Integrated genotypic analysis of hedgehog-related genes identifies subgroups of keratocystic odontogenic tumor with distinct clinicopathological features.
Integrated genotypic analysis of hedgehog-related genes identifies subgroups of keratocystic odontogenic tumor with distinct clinicopathological features.
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DOI：
10.1371/journal.pone.0070995
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sakamoto K
中科院分区：
文献类型：
--
作者：
Shimada Y;Katsube K;Kabasawa Y;Morita K;Omura K;Yamaguchi A;Sakamoto K
牙源性角化囊性肿瘤是Gorlin综合征的一部分，也可以是一种散发性病变。Hedgehog受体PTCH 1的基因突变和杂合性丢失（洛）在KCOT的发病机制中起重要作用。然而，一些KCOT病例缺乏PTCH 1基因改变的证据，表明hedgehog途径中的其他基因可能受到影响。PTCH 2和SUFU参与GS相关肿瘤的发生，但它们在KCOT发展中的作用尚不清楚。为了阐明这些基因的作用，我们在一项研究中招募了36名KCOT患者，对其PTCH 1、PTCH 2和SUFU的整个编码区进行测序。这些基因的洛缺失和免疫组化表达，以及hedgehog信号传导的下游靶点，使用切除的KCOT组织进行检查。9例遗传性KCOT患者中发现PTCH 1突变，其中4例为新突变，但在散发性KCOT患者中未发现PTCH 1突变。在所有患者中均未发现PTCH 2或SUFU致病突变。PTCH 1和SUFU位点的洛缺失与上皮出芽相关。KCOT携带一个生殖系突变（1型）显示GLI2的核定位和频繁的组织学发现，如出芽和上皮岛，以及最高的复发率。有洛缺失但无生殖系突变的KCOT（2型）较少出现这些组织学特征，复发率较低。既无生殖系突变也无洛的KCOT（3型）由两个亚组组成，3A型和3B型，其特征分别为细胞核和细胞质GLI 2定位。3B型很少表现出萌芽和复发，表现为最友好的实体。CCND1和BCL 2的表达模式倾向于与这些亚组相关。我们的数据表明PTCH 1和SUFU在KCOT的发病机制中起着重要作用，并且基因型导向的亚组构成了具有不同潜在攻击性的实体。
Keratocystic odontogenic tumor (KCOT) arises as part of Gorlin syndrome (GS) or as a sporadic lesion. Gene mutations and loss of heterozygosity (LOH) of the hedgehog receptor PTCH1 plays an essential role in the pathogenesis of KCOT. However, some KCOT cases lack evidence for gene alteration of PTCH1, suggesting that other genes in the hedgehog pathway may be affected. PTCH2 and SUFU participate in the occurrence of GS-associated tumors, but their roles in KCOT development are unknown. To elucidate the roles of these genes, we enrolled 36 KCOT patients in a study to sequence their entire coding regions of PTCH1, PTCH2 and SUFU. LOH and immunohistochemical expression of these genes, as well as the downstream targets of hedgehog signaling, were examined using surgically-excised KCOT tissues. PTCH1 mutations, including four novel ones, were found in 9 hereditary KCOT patients, but not in sporadic KCOT patients. A pathogenic mutation of PTCH2 or SUFU was not found in any patients. LOH at PTCH1 and SUFU loci correlated with the presence of epithelial budding. KCOT harboring a germline mutation (Type 1) showed nuclear localization of GLI2 and frequent histological findings such as budding and epithelial islands, as well as the highest recurrence rate. KCOT with LOH but without a germline mutation (Type 2) less frequently showed these histological features, and the recurrence rate was lower. KCOT with neither germline mutation nor LOH (Type 3) consisted of two subgroups, Type 3A and 3B, which were characterized by nuclear and cytoplasmic GLI2 localization, respectively. Type 3B rarely exhibited budding and recurrence, behaving as the most amicable entity. The expression patterns of CCND1 and BCL2 tended to correlate with these subgroups. Our data indicates a significant role of PTCH1 and SUFU in the pathogenesis of KCOT, and the genotype-oriented subgroups constitute entities with different potential aggressiveness.
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影响因子：
2.2
作者：
Kijima, Chihiro;Miyashita, Toshiyuki;Fujii, Kiyotaka
通讯作者：
Fujii, Kiyotaka
影响因子：
11.2
作者：
Lee, Youngsoo;Miller, Heather L.;McKinnon, Peter J.
通讯作者：
McKinnon, Peter J.
影响因子：
2.9
作者：
Barnfield, PC;Zhang, XY;Hui, CC
通讯作者：
Hui, CC
影响因子：
4
作者：
EVANS, DGR;LADUSANS, EJ;FARNDON, PA
通讯作者：
FARNDON, PA
影响因子：
64.8
作者：
Jones, David T. W.;Jaeger, Natalie;Kool, Marcel;Zichner, Thomas;Hutter, Barbara;Sultan, Marc;Cho, Yoon-Jae;Pugh, Trevor J.;Hovestadt, Volker;Stuetz, Adrian M.;Rausch, Tobias;Warnatz, Hans-Joerg;Ryzhova, Marina;Bender, Sebastian;Sturm, Dominik;Pleier, Sabrina;Cin, Huriye;Pfaff, Elke;Sieber, Laura;Wittmann, Andrea;Remke, Marc;Witt, Hendrik;Hutter, Sonja;Tzaridis, Theophilos;Weischenfeldt, Joachim;Raeder, Benjamin;Avci, Meryem;Amstislavskiy, Vyacheslav;Zapatka, Marc;Weber, Ursula D.;Wang, Qi;Lasitschka, Baerbel;Bartholomae, Cynthia C.;Schmidt, Manfred;von Kalle, Christof;Ast, Volker;Lawerenz, Chris;Eils, Juergen;Kabbe, Rolf;Benes, Vladimir;van Sluis, Peter;Koster, Jan;Volckmann, Richard;Shih, David;Betts, Matthew J.;Russell, Robert B.;Coco, Simona;Tonini, Gian Paolo;Schueller, Ulrich;Hans, Volkmar;Graf, Norbert;Kim, Yoo-Jin;Monoranu, Camelia;Roggendorf, Wolfgang;Unterberg, Andreas;Herold-Mende, Christel;Milde, Till;Kulozik, Andreas E.;von Deimling, Andreas;Witt, Olaf;Maass, Eberhard;Roessler, Jochen;Ebinger, Martin;Schuhmann, Martin U.;Fruehwald, Michael C.;Hasselblatt, Martin;Jabado, Nada;Rutkowski, Stefan;von Bueren, Andre O.;Williamson, Dan;Clifford, Steven C.;McCabe, Martin G.;Collins, V. Peter;Wolf, Stephan;Wiemann, Stefan;Lehrach, Hans;Brors, Benedikt;Scheurlen, Wolfram;Felsberg, Joerg;Reifenberger, Guido;Northcott, Paul A.;Taylor, Michael D.;Meyerson, Matthew;Pomeroy, Scott L.;Yaspo, Marie-Laure;Korbel, Jan O.;Korshunov, Andrey;Eils, Roland;Pfister, Stefan M.;Lichter, Peter
通讯作者：
Lichter, Peter