透明细胞肾细胞癌（ccRCC）中碳酸酐酶9和HIF-2α RNA表达的特征分析.pdf

1、Characterizing Carbonic Anhydrase 9 and HIF-2 RNA Expression in Clear Cell Renal Cell CarcinomaYu-Wei Chen1,Shayan S.Nazari2,Andrew Elliott2,Ninad Kulkarni2,Norm Smith2,Rasha Nawfal3,Pedro Barata4,Brent Rose1,Aditya Bagrodia1,Neeraj Agarwal5,Sumanta Pal6,Toni K.Choueiri3,Rana R.McKay11.University of

2、 California San Diego,San Diego,CA.2.Caris Life Sciences,Phoenix,AZ.3.Dana-Farber Caner Institute,Boston,MA.4.University Hospitals Seidman Cancer Institute,Cleveland OH.5.University of Utah,Huntsman Cancer Institute,Salt Lake City,UT;6.City of Hope,Duarte,CA VHLHIF-2CA9 AxisEXCLUSION ZONEUpstream Re

3、gulationDownstream EffectsClinical Role VHLTumor suppressor;pVHL E3 ubiquitin ligaseControls HIF-turnover70%-90%sporadic ccRCC has VHL alterations HIF-2Stabilized by pVHL loss or hypoxiaDrives transcription of angiogenesis,metabolism,pH regulatorsTherapeutic target(HIF-2 inhibitors)CA9Transcriptiona

4、l target of HIF-2Modulates extracellular/intracellular pHDiagnostic IHC marker;imaging and therapeutic target 1.Schdel et al.,European Urology 2015.2.Siebenthall et al.,EbioMedicine 2019.3.Lombardi et al.,Cell Reports 2022VHL=Von Hippel-Lindau;HIF=Hypoxia inducible factor;CA9=Carbonic anhydrase 9;pV

5、HL=Von Hippel-Lindau protein;ccRCC=Clear cell renal cell carcinoma;IHC=Immunohistochemistry.Methods Comprehensive profiling:Caris Life Sciences performed DNA(592-gene panel or whole exome)and RNA(whole transcriptome)sequencing on ccRCC specimens.Biomarker quantification:CA9 and HIF-2 expression meas

6、ured as transcripts per million(TPM)and dichotomized as High vs Low based on quartiles.Survival endpoint:Overall survival(OS)was obtained from insurance claims;calculated from initial diagnosis to death or last contact.Treatment endpoint:Time-on-treatment(TOT)defined from first to last recorded trea