ARID1A deficiency identifies molecular alterations and potential therapeutic implications in cervical clear cell...

Cervical clear cell carcinoma (CCC) is a rare and aggressive subtype of cervical adenocarcinoma whose molecular drivers and therapeutic vulnerabilities remain incompletely defined. As a key component of the SWI/SNF chromatin-remodeling complex, ARID1A has been recognized as a potential biomarker of therapeutic response across multiple human malignancies. Nevertheless, the molecular and clinical significance of ARID1A in CCC has not been systematically clarified. This study aimed to characterize the genomic landscape of CCC and explore whether ARID1A deficiency serves as a molecular signature that confers actionable therapeutic vulnerabilities for precision oncology.

We retrospectively collected clinicopathological data from 27 patients diagnosed with CCC at Sun Yat-sen University Cancer Center between August 2018 and May 2023. Targeted next-generation sequencing (NGS) was performed using a cancer-related panel with complete exon coverage of 312 genes and selected-region coverage of additional cancer-associated genes in tumor tissues and matched peripheral blood samples from 7 patients to identify recurrent genomic alterations and perturbed biological pathways. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) network analyses, were conducted to identify altered pathways and candidate hub genes. Based on the integrated genomic and network analyses, ARID1A was selected for further evaluation, and ARID1A protein expression was evaluated by immunohistochemistry in 27 CCC samples and 30 HPV-associated cervical adenocarcinoma (HPVA) samples.

The median age of enrolled patients was 47.6 years, and 74.1% of patients presented with early-stage disease (FIGO IA-IIA). With a median follow-up duration of 44.6 months, the 3- and 5-year overall survival rates were 90% and 77%, respectively. Targeted NGS identified a total of 93 somatic alterations spanning 78 genes, with recurrent alterations predominantly occurring in ARID1A, PIK3CA, SMARCA4, and JAK3. Pathway enrichment revealed significant perturbations in chromatin-remodeling, PI3K-AKT, p53, and JAK-STAT signaling pathways. PPI network analysis identified ARID1A, PIK3CA, EGFR, and CTNNB1 as core hub molecules mediating tumorigenesis. Complete loss of nuclear ARID1A expression was detected in 51.8% of CCC cases, significantly higher than the 6.0% rate detected in HPVA lesions (P < 0.001).

CCC exhibits a distinct molecular profile characterized by frequent disruption of chromatin-remodeling pathways. Enrichment analyses linked ARID1A deficiency to concurrent genomic aberrations affecting chromatin remodeling and PI3K/AKT cascades. Our findings suggest that ARID1A loss could act as a potential adjunctive diagnostic marker when interpreted together with histopathological features, HPV status, and other immunohistochemical markers, while representing a therapeutic vulnerability requiring further validation.