared lineage between LEGH and GAS.
- PGC serves as a valuable diagnostic marker for GAS.
- RET inhibition presents a promising therapeutic strategy for treating GAS.
