Integrative genomic and transcriptomic profiling reveals dysregulation of FOXA1-AGR2 axis in penoscrotal extramammary Paget's disease.

Background: Extramammary Paget's disease (EMPD) is a rare cutaneous mucinous adenocarcinoma primarily affect the penoscrotal skin, characterized by the presence of Paget cells scattered within the epidermis. The molecular features of Paget cells remain poorly understood.

Objectives: To describe the genomic and transcriptomic landscape of penoscrotal EMPD, identify the driver mutation or core transcription factor through integrative analysis, identify biological markers and provide new insights for the pathogenesis of penoscrotal EMPD.

Methods: Whole exome sequencing was performed on penoscrotal EMPD tissues from 37 patients, of whom 28 patients also underwent RNA sequencing, and the findings was validated in an additional 72 patients, encompassing 120 multi-region tumor tissues to identify core transcription factors. The dysregulation was further confirmed by immunohistochemistry.

Results: Genomic landscape did not reveal FOXA1 or SPDEF mutations penoscrotal EMPD. Transcriptomic profiling identified the upregulation of lineage-specific transcription factors FOXA1 and SPDEF, along with their targeted genes AGR2 and MUC5AC. Upregulation of FOXA1, SPDEF and AGR2 without gene fusion were consistently replicated in the validation cohort. Further analysis of multiple tissue regions confirmed FOXA1 and SPDEF as driver transcription factors in penoscrotal EMPD. We identify key transcription factors regulating co-expressed modules FOXA1-SPDEF-AGR2, suggesting goblet cells features of penoscrotal EMPD. The immunohistochemistry confirmed the co-expression of FOXA1-AGR2 pattern in Paget cells.

Conclusions: Our study provides novel insights into the molecular characteristics of Paget cells, and also highlights the critical role of FOXA1 in Paget cell development in EMPD.