Background Vulvar cancer (VC) can be sub-classified by human papilloma virus (HPV) status. HPV negative VCs frequently harbour TP53 mutations, however in-depth analysis of other potential molecular genetic alterations is lacking. We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers. Methods We performed targeted next generation sequencing (17 genes), p53 immunohistochemistry and HPV-testing on 36 VC and 82 precursors (sequencing cohort). Subsequently, the prognostic significance of the three subtypes identified in the sequencing cohort was assessed in a series of 236 VC-patients (follow-up cohort). Results Frequent recurrent mutations were identified in HPV negative vulvar (pre)cancers in TP53 (42% and 68%), NOTCH1 (28% and 41%) and HRAS (20% and 31%). Mutation frequency in HPV positive vulvar (pre)cancers was significantly lower (p-value = 0.001). Furthermore, a substantial subset of the HPV negative precursors (35/60, 58.3%) and VC (10/29, 34.5%) were TP53 wild type (wt), suggesting a third, not-previously described, molecular subtype. Clinical outcomes in the three different subtypes (HPV+, HPV-/p53wt, HPV-/p53abn) were evaluated in a follow-up cohort consisting of 236 VC patients. Local recurrence rate was 5.3% for HPV+, 16.3% for HPV-/p53wt and 22.6% for HPV-/p53abn tumors (p=0.044). HPV positivity remained an independent prognostic factor for favourable outcome in the multivariable analysis (p=0.020). Conclusion HPV- and HPV+ vulvar (pre)cancers display striking differences in somatic mutation patterns. HPV-/p53wt VC appear to be a distinct clinicopathologic subgroup with frequent NOTCH1 mutations. HPV+ VC have a significant lower local recurrence rate, independent of clinicopathological variables, opening opportunities for reducing overtreatment in VC.
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