Abstract Prostate cancer (PCa) is the second leading cause of cancer-related death in men, accounting for over 35, 000 deaths annually in the USA. While coding mutations have been extensively characterized, the contribution of non-coding somatic variants to PCa development and progression remains poorly understood. These variants are thought to influence tumor biology by modulating gene expression through regulatory elements. To address this, we mapped somatic mutation-enriched regions across the Pan-Cancer Analysis of Whole Genomes and Hartwig PCa cohorts and identified several recurrently altered enhancers. CRISPR activation of one such enhancer at 14q22. 1 increased expression of its target gene, FERMT2 (Kindlin-2), a focal-adhesion adaptor. Functional assays using CRISPR knockout and siRNA knockdown models showed that loss of FERMT2 significantly reduced migration and clonogenic survival in androgen receptor (AR) -negative, but not AR-positive, PCa cells, indicating a context-dependent role in adhesion and growth control. Multi-omic analyses of clinical datasets demonstrated that FERMT2-high tumors are enriched for extracellular matrix and focal-adhesion signaling, whereas FERMT2-low tumors rely on proliferative and DNA-damage-repair (DDR) pathways, particularly under hypoxia. Low FERMT2 expression also correlated with shorter disease-free survival. Collectively, these findings suggest that FERMT2 is a candidate biomarker of prognostic and therapeutic relevance, offering a framework for patient stratification and informing the development of targeted interventions in PCa. Ongoing work aims to elucidate the molecular mechanisms underpinning therapy response in FERMT2-high and FERMT2-low tumors. Citation Format: Victoria Blair, Nick Orr, Sarah Maguire. Investigating FERMT2 expression as a determinant of prostate cancer progression abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr A005.
Blair et al. (Tue,) studied this question.