Genomic Characterization of Upper Tract Urothelial Carcinoma.
Genomic Characterization of Upper Tract Urothelial Carcinoma.
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DOI：
10.1016/j.eururo.2015.07.039
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发表时间：
2015-12
期刊：
影响因子：
23.4
通讯作者：
Coleman JA
中科院分区：
文献类型：
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作者：
Sfakianos JP;Cha EK;Iyer G;Scott SN;Zabor EC;Shah RH;Ren Q;Bagrodia A;Kim PH;Hakimi AA;Ostrovnaya I;Ramirez R;Hanrahan AJ;Desai NB;Sun A;Pinciroli P;Rosenberg JE;Dalbagni G;Schultz N;Bajorin DF;Reuter VE;Berger MF;Bochner BH;Al-Ahmadie HA;Solit DB;Coleman JA
尽管上尿路尿路上皮癌（UTUC）和膀胱尿路上皮癌（UCB）肿瘤具有相似的组织学外观，但它们在流行病学和临床病理学上存在明显差异。探讨UTUC和UCB之间的差异是否源于内在的生物多样性。使用定制的下一代测序测定法分析来自UTUC（n = 83）和UCB（n = 102）患者的肿瘤和生殖系DNA，以鉴定300个癌症相关基因中的体细胞突变和拷贝数改变。我们描述了UTUC中的共突变模式和拷贝数改变。我们还比较了高级别UTUC（n = 59）和高级别UCB（n = 102）的突变频率。高级别UTUC和UCB的比较显示，体细胞改变的患病率有显着差异。在高级别UTUC中更常见的改变包括成纤维细胞生长因子受体3（FGFR 3; 35.6% vs 21.6%; p = 0.065），哈维大鼠肉瘤病毒癌基因同源物（HRAS; 13.6% vs 1.0%; p = 0.001）和细胞周期蛋白依赖性激酶抑制剂2B（p15，抑制CDK 4）（CDKN 2B; 15.3% vs 3.9%; p = 0.016）。在高级别UTUC中突变频率较低的基因包括肿瘤蛋白p53（TP 53; 25.4% vs 57.8%; p < 0.001）、视网膜母细胞瘤1（RB 1; 0.0% vs 18.6%; p < 0.001）和AT丰富的相互作用结构域1A（SWI样）（ARID 1A; 13.6% vs 27.5%; p = 0.050）。由于我们的测定仅限于靶向组中的基因组改变，因此未分析罕见突变和表观遗传变化。高级别UTUC肿瘤显示出与高级别UCB相似的遗传改变谱。然而，包括HRAS、TP 53和RB 1在内的几种复发突变基因的患病率存在显着差异。随着相关靶向抑制剂的开发和测试，这些结果可能对尿路上皮癌患者的位点特异性管理具有重要意义。上尿路上皮癌（UTUC）与尿路上皮膀胱癌的下一代测序比较发现，两种癌症类型中存在相似的突变，但频率不同，这表明可能需要独特的管理策略。发现UTUC肿瘤具有高突变率，可以用新疗法靶向。
Despite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences. To investigate whether the differences between UTUC and UCB result from intrinsic biological diversity. Tumor and germline DNA from patients with UTUC (n = 83) and UCB (n = 102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy-number alterations in 300 cancer-associated genes. We described co-mutation patterns and copy-number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n = 59) and high-grade UCB (n = 102). Comparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Alterations more common in high-grade UTUC included fibroblast growth factor receptor 3 (FGFR3; 35.6% vs 21.6%; p = 0.065), Harvey rat sarcoma viral oncogene homolog (HRAS; 13.6% vs 1.0%; p = 0.001), and cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) (CDKN2B; 15.3% vs 3.9%; p = 0.016). Genes less frequently mutated in high-grade UTUC included tumor protein p53 (TP53; 25.4% vs 57.8%; p < 0.001), retinoblastoma 1 (RB1; 0.0% vs 18.6%; p < 0.001), and AT rich interactive domain 1A (SWI-like) (ARID1A; 13.6% vs 27.5%; p = 0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed. High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma. Comparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.