Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
Section of Hematology Oncology, University of Oklahoma Stephenson Cancer Center, Oklahoma City, OK.
Urol Oncol. 2022 Nov;40(11):493.e1-493.e7. doi: 10.1016/j.urolonc.2022.07.002. Epub 2022 Jul 30.
Urothelial carcinoma with squamous differentiation (UCS) is the most common variant differentiation of urothelial carcinoma (UC). Although treatment is usually similar to pure UC, there is paucity of data regarding its genomic landscape and putative molecular drivers. In this study, we compared the mutational profile of tumors with UCS and UC histology.
In this IRB-approved retrospective study, patients with advanced UCS and UC undergoing tumor based comprehensive genomic profiling from a CLIA-certified laboratory were included. An independent genitourinary pathologist reviewed all cases. Patients were determined to have UCS based on presence of any component of squamous differentiation. Patients with UC having any other secondary histology variant were excluded. Genes with alterations (GA) in less than 5% of patients and variants of unknown significance were excluded from the analysis. Chi-square test was used to compare gene aberration frequency and the p-values were adjusted for false using Benjamini-Hochberg (BH) correction.
Among the 87 eligible patients with UCS (n=31) and UC (n=56), patients with UCS were more likely to be female (32.3% vs. 14.3%, p=0.047) with no significant differences in other clinicopathological features. Most common genomic alterations seen in UCS were TP53 (67.7%), KMT2D (48.4%) and ARID1A (32.3%). KMT2D mutations were significantly enriched in UCS (48.4% vs. 0%, FDR adj p <0.001, p = <0.001) compared to UC. Prevalence of CUL4A mutations was numerically higher in UCS vs. UC (12.9% vs. 1.8%, FDR adj p = 0.43, p = 0.03). Tumor mutation burden and the number of genomic aberrations per patient were not significantly different between the two groups.
These findings highlight significant enrichment of KMT2D mutations in UCS and potential role of chromatin remodeling genes as drivers and potential therapeutic targets.
具有鳞状分化的尿路上皮癌（UCS）是尿路上皮癌（UC）最常见的变异分化。虽然治疗通常与纯 UC 相似，但关于其基因组图谱和潜在的分子驱动因素的数据很少。在这项研究中，我们比较了具有 UCS 和 UC 组织学的肿瘤的突变特征。
在这项经过 IRB 批准的回顾性研究中，纳入了在经过 CLIA 认证的实验室进行基于肿瘤的全面基因组分析的晚期 UCS 和 UC 患者。一名独立的泌尿生殖系统病理学家审查了所有病例。根据存在任何鳞状分化成分，患者被确定为 UCS。排除 UC 患者中具有任何其他次要组织学变异的患者。从分析中排除了在少于 5%的患者中存在改变（GA）和意义不明的变体的基因。使用卡方检验比较基因异常频率，并用 Benjamini-Hochberg（BH）校正进行虚假调整的 p 值进行校正。
在 87 名符合条件的 UCS（n=31）和 UC（n=56）患者中，UCS 患者更有可能是女性（32.3% vs. 14.3%，p=0.047），但其他临床病理特征无显著差异。在 UCS 中最常见的基因组改变是 TP53（67.7%）、KMT2D（48.4%）和 ARID1A（32.3%）。与 UC 相比，UCS 中 KMT2D 突变明显富集（48.4% vs. 0%， FDR 调整 p <0.001，p = <0.001）。与 UC 相比，UCS 中 CUL4A 突变的发生率更高（12.9% vs. 1.8%， FDR 调整 p = 0.43，p = 0.03）。两组之间肿瘤突变负担和每个患者的基因组异常数没有显著差异。
这些发现强调了 KMT2D 突变在 UCS 中的显著富集，以及染色质重塑基因作为驱动因素和潜在治疗靶点的潜在作用。
