APOBEC3A Expression in Penile Squamous Cell Carcinoma

Abstract

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.

Genomic, transcriptomic, and viral integration profiles associated with recurrent/metastatic progression in high‐risk human papillomavirus cervical carcinomas

“…The association of APOBEC expression and activity with disease progression remains contradictory, especially with regard to HPV infection. For example, higher expression levels of APOBEC3A can be induced by HPV16 infection in oropharyngeal cancer, 62 while APOBEC3A protein levels were downregulated during invasive progression in HPV‐negative but not HPV‐positive penile squamous cell carcinomas, suggesting that HPV‐associated APOBEC3A activity is variable and context‐dependent 63 . Given that decreased APOBEC3A levels were observed as CES‐R/M group‐specific features and as unfavorable clinical outcome‐predicting features, it is assumed the APOBEC activity is repressed in metastatic tumors and may predict the disease progression and metastasis in CES with HPV infection.…”