ARID1A alterations are associated with FGFR3-wild type, poor-prognosis, urothelial bladder tumors.
ARID1A alterations are associated with FGFR3-wild type, poor-prognosis, urothelial bladder tumors.
复制标题
DOI：
10.1371/journal.pone.0062483
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Real FX
中科院分区：
文献类型：
--
作者：
Balbás-Martínez C;Rodríguez-Pinilla M;Casanova A;Domínguez O;Pisano DG;Gómez G;Lloreta J;Lorente JA;Malats N;Real FX
膀胱尿路上皮癌（UBC）在临床、病理、遗传和表观遗传水平上具有异质性。外显子组测序已确定 ARID1A 是一种新型抑癌基因，编码 UBC 中突变的染色质重塑蛋白。在这里，我们评估了两个 UBC 患者系列中 ARID1A 的改变。在第一个肿瘤系列中，我们分析了 52 个原发性 UBC 中的外显子 2-20，发现所有突变肿瘤都属于侵袭性 UBC 表型（高级非肌肉侵袭性和肌肉侵袭性肿瘤）（P = 0.05）。在第二个系列 (n = 84) 中，我们使用免疫组织化学（突变分析的替代方法）评估 ARID1A 表达，发现表达缺失随着阶段/级别的升高而增加，与 FGFR3 过表达呈负相关 (P = 0.03)，但与 p53 过表达不相关 (P = 0.30)。我们还分析了同一组肿瘤中细胞角蛋白的表达，并使用无监督聚类发现 ARID1A 表达缺失的肿瘤通常是 KRT5/6 低的。在该患者系列中，ARID1A 表达缺失也与较差的预后相关，这可能反映了在较高阶段和级别的肿瘤中发现的缺失发生率较高。这两组患者的独立研究结果强烈支持这样的观点，即 ARID1A 失活是主要发生在 FGFR3 野生型肿瘤中的膀胱癌发生的关键因素。
Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological, genetic, and epigenetic levels. Exome sequencing has identified ARID1A as a novel tumor suppressor gene coding for a chromatin remodeling protein that is mutated in UBC. Here, we assess ARID1A alterations in two series of patients with UBC. In the first tumor series, we analyze exons 2–20 in 52 primary UBC and find that all mutant tumors belong to the aggressive UBC phenotype (high grade non-muscle invasive and muscle invasive tumors) (P = 0.05). In a second series (n = 84), we assess ARID1A expression using immunohistochemistry, a surrogate for mutation analysis, and find that loss of expression increases with higher stage/grade, it is inversely associated with FGFR3 overexpression (P = 0.03) but it is not correlated with p53 overexpression (P = 0.30). We also analyzed the expression of cytokeratins in the same set of tumor and find, using unsupervised clustering, that tumors with ARID1A loss of expression are generally KRT5/6-low. In this patient series, loss of ARID1A expression is also associated with worse prognosis, likely reflecting the higher prevalence of losses found in tumors of higher stage and grade. The independent findings in these two sets of patients strongly support the notion that ARID1A inactivation is a key player in bladder carcinogenesis occurring predominantly in FGFR3 wild type tumors.
登录
查看更多内容
DOI：
10.1126/science.1226344
发表时间：
2012-10-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Iyer G;Hanrahan AJ;Milowsky MI;Al-Ahmadie H;Scott SN;Janakiraman M;Pirun M;Sander C;Socci ND;Ostrovnaya I;Viale A;Heguy A;Peng L;Chan TA;Bochner B;Bajorin DF;Berger MF;Taylor BS;Solit DB
通讯作者：
Solit DB
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
15.9
作者：
Hafner, Christian;van Oers, Johanna M. M.;Hartmann, Arndt
通讯作者：
Hartmann, Arndt
影响因子：
23.4
作者：
Guey, Lin T.;Garcia-Closas, Montserrat;Murta-Nascimento, Cristiane;Lloreta, Josep;Palencia, Laia;Kogevinas, Manolis;Rothman, Nathaniel;Vellalta, Gemma;Luz Calle, M.;Marenne, Gaelle;Tardon, Adonina;Carrato, Alfredo;Garcia-Closas, Reina;Serra, Consol;Silverman, Debra T.;Chanock, Stephen;Real, Francisco X.;Malats, Nuria
通讯作者：
Malats, Nuria
影响因子：
11.2
作者：
Lopez-knowles, Elena;Hernandez, Silvia;Real, Francisco X.
通讯作者：
Real, Francisco X.