关于外阴鳞状细胞癌(VSCC)的突变景观的信息很少,一种主要影响老年妇女的疾病。研究集中于目前公认的这种肿瘤的致病类型的突变模式[人乳头瘤病毒(HPV)相关(HPV-A),HPV非依赖性(HPV-I)与TP53突变(HPV-I/TP53mut),和HPV-I野生型TP53(HPV-I/TP53wt])特别罕见,并且几乎没有关于这些异常的预后意义的信息。对来自每个患者的60个VSCC和匹配的正常组织进行全外显子组DNA测序。HPV检测,还对p16,p53和错配修复蛋白进行了免疫组织化学(IHC).10例肿瘤(16.7%)被归类为HPV-A,37(61.7%)作为HPV-I/TP53mut,和13(21.6%)为HPV-I/TP53wt。TP53是最常见的突变基因(66.7%),其次是FAT1(28.3%),CDKN2A(25.0%),RNF213(23.3%),NFE2L2(20%)和PIK3CA(20%)。所有60个肿瘤(100%)均为DNA错配修复。17例肿瘤(28.3%)显示CCND1增加。双变量分析,针对FIGO阶段进行了调整,显示TP53突变,CCND1增益,两种改变的组合与无复发生存率(风险比=4.4,p<0.001)和疾病特异性生存率(风险比=6.1,p=0.002)密切相关.当使用p53IHC状态代替TP53状态并且当仅考虑HPV-IVSCC时,获得了类似的结果。然而,在后一类中,p53IHC仅在与CCND1增益组合时保持其预后影响。所有肿瘤都携带至少一种潜在可行的基因组改变。总之,具有CCND1增加的VSCC代表HPV-I/TP53mut肿瘤中的预后不良类别。所有VSCCs患者都是靶向治疗的潜在候选者。
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 FIGO stage, revealed that TP53 mutation, CCND1 gain, and the combination of the two alterations were strongly associated with impaired recurrence-free survival (hazard ratio=4.4, p<0.001) and disease-specific survival (hazard ratio=6.1, p=0.002). 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.