Purpose: Translocation renal cell carcinoma (tRCC) is a rare, aggressive renal cell carcinoma (RCC) subtype. There is currently limited understanding on the role of molecular alterations in the pathogenesis and progression of these tumors. We investigated the association between somatic alterations and clinical outcomes in two independent cohorts profiled using DNA sequencing. Experimental Design: Twenty-two tRCCs underwent targeted sequencing [Memorial Sloan Kettering Cancer Center (MSK)-IMPACT]; a subset was profiled using exome-sequencing and combined with exome data from The Cancer Genome Atlas (TCGA) for analysis. The prognostic value of specific somatic aberrations, tumor mutation burden (TMB), and fraction of copy-number–altered genome (FCNAg) was explored. In TCGA cases, neoantigen prediction and immune cell deconvolution were performed using RNA-sequencing and exome data. Overall survival estimates were computed using the Kaplan–Meier method; time-on-treatment was calculated for 14 MSK-IMPACT patients who underwent systemic therapy. Associations between molecular features and outcomes were evaluated using nonparametric testing. Results: Copy-number aberrant tRCCs were associated with poor overall survival ( P = 0.03). Pediatric patients had tumors with lower FCNAg ( P = 0.01). In one adult case with two chronologically distinct tumor samples sequenced, we confirmed that copy-number events occurred early during evolution. TERT promoter mutations were found exclusively in high-stage tumors. We found that tRCCs displayed distinct angiogenesis and PD-L1 gene expression profiles compared with other RCC subtypes. Conclusions: Tumors molecularly defined by increased copy-number variations were associated with aggressive disease in tRCC. A higher burden of genomic events in adults compared with pediatric cases likely reflects a more aggressive clinical course. The unique immunophenotypic characteristics of tRCC merit further exploration.

中文翻译：

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易位肾细胞癌的综合基因组分析揭示了拷贝数变异是疾病进展的驱动因素。


目的：易位肾细胞癌 (tRCC) 是一种罕见的侵袭性肾细胞癌 (RCC) 亚型。目前对分子改变在这些肿瘤的发病机制和进展中的作用的了解有限。我们利用 DNA 测序对两个独立队列进行了体细胞改变与临床结果之间的关联研究。实验设计：对 22 个 tRCC 进行靶向测序 [Memorial Sloan Kettering Cancer Center (MSK)-IMPACT]；使用外显子组测序对一个子集进行分析，并结合癌症基因组图谱 (TCGA) 的外显子组数据进行分析。探索了特定体细胞畸变、肿瘤突变负荷（TMB）和拷贝数改变基因组分数（FCNAg）的预后价值。在 TCGA 案例中，使用 RNA 测序和外显子组数据进行新抗原预测和免疫细胞解卷积。使用 Kaplan-Meier 方法计算总体生存率估计值；计算了 14 名接受全身治疗的 MSK-IMPACT 患者的治疗时间。使用非参数检验评估分子特征和结果之间的关联。结果：拷贝数异常的 tRCC 与较差的总生存率相关（P = 0.03）。儿童患者的肿瘤 FCNAg 较低（P = 0.01）。在一个对两个按时间顺序不同的肿瘤样本进行测序的成人病例中，我们证实了拷贝数事件发生在进化的早期。 TERT 启动子突变仅在晚期肿瘤中发现。我们发现，与其他 RCC 亚型相比，tRCC 显示出独特的血管生成和 PD-L1 基因表达谱。结论：通过拷贝数变异增加进行分子定义的肿瘤与 tRCC 的侵袭性疾病相关。 与儿童病例相比，成人基因组事件的负担更高，可能反映出更具侵略性的临床过程。 tRCC 独特的免疫表型特征值得进一步探索。