Penile squamous cell carcinoma (PSCC) is rare with limited treatment options. We report the first whole exome sequencing analysis and compare the molecular landscape of PSCC to other SCCs, with the goal to identify common novel targets.
PSCC and matched normal penile tissues from 34 prospectively followed patients, underwent genomic whole exome sequencing and human papilloma virus testing. We performed tumor mutation signature estimation by two methods, first to identify APOBEC-related mutation enrichments and second to classify PSCC enriched mutational patterns based on their association with the COSMIC mutation signatures. We performed an extensive genomic comparison between our PSCC cohort and other SCCs in The Cancer Genome Atlas (TCGA) studies.
We identified that most PSCC samples showed enrichment for Notch pathway (n=24,70.6%) alterations, comparable to head and neck squamous cell carcinoma (HNSC). PSCC mutation signatures are most comparable to HNSC signatures. PSCC samples showed an enrichment of 2 distinct mutational signatures, the first, associated with oncogenic activity of AID/APOBEC, and the second, associated with defective DNA mismatch repair and microsatellite instability. MP1 enrichment was positively correlated with increased TMB (CC=0.71,p<0.0001) and correlated with significantly worse survival in comparison to those with the MP2 subset (HR=10.2(1.13-92.9)p=0.039). We show the that a subset of PSCC (38%) with enrichment APOBEC-related mutation signature, had significantly higher TMB and worse overall survival in comparison to non-APOBEC enriched subset (HR=2.41 (1.11-6.77)p=0.042).
This study identified novel druggable targets and similarities in mutational signatures between PSCC and HNSC with potential clinical implications.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Jan 13 [Epub ahead of print]
Jad Chahoud, Frederico O Gleber-Netto, Barrett Z McCormick, Priya Rao, Xin Lu, Ming Guo, Maggaret B Morgan, Randy A Chu, Magaly Martinez-Ferrer, Agda Karina Eterovic, Curtis R Pickering, Curtis A Pettaway
Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute., Head and Neck Surgery, The University of Texas MD Anderson Cancer Center., Baptist Health Care., Genitourinary Medical Oncology, UT M. D. Anderson Cancer Center., University of Notre Dame., The University of Texas MD Anderson Cancer Center., Department of Pharmaceutical Sciences, University of Puerto Rico, Medical Sciences Campus., R&D, Eurofins (United States)., Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center., The University of Texas MD Anderson Cancer Center .