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Survival-Associated Molecular and Epigenetic Alterations in Endocervical Adenocarcinoma: An Exploratory TCGA
Yasemin Cakir1,2, Zeynep Bayramoglu1,2
1Department of Pathology, School of Medicine, Dokuz Eylül University, 35330 İzmir, Türkiye.
Background And Objective:
The objective of this exploratory study was to identify the molecular characteristics that influence survival outcomes in cases of cervical adenocarcinoma, utilising data from the TCGA (The Cancer Genome Atlas) database.
Methods:
The 'TCGA Firehose Legacy' dataset was accessed through the Cbioportal website. SILVA invasion patterns were independently evaluated on digitized whole-slide images by two gynecologic pathologists. Cases were categorized by overall survival status (living vs. deceased). Somatic mutations, copy number alterations, mRNA expression, RPPA protein expression, and DNA methylation profiles were analyzed. Survival analyses were performed using Kaplan-Meier methods and log-rank tests, supplemented by differential analysis. Pathway and transcription factor binding motif enrichment was evaluated via g:Profiler. p and q < 0.05 were considered statistically significant.
Results:
Among 27 cases (22 living, 5 deceased; 23 HPV-positive, 2 HPV-negative, 2 unknown), PREX1 protein expression was identified as the top-ranked differentially expressed candidate protein (p = 4.29 × 10-5, q = 8.70 × 10-3). Kaplan-Meier analysis demonstrated superior overall survival in patients with high PREX1 protein levels. DNA methylation analysis identified 8 differentially methylated genes (p, q < 0.05); 7 were hypermethylated in the deceased group (MCEMP1, RNASE2, RINL, CCL17, THBD, SFXN5, PRR19), while WDR89 was hypermethylated in the living group. Enrichment analysis of differentially methylated promoter regions revealed a distinct KLF9-binding regulatory motif (q = 0.032). Due to sample size constraints (n = 2 HPV-negative, n = 2 SILVA Pattern A), subgroup comparisons for HPV status and SILVA patterns were interpreted descriptively without inferential statistical claims.
Conclusions:
In this exploratory cohort, elevated PREX1 protein levels and promoter hypermethylation of specific immune- and metabolic-related genes were associated with overall survival in endocervical adenocarcinoma. Due to the current lack of independent public proteomic validation datasets, PREX1 emerges as a novel candidate biomarker requiring prospective tissue-based immunohistochemical and epigenetic validation in larger multi-center clinical cohorts.
