Human Papillomavirus Prevalence in Invasive Penile Cancer and Association with Clinical Outcome

Djajadiningrat, Rosa S.; Jordanova, Ekaterina S.; Kroon, Bin B. R.; Werkhoven, Erik van; Jong, Jeroen de; Pronk, Divera T.M.; Snijders, Peter J.F.; Horenblas, Simon; Heideman, Daniëlle A.M.

doi:10.1016/j.juro.2014.08.087

Cited by 104 publications

(73 citation statements)

References 28 publications

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“…Previous studies have generally shown HPV and p16 positivity to associate with favorable prognosis (17,(21)(22)(23). Likewise, although exploratory due to the limited number of samples with alterations and events, MYC and CCND1 amplifications were both significantly associated with decreased event-free survival.…”

Section: Discussionmentioning

confidence: 95%

Genomic Profiling of Penile Squamous Cell Carcinoma Reveals New Opportunities for Targeted Therapy

et al. 2015

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Penile squamous cell carcinoma (PeSCCA) is a rare malignancy for which there are limited treatment options due to a poor understanding of the molecular alterations underlying disease development and progression. Therefore, we performed comprehensive, targeted next-generation sequencing to identify relevant somatic genomic alterations in a retrospective cohort of 60 fixed tumor samples from 43 PeSCCA cases (including 14 matched primary/metastasis pairs). We identified a median of two relevant somatic mutations and one highlevel copy-number alteration per sample (range, 0-5 and 0-6, respectively). Expression of HPV and p16 was detectable in 12% and 28% of patients, respectively. Furthermore, advanced clinical stage, lack of p16 expression, and MYC and CCND1 amplifications were significantly associated with shorter time to progression or PeSCCA-specific survival. Notably, four cases harbored EGFR amplifications and one demonstrated CDK4 amplification, genes for which approved and investigational targeted therapies are available. Importantly, although paired primary tumors and lymph node metastases were largely homogeneous for relevant somatic mutations, we identified heterogeneous EGFR amplification in primary tumor/lymph node metastases in 4 of 14 cases, despite uniform EGFR protein overexpression. Likewise, activating HRAS mutations occurred in 8 of 43 cases. Taken together, we provide the first comprehensive molecular PeSCCA analysis, which offers new insight into potential precision medicine approaches for this disease, including strategies targeting EGFR.

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Section: Discussionmentioning

confidence: 95%

Genomic Profiling of Penile Squamous Cell Carcinoma Reveals New Opportunities for Targeted Therapy

et al. 2015

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“…[2][3][4] In circumcised men, HPV prevalence is lower than in uncircumcised men, and penile cancer is rare in populations that routinely practice circumcision. 5 Some published studies state that HPV16, 18,31,33,35,39,45,51,52,56,58,59,66, and 68 have been associated with intraepithelial neoplasia and carcinoma of the cervix. [6][7][8] The studies indicate that these types of HPV were considered primary high-risk (carcinogenic) genotypes.…”

Section: Resultsmentioning

confidence: 99%

High-risk Oncogenic Human Papilloma Virus Infection of the Foreskin and Microbiology of Smegma in Prepubertal Boys

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Tuncel

Baran

et al. 2015

Urology

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“…While an APOBEC signature has recently been detected in penile cancer when the HPV load was high [18], this finding was not reflected by the overall mutational load, which was not found to be significantly increased [18]. Moreover, HPV-associated penile SCCs have been shown to have a more favorable prognosis than HPV-negative tumors, which would also argue against enhanced mutagenesis and genomic instability [25,26]. In addition, the expression of APOBECs has been found to correlate only weakly with the actual APOBEC mutational signatures and HPV oncogene expression [3].…”

Section: Discussionmentioning

confidence: 96%

“…The assay can detect 15 high-risk types (16,18,31,33,35,39,45, 51, 52, 56, 58, 59, 68, 73, 82), 3 putative high-risk types (26,53,66), and 6 low-risk types (6,11,42,43,44,70). DNA for the test was extracted from formalin-fixed, paraffin-embedded sections using the DNeasy Blood and Tissue Kit (Qiagen, Hilden, Germany).…”

Section: Hpv Genotypingmentioning

confidence: 99%

APOBEC3A Expression in Penile Squamous Cell Carcinoma

et al. 2017

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Background: APOBECs (apolipoprotein B mRNA-editing catalytic polypeptides) are cytidine deaminases that have been implicated in the host defense against viruses by blocking viral replication. They have also been shown to play a role in genome hypermutation in several human cancers. An APOBEC3 hypermutation signature has been discovered in cervical cancer, which is intimately associated with infection by high-risk human papillomaviruses (HPVs). At the same time, HPV genomes themselves are subject to DNA editing by APOBECs. Similar to cervical cancer, a proportion of penile squamous cell carcinomas (SCCs) is etiologically driven by high-risk HPVs, but very little is known about the role of APOBECs in penile SCC development and progression. Methods: A series of 34 penile SCCs was analyzed for the expression of APOBEC3A protein by immunohistochemistry. HPV genotyping was carried out using a bead-based multiplex hybridization assay preceded by BSGP5+6+ primer-based amplification. Results: We found a frequent reduction of APOBEC3A protein expression in the invasive parts of the majority of HPV-negative penile SCCs. In contrast, the majority of HPV-positive penile SCCs retained APOBEC3A expression during malignant progression. Conclusion: Our results suggest that APOBEC3A expression is downregulated during progression towards invasiveness in HPV-negative penile SCC, but maintained in HPV-positive penile SCC. How high-risk HPV-infected tumor cells tolerate high APOBEC3A, which appears to exert tumor suppressive functions in HPV-negative penile SCCs, remains to be elucidated.

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Human Papillomavirus Prevalence in Invasive Penile Cancer and Association with Clinical Outcome

Abstract: High risk human papillomavirus-DNA was observed in a quarter of penile cancer cases. No relevant increase in high risk human papillomavirus prevalence in recent decades was observed. The presence of high risk human papillomavirus-DNA in penile cancer confers a survival advantage.

Cited by 104 publications

References 28 publications

Genomic Profiling of Penile Squamous Cell Carcinoma Reveals New Opportunities for Targeted Therapy

Genomic Profiling of Penile Squamous Cell Carcinoma Reveals New Opportunities for Targeted Therapy

High-risk Oncogenic Human Papilloma Virus Infection of the Foreskin and Microbiology of Smegma in Prepubertal Boys

APOBEC3A Expression in Penile Squamous Cell Carcinoma

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