JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation: implications for clinical management

Sounak Gupta, John Cheville, Achim A. Jungbluth, Yanming Zhang, Lei Zhang, Ying Bei Chen, Satish K. Tickoo, Samson W. Fine, Anuradha Gopalan, Hikmat A. Al-Ahmadie, Sahussapont J. Sirintrapun, Kyle A. Blum, Christine M. Lohse, A. Ari Hakimi, R. Houston Thompson, Bradley Leibovich, Michael F. Berger, Maria E. Arcila, Dara S. Ross, Marc LadanyiCristina R. Antonescu, Victor E. Reuter

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalModern Pathology
DOIs
StateAccepted/In press - Jan 1 2019

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Renal Cell Carcinoma
Neoplasms
Kidney
Fluorescence In Situ Hybridization
Immunotherapy
Immunohistochemistry
Immune Evasion
Atlases
Up-Regulation
Genome

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation : implications for clinical management. / Gupta, Sounak; Cheville, John; 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; Berger, Michael F.; Arcila, Maria E.; Ross, Dara S.; Ladanyi, Marc; Antonescu, Cristina R.; Reuter, Victor E.

In: Modern Pathology, 01.01.2019.

Research output: Contribution to journalArticle

Gupta, S, Cheville, J, Jungbluth, AA, Zhang, Y, Zhang, L, Chen, YB, Tickoo, SK, Fine, SW, Gopalan, A, Al-Ahmadie, HA, Sirintrapun, SJ, Blum, KA, Lohse, CM, Hakimi, AA, Thompson, RH, Leibovich, B, Berger, MF, Arcila, ME, Ross, DS, Ladanyi, M, Antonescu, CR & Reuter, VE 2019, 'JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation: implications for clinical management', Modern Pathology. https://doi.org/10.1038/s41379-019-0269-x
Gupta, Sounak ; Cheville, John ; 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 ; Berger, Michael F. ; Arcila, Maria E. ; Ross, Dara S. ; Ladanyi, Marc ; Antonescu, Cristina R. ; Reuter, Victor E. / JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation : implications for clinical management. In: Modern Pathology. 2019.
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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.",
author = "Sounak Gupta and John Cheville and Jungbluth, {Achim A.} and Yanming Zhang and Lei Zhang and Chen, {Ying Bei} and Tickoo, {Satish K.} and Fine, {Samson W.} and Anuradha Gopalan and Al-Ahmadie, {Hikmat A.} and Sirintrapun, {Sahussapont J.} and Blum, {Kyle A.} and Lohse, {Christine M.} and Hakimi, {A. Ari} and Thompson, {R. Houston} and Bradley Leibovich and Berger, {Michael F.} and Arcila, {Maria E.} and Ross, {Dara S.} and Marc Ladanyi and Antonescu, {Cristina R.} and Reuter, {Victor E.}",
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T1 - JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation

T2 - implications for clinical management

AU - Gupta, Sounak

AU - Cheville, John

AU - Jungbluth, Achim A.

AU - Zhang, Yanming

AU - Zhang, Lei

AU - Chen, Ying Bei

AU - Tickoo, Satish K.

AU - Fine, Samson W.

AU - Gopalan, Anuradha

AU - Al-Ahmadie, Hikmat A.

AU - Sirintrapun, Sahussapont J.

AU - Blum, Kyle A.

AU - Lohse, Christine M.

AU - Hakimi, A. Ari

AU - Thompson, R. Houston

AU - Leibovich, Bradley

AU - Berger, Michael F.

AU - Arcila, Maria E.

AU - Ross, Dara S.

AU - Ladanyi, Marc

AU - Antonescu, Cristina R.

AU - Reuter, Victor E.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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