Genomic Landscape of Chinese Clear Cell Renal Cell Carcinoma Patients With Venous Tumor Thrombus Identifies Chromosome 9 and 14 Deletions and Related Immunosuppressive Microenvironment.
Genomic Landscape of Chinese Clear Cell Renal Cell Carcinoma Patients With Venous Tumor Thrombus Identifies Chromosome 9 and 14 Deletions and Related Immunosuppressive Microenvironment.
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DOI：
10.3389/fonc.2021.646338
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发表时间：
2021
影响因子：
4.7
通讯作者：
Wang B
中科院分区：
文献类型：
--
作者：
Niu S;Liu K;Xu Y;Peng C;Yu Y;Huang Q;Wu S;Cui B;Huang Y;Ma X;Zhang X;Wang B
透明细胞肾细胞癌 (ccRCC) 伴静脉瘤栓 (VTT) 与不良的临床结果相关。尽管一些研究已经检查了 ccRCC 的基因组特征，但 VTT 及其匹配的原发肿瘤的遗传图谱尚未完全阐明。收集 ccRCC 患者 (n = 25) 的 VTT 组织和匹配的原发肿瘤组织样本，以及无 VTT 的患者 (n = 25) 的原发肿瘤组织样本，并使用全外显子组测序进行分析。另外四名不适合手术的 ccRCC 患者接受了抗程序性死亡受体 1 (PD-1) 单克隆抗体（特瑞普利单抗，240 mg，Q3W，IV）治疗。通过比较伴有或不伴有 VTT 的 ccRCC 患者的原发性肾肿瘤，发现伴有 VTT 的 ccRCC 患者中 BAP1 和 KDM5C 改变的发生率相对较高，并且这些改变与肾透明细胞癌 (KIRC) 数据库中较差的总体生存率相关。根据亚克隆分析，VTT 预计主要直接源自原发性肾肿块。与匹配的原发肿瘤相比，VTT 中 CELSR2 和 TET2 改变的发生率显着更高。在患有 VTT 的 ccRCC 患者中发现 DNA 损伤修复基因的患病率增加，特别是那些涉及同源重组修复和非同源末端连接的基因。值得注意的是，VTT 的特点是整个外显子组拷贝数丢失的发生率增加 (p < 0.05)，特别是在 9 号和 14 号染色体区域。 9号和14号染色体的缺失与较差的生存率、不利的临床特征以及免疫抑制微环境的存在相关，其特征是调节性T细胞、滤泡辅助性T细胞和静息肥大细胞的浸润较高，但静息CD4记忆T细胞和CD8阳性T细胞计数较低。与匹配的原发肿瘤相比，VTT 样本中 CD4+ 和 CD8+ 肿瘤浸润淋巴细胞的数量显着降低。值得注意的是，在我们的队列中，接受抗 PD-1 治疗的 4 名患有 VTT 的 ccRCC 患者中，有 3 名的肾脏质量显着缓解，但 VTT 质量没有显着缩小。我们的研究揭示了患有 VTT 的中国 ccRCC 患者的基因谱，并确定了与已知不良结局相关的多个特征，包括基因改变和拷贝数丢失。 9 号和 14 号染色体的缺失以及相关的免疫抑制微环境可能表明 VTT 中抗 PD-1/PD-L1 单一疗法的敏感性有限。
Clear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is associated with a poor clinical outcome. Although several studies have examined the genomic features of ccRCC, the genetic profile of VTT along with its matched primary tumor has not been fully elucidated. Samples of VTT tissues and matched primary tumor tissues from ccRCC patients (n = 25), as well as primary tumor tissues from patients without VTT (n = 25) were collected and analyzed using whole-exome sequencing. Four additional ccRCC patients who were unfit for surgery were treated with an anti-programmed death receptor-1 (PD-1) monoclonal antibody (Toripalimab, 240 mg, Q3W, IV). By comparing the primary kidney tumors from ccRCC patients with or without VTT, a relatively higher prevalence of BAP1 and KDM5C alterations were found in ccRCC patients with VTT, and these alterations were associated with worse overall survival in the kidney renal clear cell carcinoma (KIRC) database. Based on subclone analysis, VTT was predicted to primarily originate directly from the primary renal mass. A significantly higher prevalence of CELSR2 and TET2 alterations were identified in the VTTs compared with the matched primary tumors. An increased prevalence of DNA damage repair genes, especially those involved in homologous recombination repair and non-homologous end joining, was found in ccRCC patients with VTT. Notably, VTT was characterized by the increase incidence of copy number loss in the whole exome (p < 0.05), particularly in the chromosome 9 and 14 regions. Deletion of chromosome 9 and 14 was associated with worse survival, unfavorable clinical features, and the presence of an immunosuppressive microenvironment, which was characterized by higher infiltration of regulatory T cells, follicular helper T cells, and resting mast cells, but lower counts of resting CD4 memory T cells and CD8 positive T cells. A significantly lower count of CD4+ and CD8+ tumor-infiltrated lymphocytes was identified in the VTT samples comparing with matched primary tumor. Of note, three out of the four ccRCC patients with VTT in our cohort who were treated with the anti-PD-1 therapy exhibited remarkable remission in the renal mass but no notable shrinkage in the VTT mass. Our study revealed the genetic profile of Chinese ccRCC patients with VTT, and identified multiple features associated with known poor outcomes, including gene alterations and copy number loss. The deletions in chromosomes 9 and 14, and the associated immunosuppressive microenvironment may indicate limited sensitivity to anti-PD-1/PD-L1 monotherapy in VTT.
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影响因子：
8.8
作者：
El-Mokadem, I.;Fitzpatrick, J.;Bondad, J.;Rauchhaus, P.;Cunningham, J.;Pratt, N.;Fleming, S.;Nabi, G.
通讯作者：
Nabi, G.
将基于SNP阵列的同源重组缺乏措施迁移到下一代乳腺癌数据。
影响因子：
5.9
作者：
Sztupinszki Z;Diossy M;Krzystanek M;Reiniger L;Csabai I;Favero F;Birkbak NJ;Eklund AC;Syed A;Szallasi Z
通讯作者：
Szallasi Z
DOI：
10.1016/j.urolonc.2011.12.006
发表时间：
2013-10-01
影响因子：
2.7
作者：
Reese, Adam C.;Whitson, Jared M.;Meng, Maxwell V.
通讯作者：
Meng, Maxwell V.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
15.9
作者：
Shenoy, Niraj;Bhagat, Tushar D.;Verma, Amit
通讯作者：
Verma, Amit