N6-methyladenosine RNA modification (m6A) is of prognostic value in HPV-dependent vulvar squamous cell carcinoma

Background Vulvar squamous cell carcinoma (VSCC) is an uncommon gynecologic malignancy but with an increasing incidence in recent years. Etiologically, VSCC is classified into two subtypes: HPV-dependent and HPV-independent. Localized VSCC is treated surgically and/or with radiation therapy, but for advanced, metastatic or recurrent disease, therapeutic options are still limited. N6-methyladenosine (m6A) is the most prevalent post-transcriptional messenger RNA (mRNA) modification and involved in many physiological processes. The group of m6A proteins can be further divided into: ,writers' (METTL3, METTL4, METTL14, WTAP, KIAA1429), ,erasers' (FTO, ALKBH5), and ,readers' (HNRNPA2B1, HNRNPC, YTHDC1, YTHDF1-3). Dysregulated m6A modification is implicated in carcinogenesis, progression, metastatic spread, and drug resistance across various cancer entities. Up to date, however, only little is known regarding the role of m6A in VSCC. Methods Here, we comprehensively investigated protein expression levels of a diverse set of m6A writers, readers and erasers by applying immunohistochemical staining in 126 patients with primary VSCC. Results In the entire study cohort, dominated by HPV-independent tumors, m6A protein expression was not associated with clinical outcome. However, we identified enhanced protein expression levels of the ,writers' METTL3, METTL14 and the ,reader' YTHDC1 as poor prognostic markers in the 23 patients with HPV-dependent VSCC. Conclusion Our study suggests dysregulated m6A modification in HPV-associated VSCC.

Automated summary

This study comprehensively investigated the protein expression levels of m6A writers, readers, and erasers in VSCC and found that enhanced expression levels of certain m6A proteins were associated with poor prognosis in HPV-dependent VSCC patients.