# Identification of the Carcinogenic Process from Lobular Endocervical Glandular Hyperplasia to Gastric-Type Adenocarcinoma of the Uterine Cervix via Whole-Exome Sequencing

## TL;DR

This study uses whole-exome sequencing to trace the genetic changes from a precancerous cervical condition to a rare, aggressive cervical cancer, revealing possible pathways and key mutations involved.

## Contribution

The study identifies sequential genetic transitions and candidate mutations in the progression from lobular endocervical glandular hyperplasia to gastric-type adenocarcinoma of the uterine cervix.

## Key findings

- Some cases show a sequential transition from lobular endocervical glandular hyperplasia to gastric-type adenocarcinoma.
- Mutations in PTPRF, PTPRT, STK11, and ARID1A are associated with early stages, while SMAD4 and SMAD2 alterations occur in later stages.
- Phylogenetic analysis reveals heterogeneous pathways of tumor development in different cases.

## Abstract

Gastric-type adenocarcinoma of the uterine cervix is a rare but aggressive cancer that is difficult to detect early and often has a poor prognosis. Lobular endocervical glandular hyperplasia is considered a possible precursor lesion, but the genetic relationship between these lesions has not been fully clarified. In this study, we analyzed tissue samples of normal cervical glands, lobular endocervical glandular hyperplasia, and gastric-type adenocarcinoma obtained from the same patients using whole-exome sequencing. By comparing genetic alterations across these lesions, we found that some cases showed evidence supporting a sequential transition from lobular endocervical glandular hyperplasia to gastric-type adenocarcinoma, whereas other cases appeared to develop through alternative pathways. We also identified candidate genetic changes that may occur at early and late stages of tumor development. These findings provide new insights into the heterogeneous carcinogenic processes of this rare cervical cancer and may contribute to improved understanding of its development and inform future research on diagnosis and treatment.

Background: Gastric-type adenocarcinoma (GAS) of the uterine cervix is a rare malignancy with poor clinical outcomes. However, the carcinogenic processes involved remain unclear. Methods: Normal cervical glands, lobular endocervical glandular hyperplasia (LEGH), and GAS from the same patients were collected using laser microdissection for whole-exome sequencing. Single nucleotide variants (SNVs) and copy number alterations (CNAs) were analyzed. Phylogenetic trees were constructed based on the SNV and CNA profiles. Results: Analysis of seven matched samples demonstrated higher frequency of somatic mutations in the exonic regions in GAS than in LEGH. CNAs were prevalent in GAS but rare in LEGH. The phylogenetic analyses revealed various branching patterns. However, in three cases, the data suggested a sequential transition from LEGH to GAS, potentially associated with mutations in receptor-type protein tyrosine phosphatases such as PTPRF and PTPRT. STK11 and ARID1A mutations were present in LEGH, with an increased variant allele frequency observed in GAS. In contrast, SMAD4 and SMAD2 showed frequent loss-of-function–type alterations in GAS, including copy-number loss, but were not detected in LEGH. Conclusions: These findings provide insights into the genomic landscapes of LEGH and GAS and suggest potential molecular markers for this transition, which may inform future diagnostic and therapeutic research.