TP53 loss-of-function (TP53LOF) mutations might be a driver of poor prognosis and chemoresistance in both human papillomavirus (HPV)-independent (HPV-) and HPV-associated (HPV+) penile squamous cell carcinoma (PSCC).
Here, we aim to describe transcriptomic differences in the PSCC microenvironment stratified by TP53LOF and HPV status.
We used single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing to obtain a comprehensive atlas of the cellular architecture of PSCC. TP53LOF and HPV status were determined by targeted next-generation sequencing and sequencing HPV-DNA reads. Six HPV+ TP53 wild type (WT), six HPV- TP53WT, and four TP53LOF PSCC samples and six controls were included. Immunohistochemistry and hematoxylin-eosin confirmed the morphological context of the observed signatures. Prognostic differences between patient groups were validated in 541 PSCC patients using Kaplan-Meier survival estimates.
Patients with aberrant p53 staining fare much worse than patients with either HPV- or HPV+ tumors and WT p53 expression. Using scRNA-seq, we revealed 65 cell subtypes within 83 682 cells. TP53LOF tumors exhibit a partial epithelial-to-mesenchymal transition, immune-excluded, angiogenic, and morphologically invasive environment, underlying their aggressive phenotype. HPV- TP53WT tumors show stemness and immune exhaustion. HPV+ TP53WT tumors mirror normal epithelial maturation with upregulation of antibody-drug-conjugate targets and activation of innate immunity. Inherent to the scRNA-seq analysis, low sample size is a limitation and validation of signatures in large PSCC cohorts is needed.
This first scRNA-seq atlas offers unprecedented in-depth insights into PSCC biology underlying prognostic differences based on TP53 and HPV status. Our findings provide clues for testing novel biomarker-driven therapies in PSCC.
Here, we analyzed tissues of penile cancer at the level of individual cells, which helps us understand why patients who harbor a deactivating mutation in the TP53 gene do much worse than patients lacking such a mutation. Such an analysis may help us tailor future therapies based on TP53 gene mutations and human papillomavirus status of these tumors.
European urology. 2024 Apr 25 [Epub ahead of print]
Laura Elst, Gino Philips, Kaat Vandermaesen, Ayse Bassez, Francesca Lodi, Manon T A Vreeburg, Oscar R Brouwer, Rogier Schepers, Thomas Van Brussel, Sambit K Mohanty, Anil V Parwani, Lien Spans, Isabelle Vanden Bempt, Gerd Jacomen, Marcella Baldewijns, Diether Lambrechts, Maarten Albersen
Center for Cancer Biology, Laboratory of Translational Genetics, VIB-KU Leuven, Leuven, Belgium; Department of Urology, University Hospitals Leuven, Leuven, Belgium; Department of Development and Regeneration, KU Leuven, Leuven, Belgium., Center for Cancer Biology, Laboratory of Translational Genetics, VIB-KU Leuven, Leuven, Belgium., Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands., Department of Pathology and Laboratory Medicine, Advanced Medical Research Institute, Bhubaneswar, India; Department of Pathology and Laboratory Medicine, CORE Diagnostics, Gurgaon, India., Department of Pathology, Wexner Medical Center, Columbus, OH, USA., Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium., Laboratory of Pathological Anatomy, AZ Sint-Maarten, Mechelen, Belgium., Department of Pathology, University Hospitals Leuven, Leuven, Belgium., Department of Urology, University Hospitals Leuven, Leuven, Belgium; Department of Development and Regeneration, KU Leuven, Leuven, Belgium. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/38670879