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Abstract
Introduction/Background There is limited information on the mutational landscape of vulvar squamous cell carcinoma (VSCC) and the mutational patterns of its main ethio-pathogenic types: human papillomavirus-associated VSCC (HPV-associated), HPV-independent VSCC with TP53 mutation (HPV-independent/TP53mut) and HPV-independent VSCC with wild-type TP53 (HPV-independent/TP53wt). Besides, the prognostic implications of the molecular abnormalities associated with VSCC have been poorly explored.
Methodology Whole exome DNA sequencing of 60 VSCC and matched normal tissue for each individual was performed on an Illumina NovaSeq6000. Somatic point mutations and copy number alterations were analyzed. HPV detection and p16 immunohistochemistry were conducted, as well as microsatellite instability scoring. Uni- and multivariate analyses were performed to evaluate molecular risk factors for recurrence-free and disease-specific survival.
Results Ten tumors were classified as HPV-associated, 37 as HPV-independent/TP53mut, and 13 as HPV-independent/TP53wt. TP53 was the predominant mutation (66.7%), followed by FAT1 (28.3%), CDKN2A (25.0%), RNF213 (23.3%), NFE2L2 (20%) and PIK3CA (20%). RAD50 was identified as a tumor driver in HPV-associated tumors; TP53, NFE2L2, and PIK3CA were identified as tumor drivers in HPV-independent/TP53mut VSCC, and DNM2 in HPV-independent/TP53wt tumors. High rates of microsatellite instability were identified (45/60; 75.0%). On multivariate analysis, HPV status, TP53 mutations, CCND1 gains, and particularly, both alterations combined were significantly associated with shorter recurrence-free and disease-specific survival (figure 1). All the 60 patients (100%) carried at least one potentially actionable genomic alteration.
Conclusion HPV-associated VSCC, HPV-independent/TP53mut VSCC and HPV-independent/TP53wt VSCC share a substantial number of mutations and altered pathways, but harbor distinct tumor driver genes and prognostic features. VSCC patients harboring both TP53 mutations and CCND1 gains have particularly adverse survival. A large part of patients in this series harbored at least one potentially actionable genomic alteration.
Disclosures Project ‘PI20/00368; Caracterización genómica de los carcinomas de vulva independientes de virus del papiloma humano y de sus precursores’, funded by Instituto de Salud Carlos III and co-funded by the European Union (ERDF) ‘A way to make Europe’.
