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

<b>Background</b>: Gastric-type adenocarcinoma (GAS) of the uterine cervix is a rare malignancy with poor clinical outcomes. However, the carcinogenic processes involved remain unclear. <b>Methods</b>: 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. <b>Results</b>: 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 <i>PTPRF</i> and <i>PTPRT</i>. <i>STK11</i> and <i>ARID1A</i> mutations were present in LEGH, with an increased variant allele frequency observed in GAS. In contrast, <i>SMAD4</i> and <i>SMAD2</i> showed frequent loss-of-function-type alterations in GAS, including copy-number loss, but were not detected in LEGH. <b>Conclusions</b>: 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.