Molecular characterization and natural history of linear porokeratosis: a case series

Here we employed immunohistochemistry and genetic testing by whole-exome or Sanger sequencing, to characterize six cases with linear porokeratosis (LP), all having negative family history for porokeratosis (Table 1).
Histopathologically, cornoid lamellae were present in five patients. In two cases, the proximity to eccrine gland ducts led to misinterpretation of the diagnosis that was clarified by genetic testing. Porokeratosis was accompanied by increased proliferation of basal keratinocytes without evidence for increased apoptosis, and by an inflammatory infiltrate rich in CD4 and CD8 cells in three samples that were studied (Mendely Supplemental Fig. 1). The identified mutations, PMVK c.329G>A, p.R110Q and MVD c.70+5G>A have been reported before. In addition, we identified the unreported variant, MVK c.943_944del, p.L315Gfs*51. Second-hits led to loss-of-heterozygosity in LP. PMKV and MVK mutations were associated with verrucous and erythematous lesions, whereas, the MVD-associated LP were superficial and less inflammatory (Figure 1). Concerning the natural history, in all patients skin lesions grew and disseminated during childhood (Mendely Supplemental Fig. 2). At the age of 50 years, the oldest case in this series developed on the LP a squamous cell carcinoma (SCC) that was excised but recurred. Although only one LP-SCC was available for analysis, we analyzed its somatic mutations looking for insights into the drivers of carcinogenesis in LP. In the LP-SCC, 100 somatic mutations were identified and included the mutational signatures 7 (UV), 1 (“clock-like”) and 13 (AID/APOBEC family of cytidine deaminases) (Mendely Supplemental Fig. 3 and Tables). There were no typical mutations found in sporadic cutaneous SCC; the variant c.533C>T, p.L178S and a copy number gain were found in EP300, a gene reported to be genetically or epigenetically altered in various cancers.

本研究中，我们采用免疫组化技术和全外显子测序或Sanger测序的遗传检测方法，对六例线性角化棘层瘤（LP）病例进行了特征描述，所有病例均无角化棘层瘤家族史（见表1）。组织病理学检查显示，五名患者存在角质层板层。在两例病例中，由于与汗腺导管相邻而导致诊断误判，通过遗传检测得以澄清。角化棘层瘤伴随基底层角质细胞增殖增加，而无凋亡增加的证据，并在三个研究样本中观察到富含CD4和CD8细胞的炎症浸润（Mendely补充图1）。已确定的突变包括PMVK c.329G>A、p.R110Q和MVD c.70+5G>A，这些突变之前已有报道。此外，我们还鉴定了一种未报道的变异，即MVK c.943_944del，p.L315Gfs*51。第二击导致LP中杂合性丢失。PMKV和MVK突变与疣状和红斑性病变相关，而与MVD相关的LP则呈表浅且炎症较轻（图1）。关于自然史，所有患者的皮肤病变均在儿童期生长和扩散（Mendely补充图2）。在本系列病例中，年龄最大的患者在50岁时在LP上发生鳞状细胞癌（SCC），该癌肿已被切除但复发。尽管只有一例LP-SCC可供分析，但我们分析了其体细胞突变，以寻找LP致癌机制方面的见解。在LP-SCC中，共鉴定了100个体细胞突变，包括突变特征7（UV）、1（“钟表样”）和13（AID/APOBEC家族的胞嘧啶脱氨酶）（Mendely补充图3和表）。在散发性皮肤SCC中未发现典型突变；在EP300基因中发现了变异c.533C>T、p.L178S和拷贝数增加，该基因被认为在多种癌症中存在遗传或表观遗传改变。