XVII型胶原蛋白α1（COL17A1）在表皮-真皮连接处编码半网粒蛋白，其变体与起泡性皮肤病有关。最近在啮齿动物中的实验表明，Col17a1在表皮起源的干细胞和黑色素瘤癌变中起关键作用。在本研究中,使用日本老年单核苷酸多态性数据库中的索引连续尸检病例，调查了COL17A1中的种系变异是否与皮肤癌和其他癌症类型相关(n=2,343；平均年龄，80年）。该数据库包括12名皮肤癌患者。分析外显子组芯片上的总共53个COL17A1错义变体。一种变体，p.Ser1029Ala(rs118166857),其次要等位基因频率为1.0%，表现出与皮肤癌相关的名义上的阳性迹象[Fisher精确P=0.002，比值比（OR）=16.93，95％CI：4.44-64.64]。在2/2的粘膜恶性黑色素瘤（mMM）患者和1/3的乳腺外Paget病患者中检测到这种变异，在所有非黑色素瘤患者中，例如，鳞状细胞癌和基底细胞癌。在数据库中搜索了其他癌症类型，p.Ser1029Ala变异与乳腺癌名义上相关（P=0.006，OR=4.17，95％CI：1.72-10.11）。在两种MMM情况下，55个癌症易感基因（包括肿瘤蛋白53，BRCA1/2和错配修复基因）的靶向外显子组测序未检测到明显的致病变异，但在axin2，DNA定向聚合酶ζ催化亚基和contactin6中显示出未知意义的变体。由于COL17A1为黑素细胞干细胞提供了一个利基，假设COL17A1胞外域中的p.Ser1029Ala变体可能会影响微环境，例如，细胞竞争。这是从人类尸检病例中产生的有效假设，需要进一步的流行病学和分子生物学验证。
Collagen type XVII α1 (COL17A1) encodes a hemidesmosomal protein at the epidermal-dermal junction and its variants are implicated in blistering skin diseases. Recent experiments in rodents revealed that Col17a1 has critical roles in stem cells of epidermal origin and in melanoma carcinogenesis. In the present
study, it was investigated whether germline variants in COL17A1 are associated with skin cancer and other cancer types using indexed consecutive autopsy cases from the Japanese Geriatric Single Nucleotide Polymorphism database (n=2,343; mean age, 80 years). The database included 12 patients with skin cancer. A total of 53 COL17A1 missense variants on an exome chip were analyzed. One variant, p.Ser1029Ala (rs118166857), which had a minor allele frequency of 1.0%, exhibited a nominal positive sign of association with skin cancer [Fisher\'s exact P=0.002, odds ratio (OR)=16.93, 95% CI: 4.44-64.64]. This variant was detected in 2/2 patients with mucosal malignant melanoma (mMM) and 1/3 patients with extramammary Paget\'s disease, and in none of the patients with non-melanoma cancer, e.g., squamous cell and basal cell carcinoma. Other cancer types were searched in the database and the p.Ser1029Ala variant was indicated to be nominally associated with breast cancer (P=0.006, OR=4.17, 95% CI: 1.72-10.11). In the two mMM cases, targeted exome sequencing of 55 cancer-predisposing genes (including tumor protein 53, BRCA1/2 and mismatch repair genes) detected no apparent pathogenic variants, but revealed variants of unknown significance in axin 2, DNA directed polymerase ζ catalytic subunit and contactin 6. Since COL17A1 provides a niche for melanocyte stem cells, it was hypothesized that the p.Ser1029Ala variant in the COL17A1 ectodomain may affect the microenvironment, e.g., the cell competition. This is a working hypothesis generated from human autopsy cases and warrants further epidemiological and molecular biological validation.
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