Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation.
Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation.
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DOI：
10.1038/modpathol.2017.153
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Solomon DA
中科院分区：
文献类型：
--
作者：
Goode B;Joseph NM;Stevers M;Van Ziffle J;Onodera C;Talevich E;Grenert JP;Yeh I;Bastian BC;Phillips JJ;Garg K;Rabban JT;Zaloudek C;Solomon DA
腺瘤样瘤是附睾最常见的肿瘤，组织学上相似的腺瘤样瘤也常发生在子宫和输卵管。为了研究这些肿瘤的分子发病机制，我们对31例男性和女性生殖道腺瘤样肿瘤进行了基因组分析。我们发现所有肿瘤都在TRAF 7基因中存在体细胞错义突变，该基因编码属于肿瘤坏死因子受体相关因子（TRAFs）家族的E3泛素连接酶。这些突变全部聚集在蛋白质C末端的WD 40重复结构域内的五个复发热点之一中。体外功能研究显示，突变型而非野生型TRAF 7的表达导致核因子-κ B（NF-kB）磷酸化增加和L1细胞粘附分子（L1 CAM）表达增加，L1 CAM是NF-kB途径活化的标志物。免疫组化显示，在腺瘤样肿瘤中，L1 CAM的表达是不存在的正常间皮瘤细胞，恶性腹膜间皮瘤，和多房性腹膜包涵体囊肿。总之，这些研究表明，男性和女性生殖道的腺瘤样肿瘤在遗传上是由TRAF 7突变决定的，TRAF 7突变驱动了异常的NF-κ B通路激活。
Adenomatoid tumors are the most common neoplasm of the epididymis, and histologically similar adenomatoid tumors also commonly arise in the uterus and fallopian tube. To investigate the molecular pathogenesis of these tumors, we performed genomic profiling on a cohort of 31 adenomatoid tumors of the male and female genital tracts. We identified that all tumors harbored somatic missense mutations in the TRAF7 gene, which encodes an E3 ubiquitin ligase belonging to the family of tumor necrosis factor receptor-associated factors (TRAFs). These mutations all clustered into one of five recurrent hotspots within the WD40 repeat domains at the C-terminus of the protein. Functional studies in vitro revealed that expression of mutant but not wildtype TRAF7 led to increased phosphorylation of nuclear factor-kappa B (NF-kB) and increased expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation. Immunohistochemistry demonstrated robust L1CAM expression in adenomatoid tumors that was absent in normal mesothelial cells, malignant peritoneal mesotheliomas, and multilocular peritoneal inclusion cysts. Together, these studies demonstrate that adenomatoid tumors of the male and female genital tract are genetically defined by TRAF7 mutation that drives aberrant NF-kB pathway activation.
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影响因子：
64.8
作者：
Lawrence, T;Bebien, M;Karin, M
通讯作者：
Karin, M
影响因子：
4.4
作者：
Mattioli, I;Sebald, A;Schmitz, ML
通讯作者：
Schmitz, ML
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1093/bioinformatics/bts378
发表时间：
2012-09-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Rausch T;Zichner T;Schlattl A;Stütz AM;Benes V;Korbel JO
通讯作者：
Korbel JO
DOI：
10.1126/science.1233009
发表时间：
2013-03-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Clark VE;Erson-Omay EZ;Serin A;Yin J;Cotney J;Ozduman K;Avşar T;Li J;Murray PB;Henegariu O;Yilmaz S;Günel JM;Carrión-Grant G;Yilmaz B;Grady C;Tanrikulu B;Bakircioğlu M;Kaymakçalan H;Caglayan AO;Sencar L;Ceyhun E;Atik AF;Bayri Y;Bai H;Kolb LE;Hebert RM;Omay SB;Mishra-Gorur K;Choi M;Overton JD;Holland EC;Mane S;State MW;Bilgüvar K;Baehring JM;Gutin PH;Piepmeier JM;Vortmeyer A;Brennan CW;Pamir MN;Kiliç T;Lifton RP;Noonan JP;Yasuno K;Günel M
通讯作者：
Günel M