JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation: Implications for clinical management Journal Article
| Authors: | Gupta, S.; Cheville, J. C.; Jungbluth, A. A.; Zhang, Y.; Zhang, L.; Chen, Y. B.; Tickoo, S. K.; Fine, S. W.; Gopalan, A.; Al-Ahmadie, H. A.; Sirintrapun, S. J.; Blum, K. A.; Lohse, C. M.; Hakimi, A. A.; Thompson, R. H.; Leibovich, B. C.; Berger, M. F.; Arcila, M. E.; Ross, D. S.; Ladanyi, M.; Antonescu, C. R.; Reuter, V. E. |
| Article Title: | JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation: Implications for clinical management |
| Abstract: | 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 ≥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. © 2019, United States & Canadian Academy of Pathology. |
| Journal Title: | Modern Pathology |
| Volume: | 32 |
| Issue: | 9 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2019-09-01 |
| Start Page: | 1344 |
| End Page: | 1358 |
| Language: | English |
| DOI: | 10.1038/s41379-019-0269-x |
| PUBMED: | 30996253 |
| PROVIDER: | scopus |
| PMCID: | PMC7189735 |
| DOI/URL: | |
| Notes: | Source: Scopus |
Altmetric
Citation Impact
MSK Authors
Related MSK Work