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

Purpose N6-methyladenosine (m6A) represents the most prevalent posttranscriptional modification of mRNA and is implicated in widespread physiological processes. m6A modification is orchestrated by a dynamic interaction of methylases (‘writers’; METTL3, METTL4, METTL14, WTAP, KIAA1429) and demethylases (‘erasers’; FTO, ALKBH5). These modifications are recognized by m6A binding proteins (‘readers’; HNRNPA2B1, HNRNPC, YTHDC1, YTHDC1, YTHDF1-3) driving downstream biological effects. Dysregulated m6A modification is implicated in carcinogenesis, metastatic spread, and drug resistance across various cancer entities. Further, research has shown that m6A modification is involved in viral infection influencing both, the susceptibility of the host cell to viral infection, and replication of the virus in the host cell. To date, sparse in known regarding m6A modification in the context of vulvar (VSCC) and cervical squamous cancer (CSCC).

Methods In this study, we comprehensively examined the protein expression of m6A writers, readers and erasers by immunohistochemical staining in N=126 patients with VSCC and N=118 patients CSCC with regard to clinical outcomes. In the VSCC-cohort, HPV-dependent and HPV-independent tumors were analyzed separately.

Results Enhanced protein expression levels of METTL14, WTAP, KIAA1429, ALKBH5, HNRNPC, YTHDC1, and YTHDF3 were associated with unfavorable outcome in CSCC. In the entire VSCC study cohort irrespective of HPV status, m6A protein expression was not associated with clinical outcomes. However, in the subgroup of patients with HPV-dependent VSCC (N=23), enhanced protein expression levels of METTL3, METTL4, METTL14, YTHDC1, and YTHDF2 predicted poor prognosis.

Summary Our study point towards dysregulated m6A modification in HPV-dependent gynecologic malignancies.

Publikationsverlauf

Artikel online veröffentlicht:
11. Oktober 2022