CSN1 Somatic Mutations in Penile Squamous Cell Carcinoma.
CSN1 Somatic Mutations in Penile Squamous Cell Carcinoma.
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DOI：
10.1158/0008-5472.can-15-3134
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发表时间：
2016-08-15
期刊：
影响因子：
11.2
通讯作者：
Kelly JD
中科院分区：
文献类型：
--
作者：
Feber A;Worth DC;Chakravarthy A;de Winter P;Shah K;Arya M;Saqib M;Nigam R;Malone PR;Tan WS;Rodney S;Freeman A;Jameson C;Wilson GA;Powles T;Beck S;Fenton T;Sharp TV;Muneer A;Kelly JD
除了与HPV感染的相关性外，对决定阴茎癌发展的遗传改变知之甚少。虽然阴茎癌在发达国家很少见，但它在发展中国家造成了重大负担。在这里，我们报告了全外显子组测序（WES）的结果，以确定阴茎癌的体细胞突变景观。对27名接受手术切除的患者的阴茎癌和匹配的生殖系DNA进行了WES。在一个独立的70名患者队列中进行候选基因的靶向重测序。突变数据还与来自相同患者的DNA甲基化和拷贝数信息相结合。我们在HPV阴性疾病中鉴定了HPV相关的APOBEC突变特征和NpCpG特征。我们还发现了新的阴茎癌肿瘤抑制基因CSN1（GPS1）和FAT1的复发突变。CSN1突变体在细胞中的表达导致与AGO2在细胞质P体中共定位，最终导致miRNA介导的基因沉默的丧失，这可能有助于疾病的病因学。我们的研究结果代表了阴茎癌体细胞改变的第一次全面分析，突出了这种恶性肿瘤改变的复杂景观。
Other than an association with HPV infection, little is known about the genetic alterations determining the development of penile cancer. Although penile cancer is rare in the developed world, it presents a significant burden in developing countries. Here, we report the findings of whole-exome sequencing (WES) to determine the somatic mutational landscape of penile cancer. WES was performed on penile cancer and matched germline DNA from 27 patients undergoing surgical resection. Targeted resequencing of candidate genes was performed in an independent 70 patient cohort. Mutation data were also integrated with DNA methylation and copy-number information from the same patients. We identified an HPV-associated APOBEC mutation signature and an NpCpG signature in HPV-negative disease. We also identified recurrent mutations in the novel penile cancer tumor suppressor genes CSN1(GPS1) and FAT1. Expression of CSN1 mutants in cells resulted in colocalization with AGO2 in cytoplasmic P-bodies, ultimately leading to the loss of miRNA-mediated gene silencing, which may contribute to disease etiology. Our findings represent the first comprehensive analysis of somatic alterations in penile cancer, highlighting the complex landscape of alterations in this malignancy.