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Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.

Ziad BakounyDavid A BraunSachet A ShuklaWenting PanXin GaoYue HouAbdallah FlaifelStephen TangAlice Bosma-MoodyMeng Xiao HeNatalie I VokesJackson NymanWanling XieAmin H NassarSarah Abou AlaiwiRonan FlippotGabrielle BouchardJohn A SteinharterPier Vitale NuzzoMiriam FicialMiriam Sant'AngeloJuliet FormanJacob E BerchuckShaan DudaniKevin BiJihye ParkSabrina CampMaura Sticco-IvinsLaure HirschSylvan C BacaMegan Wind-RotoloPetra Ross-MacdonaldMaxine SunGwo-Shu Mary LeeSteven L ChangXiao X WeiBradley A McGregorLauren C HarshmanGiannicola GenoveseLeigh EllisMark PomerantzMichelle S HirschMatthew L FreedmanMichael B AtkinsCatherine J WuThai H HoW Marston LinehanDavid F McDermottDaniel Y C HengSrinivas R ViswanathanSabina SignorettiEliezer Van AllenToni K Choueiri
Published in: Nature communications (2021)
Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.
Keyphrases
  • renal cell carcinoma
  • clinical trial
  • poor prognosis
  • transcription factor
  • public health
  • randomized controlled trial
  • signaling pathway
  • cancer therapy
  • long non coding rna
  • heat stress