Facultat de Medicina i Ciències de la Salut, Department de Fonaments Clinics, Universitat de Barcelona, Barcelona, Spain; Barcelona Institute of Global Health (ISGlobal)-University of Barcelona, Barcelona, Spain.
Barcelona Institute of Global Health (ISGlobal)-University of Barcelona, Barcelona, Spain; Department of Pathology, Hospital Clínic of Barcelona-University of Barcelona, Barcelona, Spain.
Mod Pathol. 2024 Oct;37(10):100574. doi: 10.1016/j.modpat.2024.100574. Epub 2024 Jul 31.
Very little information is available on the mutational landscape of vulvar squamous cell carcinoma (VSCC), a disease that mainly affects older women. Studies focusing on the mutational patterns of the currently recognized etiopathogenic types of this tumor (human papillomavirus [HPV]-associated [HPV-A], HPV-independent [HPV-I] with TP53 mutation [HPV-I/TP53mut], and HPV-I with wild-type TP53 [HPV-I/TP53wt]) are particularly rare, and there is almost no information on the prognostic implications of these abnormalities.Whole-exome DNA sequencing of 60 VSCC and matched normal tissues from each patient was performed. HPV detection, immunohistochemistry (IHC) for p16, p53, and mismatch repair proteins were also performed. Ten tumors (16.7%) were classified as HPV-A, 37 (61.7%) as HPV-I/TP53mut, and 13 (21.6%) as HPV-I/TP53wt. TP53 was the most frequently mutated gene (66.7%), followed by FAT1 (28.3%), CDKN2A (25.0%), RNF213 (23.3%), NFE2L2 (20%) and PIK3CA (20%). All the 60 tumors (100%) were DNA mismatch repair proficient. Seventeen tumors (28.3%) showed CCND1 gain. Bivariate analysis, adjusted for International Federation of Gynecology and Obstetrics stage, revealed that TP53 mutation, CCND1 gain, and the combination of the 2 alterations were strongly associated with impaired recurrence-free survival (hazard ratio, 4.4; P < .001) and disease-specific survival (hazard ratio, 6.1; P = .002). Similar results were obtained when p53 IHC status was used instead of TP53 status and when considering only HPV-I VSCC. However, in the latter category, p53 IHC maintained its prognostic impact only in combination with CCND1 gains. All tumors carried at least one potentially actionable genomic alteration. In conclusion, VSCCs with CCND1 gain represent a prognostically adverse category among HPV-I/TP53mut tumors. All patients with VSCCs are potential candidates for targeted therapy.
外阴鳞状细胞癌 (VSCC) 的突变景观信息很少，这种疾病主要影响老年女性。目前针对这种肿瘤的公认病因类型（人乳头瘤病毒 [HPV]-相关 [HPV-A]、HPV 不相关 [HPV-I] 伴 TP53 突变 [HPV-I/TP53mut] 和 HPV-I 伴野生型 TP53 [HPV-I/TP53wt]）的突变模式的研究特别少见，几乎没有关于这些异常的预后意义的信息。对 60 例 VSCC 患者的肿瘤组织及其相应的正常组织进行了全外显子组 DNA 测序。还进行了 HPV 检测、p16、p53 和错配修复蛋白的免疫组化 (IHC)。10 例肿瘤 (16.7%) 被归类为 HPV-A，37 例 (61.7%) 为 HPV-I/TP53mut，13 例 (21.6%) 为 HPV-I/TP53wt。TP53 是最常突变的基因（66.7%），其次是 FAT1（28.3%）、CDKN2A（25.0%）、RNF213（23.3%）、NFE2L2（20%）和 PIK3CA（20%）。所有 60 例肿瘤（100%）均具有 DNA 错配修复功能。17 例肿瘤（28.3%）显示 CCND1 获得。调整国际妇产科联盟分期的双变量分析显示，TP53 突变、CCND1 获得以及这两种改变的联合与无复发生存率（危险比，4.4；P<.001）和疾病特异性生存率（危险比，6.1；P =.002）受损显著相关。当使用 p53 IHC 状态代替 TP53 状态以及仅考虑 HPV-I VSCC 时，得到了相似的结果。然而，在后一类中，p53 IHC 仅在与 CCND1 获得联合时才保持其预后意义。所有肿瘤均携带至少一种潜在的可靶向基因组改变。总之，CCND1 获得的 VSCC 代表 HPV-I/TP53mut 肿瘤中预后不良的一类。所有 VSCC 患者都是靶向治疗的潜在候选者。
