Ermakov Mikhail S, Kashofer Karl, Regauer Sigrid
Diagnostic and Research Institute of Pathology, Medical University Graz, MedCampus Graz, Graz, Austria.
Diagnostic and Research Institute of Pathology, Medical University Graz, MedCampus Graz, Graz, Austria.
Mod Pathol. 2023 Oct;36(10):100250. doi: 10.1016/j.modpat.2023.100250. Epub 2023 Jun 21.
Penile squamous cell carcinomas (SCC) are rare cancers that arise after transforming human papillomavirus (HPV) infections or independent of HPV in the background of chronic dermatoses. Limited knowledge about genetic alterations driving penile carcinogenesis comes from studies of mainly small cohorts of typically mixed etiology. In this comparative genetic study of HPV-induced and HPV-independent invasive penile SCC of 156 patients from a single institution in a low-incidence country, hotspots of 50 cancer-relevant genes were analyzed with targeted next-generation sequencing. Seventy-nine of 156 SCC were classified as HPV induced, and 77 of 156 SCC arose independent of HPV. Only 28 (35%) of 79 HPV-induced penile SCC, but 69 (90%) of 77 HPV-independent SCC carried somatic gene mutations. PIK3CA, FGFR3, and FBXW7 mutations occurred in both groups in similar numbers as seen in other human cancers. In contrast, mutations in TP53 (44/77; 57%), CDKN2A (35/77; 45%), and HRAS (13/77; 17%) genes occurred with one exception of a HIV positive patient exclusively in HPV-independent SCC with a frequent co-occurrence of TP53 and CDKN2A mutations (28/77; 42%). Mutations in multiple genes occurred in 9 (11%) of 79 HPV-induced SCC versus 47 (62%) of 77 HPV-independent SCC (χ; P < .001). More than one mutation per gene (multi hits) was characteristic for HPV-independent SCC in 14 (18%) of 77 compared with only 3 (4%) of 79 HPV-induced SCC (χ; P < .001). The total number of mutations in HPV-induced penile SCC (47 mutations) was significantly lower than that in HPV-independent SCC (143 mutations; Welsh test; P < .001). The presence of somatic driver gene mutations did not correlate with the age of patients, histology, or tumor stage of the primary SCC in either etiologic group, suggesting that acquisition of driver gene mutations is an early event after invasion. This large cohort analysis identified characteristic differences in mutational landscapes for the 2 etiologies. While genetic mutations in tumor suppressor genes drive HPV-independent penile carcinogenesis, oncogenic action of E6 and E7 substitute for mutations in HPV-induced SCC. A subgroup of patients with advanced SCC may be candidates for targeted therapy and clinical trials, although the majority of advanced penile SCC remain a therapeutic challenge.
阴茎鳞状细胞癌（SCC）是一种罕见的癌症，它在人乳头瘤病毒（HPV）感染转化后或在慢性皮肤病背景下独立于HPV发生。关于驱动阴茎癌发生的基因改变的了解有限，主要来自对病因通常混合的小队列研究。在这项对来自低发病率国家单一机构的156例患者的HPV诱导型和HPV非依赖型浸润性阴茎SCC的比较基因研究中，通过靶向二代测序分析了50个与癌症相关基因的热点区域。156例SCC中，79例被归类为HPV诱导型，77例独立于HPV发生。在79例HPV诱导的阴茎SCC中，只有28例（35%）携带体细胞基因突变，而在77例HPV非依赖型SCC中，有69例（90%）携带体细胞基因突变。PIK3CA、FGFR3和FBXW7突变在两组中的发生数量与其他人类癌症相似。相比之下，TP53（44/77；57%）、CDKN2A（35/77；45%）和HRAS（13/77；17%）基因的突变，除了一名HIV阳性患者外，仅在HPV非依赖型SCC中出现，且TP53和CDKN2A突变经常同时发生（28/77；42%）。79例HPV诱导的SCC中有9例（11%）发生多个基因的突变，而77例HPV非依赖型SCC中有47例（62%）发生多个基因的突变（χ检验；P < 0.001）。在77例HPV非依赖型SCC中，14例（18%）每个基因有不止一个突变（多重打击），而79例HPV诱导的SCC中只有3例（4%）（χ检验；P < 0.001）。HPV诱导的阴茎SCC中的突变总数（47个突变）显著低于HPV非依赖型SCC中的突变总数（143个突变；威尔士检验；P < 0.001）。在任一病因组中，体细胞驱动基因突变的存在与患者年龄、组织学或原发性SCC的肿瘤分期均无相关性，这表明驱动基因突变的获得是侵袭后的早期事件。这项大型队列分析确定了两种病因在突变图谱上的特征差异。虽然肿瘤抑制基因的基因突变驱动HPV非依赖型阴茎癌发生，但E6和E7的致癌作用替代了HPV诱导型SCC中的基因突变。尽管大多数晚期阴茎SCC仍然是治疗上的挑战，但晚期SCC患者亚组可能是靶向治疗和临床试验的候选者。
