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Purpose: Penile squamous cell carcinoma (PSCC) is rare with limited treatment options. We report the first whole-exome sequencing (WES) analysis and compare the molecular landscape of PSCC with other squamous cell carcinomas (SCC), with the goal to identify common novel targets. Experimental Design: PSCC and matched normal penile tissues from 34 prospectively followed patients, underwent genomic WES 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 Catalogue of Somatic Mutations in Cancer mutation signatures. We performed an extensive genomic comparison between our PSCC cohort and other SCCs in The Cancer Genome Atlas studies. Results: We identified that most PSCC samples showed enrichment for Notch pathway (n = 24, 70.6%) alterations, comparable with head and neck squamous cell carcinoma (HNSC). PSCC mutation signatures are most comparable with HNSC signatures. PSCC samples showed an enrichment of two 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 tumor mutation burden (TMB; CC, 0.71; P < 0.0001) and correlated with significantly worse survival in comparison with those with the MP2 subset [HR, 10.2 (1.13–92.9); P = 0.039]. We show that a subset of PSCC (38%), with enrichment of APOBEC-related mutation signature, had significantly higher TMB and worse overall survival in comparison with non-APOBEC–enriched subset [HR, 2.41 (1.11–6.77); P = 0.042]. Conclusions: This study identified novel druggable targets and similarities in mutational signatures between PSCC and HNSC with potential clinical implications. See related commentary by McGregor and Sonpavde, p. 2375

Human cancer cell lines are the most frequently used preclinical models in the study of cancer biology and the development of therapeutics. Although anatomically diverse, human papillomavirus (HPV)-driven cancers have a common etiology and similar mutations that overlap with but are distinct from those found in HPV-negative cancers. Building on prior studies that have characterized subsets of head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESC) cell lines separately, we performed genomic, viral gene expression, and viral integration analyses on 74 cell lines that include all readily-available HPV-positive (9 HNSCC, 8 CESC) and CESC (8 HPV-positive, 2 HPV-negative) cell lines and 55 HPV-negative HNSCC cell lines. We used over 700 human tumors for comparison. Mutation patterns in the cell lines were similar to those of human tumors. We confirmed HPV viral protein and mRNA expression in the HPV-positive cell lines. We found HPV types in three CESC cell lines that are distinct from those previously reported. We found that cell lines and tumors had similar patterns of viral gene expression; there were few sites of recurrent HPV integration. As seen in tumors, HPV integration did appear to alter host gene expression in cell lines. The HPV-positive cell lines had higher levels of p16 and lower levels of Rb protein expression than did the HPV-negative lines. Although the number of HPV-positive cell lines is limited, our results suggest that these cell lines represent suitable models for studying HNSCC and CESC, both of which are common and lethal.

BackgroundThe erbB receptors and their ligands are involved in the pathogenesis and progression of oral squamous cell carcinoma (OSCC). Although EGFR and Her-2 are frequently overexpressed in OSCC, few studies evaluated these proteins in saliva and their association with the tumor, which may represent potential usefulness in a clinical setting.MethodsThe levels of EGFR, Her-2, and EGF were evaluated in saliva of 46 patients with OSCC before and after the surgical removal of the lesion, as well as in matched healthy controls. The relationship of salivary levels and EGFR and Her-2 immunoexpression in tumor samples with clinicopathological features was analyzed.ResultsEGFR and Her-2 salivary levels did not show difference between to pre-surgery and control groups, however, both demonstrated an increase after surgical removal of the tumor. No association was detectable among receptor salivary levels, tissue expression and clinicopathological features. EGF levels in pre-surgery group were significantly lower when compared to the control group.ConclusionsEGFR and Her-2 were not considered to be valuable salivary tumor markers in OSCC, however, lower levels of EGF in saliva may suggest a higher susceptibility for OSCC development.