PDF(Pubmed)
Abstract：
Because of long-term immunosuppression, solid organ transplant recipients are at increased risk for keratinocyte cancer. We matched solid organ transplant patients (n = 150), cases with keratinocyte cancers and tumor-free controls, considering the most important risk factors for keratinocyte cancer in solid organ transplant recipients. Using whole exome data of germline DNA from this patient cohort, we identified several genetic loci associated with the occurrence of multiple keratinocyte cancers. We found one genome-wide significant association of a common single nucleotide polymorphism located in EXOC3 (rs72698504). In addition, we found several variants with a p-value of less than 10-5 associated with the number of keratinocyte cancers. These variants were located in the genes CYB561, WASHC1, PITRM1-AS1, MUC8, ABI3BP, and THBS2-AS1. Using whole exome sequencing data, we performed groupwise tests for rare missense variants in our dataset and found robust associations (p < 10-6, Burden Zeggini test) between MC1R, EPHA8, EPO, MYCT1, ADGRG3, and MGME1 and keratinocyte cancer. Thus, overall, we detected genes involved in pigmentation/UV protection, tumor suppression, immunomodulation, intracellular traffic, and response to UV as genetic risk factors for multiple keratinocyte cancers in solid organ transplant recipients. We also grouped selected genes to pathways and found a selection of genes involved in the \"cellular response to UV\" to be significantly associated with multiple keratinocyte cancers.
摘要：
因为长期的免疫抑制,实体器官移植受者患角质形成细胞癌的风险增加.我们匹配实体器官移植患者（n=150），角质形成细胞癌和无肿瘤对照的病例，考虑到实体器官移植受者角质形成细胞癌的最重要风险因素。使用来自该患者队列的种系DNA的整个外显子组数据，我们确定了几个与多种角质形成细胞癌发生相关的基因位点.我们发现位于EXOC3（rs72698504）中的一个常见单核苷酸多态性与全基因组的显着关联。此外,我们发现一些p值小于10-5的变异与角质形成细胞癌的数量相关.这些变体位于CYB561，WASHC1，PITRM1-AS1，MUC8，ABI3BP，和THBS2-AS1。使用整个外显子组测序数据，我们对我们的数据集中的罕见错义变体进行了分组测试，并发现MC1R之间的强关联（p<10-6，BurdenZeggini检验），EPHA8EPO,MYCT1、ADGRG3和MGME1与角质形成细胞癌。因此，总的来说,我们检测到与色素沉着/紫外线保护有关的基因，肿瘤抑制，免疫调节,细胞内交通，和对紫外线的反应是实体器官移植受体中多种角质形成细胞癌的遗传危险因素。我们还将选择的基因分组到通路中，并发现参与“细胞对紫外线的反应”的基因选择与多种角质形成细胞癌症显着相关。
