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

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; Sirintrapun, S. Joseph; 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.

doi:10.1038/s41379-019-0269-x

Cited by 52 publications

(47 citation statements)

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“…A subsequent study that included 252 sRCCs from a total dataset of 2,636 RCCs supported the findings of Malouf et al 94 by showing increased prevalence of JAK2 (9p24.1) amplifications in sRCCs: JAK2 amplifications were present in 5.95% of sRCCs compared with 0.6% of all RCC tumours (P < 0.001) 99 . Additionally, co-amplified genes at the 9p24.1 locus included PDL1 and PDL2, and these amplification events correlated with immunohistochemistry-based programmed cell death 1 ligand 1 (PDL1) expression (mean H score: 222/300, n = 10).…”

Section: Next-generation Sequencingsupporting

confidence: 64%

“…Additionally, co-amplified genes at the 9p24.1 locus included PDL1 and PDL2, and these amplification events correlated with immunohistochemistry-based programmed cell death 1 ligand 1 (PDL1) expression (mean H score: 222/300, n = 10). Amplification of PDL1 and PDL2 was often absent in low-grade epithelial components and restricted to the sarcomatoid tumour component 99 ( fig. 4).…”

Section: Next-generation Sequencingmentioning

confidence: 99%

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Sarcomatoid renal cell carcinoma: biology, natural history and management

et al. 2020

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Renal cancers are estimated to be diagnosed in 73,750 people in the USA in 2020, and to contribute to 14,830 deaths 1. The 2018 GLOBOCAN report on the global incidence of renal cancers has described 403,262 patients with renal cancer, and 175,098 deaths caused by renal cancers worldwide 2,3. Approximately 90% of all diagnosed renal parenchymal malignancies are renal cell carcinomas (RCCs) 4. A rare transformation called sarcomatoid dedifferentiation can occur in most RCC histological subtypes and portends an especially poor prognosis. RCCs in which sarcomatoid dedifferentiation has occurred are commonly referred to as sarcomatoid RCCs (sRCCs), and patients with sRCCs often present with advanced or metastatic disease and rarely survive >1 year 5-7. Sarcomatoid features are present in approximately 4-5% of all RCCs 8-11. However, this proportion can range from 1 to 29% depending on the primary histology and the reporting study 7,9-13. Although infrequently diagnosed in the localized setting (~20-40% of all sRCCs) 14,15 , approximately 20% of patients with metastatic RCC harbour sarcomatoid dedifferentiation 15. Patients commonly present with an sRCC at between 54 and 63 years of age 6,7,13,14,16,17 , and the male-to-female ratio ranges from 1.3:1 to 2:1 (refs 6,13,14,18,19). Similar to all other RCCs, the mechanisms underlying this gender difference remain unclear. However, possibilities include historical gender differences in occupational exposure or smoking habits, or the influence of sex hormones on tumour biology 20. The natural history and prognosis of sRCCs are poor, as approximately 60-80% of patients present with advanced or late-stage disease 14,15. Median survival is approximately 6-13 months and a higher percentage of sarcomatoid dedifferentiation on histology has been reported to confer a worse prognosis 6,7,11,21,22. Retrospective reports have shown reduced overall survival and cancer-specific survival in patients with increased sarcomatoid features 11,21. Compared with patients without sarcomatoid features, patients with ≥25% sarcomatoid features had ~30% increased overall risk of dying of any cause (HR 2.07, P = 0.048) 11 and those with ≥30% sarcomatoid features had a 52% increased risk of

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Section: Next-generation Sequencingsupporting

confidence: 64%

Section: Next-generation Sequencingmentioning

confidence: 99%

Sarcomatoid renal cell carcinoma: biology, natural history and management

et al. 2020

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“…Indeed, PD-L1 expression was reported in 23% of ccRCC, 10% of pRCC, 5.6% of cRCC, 30% of t RCC and 20% in collecting duct carcinoma [34,35]. An amplification of 9p24.1, locus of PD-L1, was recently identify in RCC with sarcomatoid component leading to PD-L1 constitutive expression [36].…”

Section: Immune Componentmentioning

confidence: 98%

Immunotherapy in Renal Cell Carcinoma: The Future Is Now

Deleuze

Saout

Dugay

et al. 2020

IJMS

148

132

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Renal cell carcinoma is the third type of urologic cancer and has a poor prognosis with 30% of metastatic patients at diagnosis. The antiangiogenics and targeted immunotherapies led to treatment remodeling emphasizing the role of the tumour microenvironment. However, long-term responses are rare with a high rate of resistance. New strategies are emerging to improve the efficacy and the emerging drugs are under evaluation in ongoing trials. With the different treatment options, there is an urgent need to identify biomarkers in order to predict the efficacy of drugs and to better stratify patients. Owing to the limitations of programmed death-ligand 1 (PD-L1), the most studied immunohistochemistry biomarkers, and of the tumor mutational burden, the identification of more reliable markers is an unmet need. New technologies could help in this purpose.

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“…2b). Meanwhile, PD-L1 expression could be enhanced not only by PD-L1 ampli cation but also by JAK2 activation [4,17].…”

Section: Discussionmentioning

confidence: 99%

DLBCL with amplification of JAK2/PD-L2 exhibits PMBCL-like CNA pattern and worse clinical outcome resembling those with MYD88 L265P mutation

Xue

Huang

Qiu

et al. 2020

Preprint

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Background: Recently, copy number alteration (CNA) of 9p24.1 were demonstrated in 10% of diffuse large b-cell lymphoma (DLBCL), with gene expression and mutation profiles that were similar to those of primary mediastinal large B-cell lymphoma(PMBCL). However, their CNA-based profile and clinical impact still remain unclear. Methods: Multiplex ligation-dependent probe amplification were employed to investigate the prevalence of JAK2/PD-L2 amplification in DLBCL and their CNA-based pattern of driver genes. The clinical outcome and characteristics were also analyzed. Results: Using unsupervised hierarchical clustering, a small group of DLBCL (10.5%, 8/76) was clustered together with PMBCL as Cluster_2, demonstrating amplification of JAK2 (100%,8/8) and PD-L2 (75.0%,6/8). This subgroups of DLBCL demonstrated significant higher expression of PD-L1 than those with MYD88 L265P mutation(p=0.024). And they exhibited dismal OS and PFS as compared with DLBCL_others(p=0.003 and 0.001, respectively), which is similar to DLBCL with MYD88 L265P mutation. Conclusions: DLBCL with amplification of JAK2/PD-L2 exhibits CNA pattern that is similar to PMBCL, and demonstrates unfavorable clinical outcome that resembles those with MYD88 L265P mutation. It is essential to identify this subgroup of DLBCL who may acquire more benefits from the JAK2 and PD-L1 signaling inhibition.

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

Cited by 52 publications

References 50 publications

Sarcomatoid renal cell carcinoma: biology, natural history and management

Sarcomatoid renal cell carcinoma: biology, natural history and management

Immunotherapy in Renal Cell Carcinoma: The Future Is Now

DLBCL with amplification of JAK2/PD-L2 exhibits PMBCL-like CNA pattern and worse clinical outcome resembling those with MYD88 L265P mutation

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