Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Cell Rep. 2022 Jan 4;38(1):110190. doi: 10.1016/j.celrep.2021.110190.
Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8 T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.
易位性肾细胞癌（tRCC）是一种特征不明显的肾癌亚型，由 MiT/TFE 基因融合驱动。在这里，我们通过对基因组、临床试验和回顾性队列中鉴定的 152 例 tRCC 患者的综合分析，定义了 tRCC 的特征。除了 MiT/TFE 融合和 9p21.3 染色体的纯合性缺失（占病例的 19.2%）外，大多数 tRCC 仅有少数体细胞改变。在转录水平上，tRCC 显示出增强的 NRF2 驱动的抗氧化反应，这与对靶向治疗的耐药性有关。一致地，我们发现接受血管内皮生长因子受体抑制剂（VEGFR-TKIs）治疗的 tRCC 患者的预后比接受免疫检查点抑制剂（ICI）治疗的患者差。通过多参数免疫荧光，我们发现肿瘤浸润了 CD8 T 细胞，尽管这些 T 细胞具有不同于透明细胞肾细胞癌的衰竭免疫表型。我们的研究结果全面定义了 tRCC 的临床和分子特征，并可能激发新的治疗假说。
