Comprehensive genomic profiling of penile squamous cell carcinoma and the impact of human papillomavirus status on immune checkpoint inhibitor related biomarkers


Bassel Nazha MD, MPH1,2, Tony Zhuang MD3, Sharon Wu PhD4, Jacqueline T. Brown MD1,2, Daniel Magee PhD4, Bradley C. Carthon MD, PhD1,2. Omer Kucuk MD1,2, Chadi Nabhan MD, MBA4, Pedro C. Barata MD, MSc5, Elisabeth I. Heath MD6, Charles J. Ryan MD7, Rana R. McKay MD8, Viraj A. Master MD, PhD1,9, Mehmet Asim Bilen MD1,2


Background: Advanced penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy with limited success of immune‐checkpoint inhibitors (ICIs). Approximately half of pSCC cases are associated with human papillomavirus (HPV) infection.

Methods: Evaluation was done retrospectively of the landscape of somatic alter-ations and ICI‐related biomarkers in pSCC by using the Caris Life Sciences data set with the aim to establish signatures for HPV‐dependent oncogenesis. The pSCC tumors were analyzed by using next‐generation sequencing (NGS) of DNA and RNA. Programmed death ligand 1 (PD‐L1) expression was evaluated by immunohisto- chemistry (IHC). Microsatellite instability (MSI) was tested by fragment analysis, IHC (SP142; ≥1%), and NGS. Tumor mutational burden (TMB)–high was defined as ≥10 mutations/Mb. HPV16/18 status was determined by using whole‐exome sequencing (WES) when available. Significance was adjusted for multiple compari- sons (q value < .05).

Results: NGS of the overall cohort (N = 108) revealed TP53 (46%), CDKN2A (26%), and PIK3CA (25%) to be the most common mutations. Overall, 51% of tumors were PD‐L1þ, 10.7% had high TMB, and 1.1% had mismatch repair–deficient (dMMR)/MSI‐high status. Twenty‐nine patients had their HPV status made available by WES (HPV16/18þ, n = 13; HPV16/18−, n = 16). KMT2C mutations (33% vs. 0%) and FGF3 amplifications (30.8% vs. 0%) were specific to HPV16/18þ tumors, whereas CDKN2A mutations (0% vs. 37.5%) were exclusive to HPV16/18− tumors. TMB‐high was exclusively found in the HPV16/18þ group (30.8%). The two groups had comparable PD‐L1 and dMMR/MSI‐H status.

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