%0 Journal Article
%T JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation: implications for clinical management
%J -
%D 2019
%R https://doi.org/10.1038/s41379-019-0269-x
%X Amplifications of JAK2, PD-L1, and PD-L2 at 9p24.1 lead to constitutive expression of PD-L1. This, coupled with JAK2-activation dependent upregulation of PD-L1 and adaptive/induced expression leads to higher tumor PD-L1 expression and immune evasion. Renal tumors were therefore evaluated for 9p24.1 amplifications. A combination of next generation sequencing-based copy number analysis, fluorescence in situ hybridization for JAK2/INSL6 and PD-L1/PD-L2 and immunohistochemistry for phospho-STAT3 (downstream target of JAK2), PD-L1, PD-L2, and PD-1 was performed. In this study we interrogated a ¡°Discovery¡± cohort of 593 renal tumors, a ¡°Validation¡± cohort of 398 high-grade renal tumors, The Cancer Genome Atlas (879 cases) and other public datasets (846 cases). 9p24.1 amplifications were significantly enriched in renal tumors with sarcomatoid transformation (5.95%, 15/252) when compared to all histologic subtypes in the combined ¡°Discovery¡±, ¡°Validation¡± and public datasets (16/2636, 0.6%, p£¿<£¿0.00001). Specifically, 9p24.1 amplifications amongst sarcomatoid tumors in public datasets, the ¡°Discovery¡± and ¡°Validation¡± cohorts were 7.7% (6/92), 15.1% (5/33), and 3.1% (4/127), respectively. Herein, we describe 13 cases and amplification status for these was characterized using next generation sequencing (n£¿=£¿9) and/or fluorescence in situ hybridization (n£¿=£¿10). Correlation with PD-L1 immunohistochemistry (n£¿=£¿10) revealed constitutive expression (mean H-score: 222/300, n£¿=£¿10). Analysis of outcomes based on PD-L1 expression in tumor cells performed on 282 cases (¡°Validation¡± cohort) did not reveal a significant prognostic effect and was likely reflective of advanced disease. A high incidence of constitutive PD-L1 expression in tumor cells in the ¡°Validation¡± cohort (H-Score ¡İ250/300) was noted amongst 83 rhabdoid (6%) and 127 sarcomatoid renal tumors (7.1%). This suggests additional mechanisms of constitutive expression other than amplification events. Importantly, two patients with 9p24.1-amplified sarcomatoid renal tumors showed significant response to immunotherapy. In summary, a subset of renal tumors with sarcomatoid transformation exhibits constitutive PD-L1 overexpression and these patients should be evaluated for enhanced response to immunotherapy
%U https://www.nature.com/articles/s41379-019-0269-x