| Autor: |
Gupta, Sounak, Cheville, John C., Jungbluth, Achim A., Zhang, Yanming, Zhang, Lei, Chen, Ying-Bei, Tickoo, Satish K., Fine, Samson W., Gopalan, Anuradha, Al-Ahmadie, Hikmat A., Sirintrapun, Sahussapont J., Blum, Kyle A., Lohse, Christine M., Hakimi, A.Ari, Thompson, R.Houston, Leibovich, Bradley C., Berger, Michael F., Arcila, Maria E., Ross, Dara S., Ladanyi, Marc, Antonescu, Cristina R., Reuter, Victor E. |
| Zdroj: |
Modern Pathology; September 2019, Vol. 32 Issue: 9 p1344-1358, 15p |
| Abstrakt: |
Amplifications of JAK2, PD-L1, and PD-L2at 9p24.1 lead to constitutive expression of PD-L1. This, coupled with JAK2-activation dependent upregulation of PD-L1and 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/INSL6and PD-L1/PD-L2and 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 ≥250/300) 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. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
Full text from SpringerLink