<div>AbstractPurpose: We aim to identify tumor-specific alternative splicing events having potential applications in the early detection, diagnosis, prognosis, and therapy for cancers.Experimental Design: We analyzed RNA-seq data on 470 clear cell renal cell carcinomas (ccRCC) and 68 kidney tissues to identify tumor-specific alternative splicing events. We further focused on the fibroblast growth factor receptor 2 (FGFR2) isoform switch and characterized ccRCCs expressing different FGFR2 isoforms by integrated analyses using genomic data from multiple platforms and tumor types.Results: We identified 113 top candidate alternatively spliced genes in ccRCC. Prominently, the FGFR2 gene transcript switched from the normal IIIb isoform (“epithelial”) to IIIc isoform (“mesenchymal”) in nearly 90% of ccRCCs. This switch is kidney specific as it was rarely observed in other cancers. The FGFR2-IIIb ccRCCs show a transcriptome and methylome resembling those from normal kidney, whereas FGFR2-IIIc ccRCCs possess elevated hypoxic and mesenchymal expression signatures. Clinically, FGFR2-IIIb ccRCCs are smaller in size, of lower tumor grade, and associated with longer patient survival. Gene set enrichment and DNA copy number analyses indicated that FGFR2-IIIb ccRCCs are closely associated with renal oncocytomas and chromophobe RCCs (chRCC). A reexamination of tumor histology by pathologists identified FGFR2-IIIb tumors as chRCCs and clear cell papillary RCCs (ccpRCC).Conclusions: FGFR2 IIIb RCCs represent misdiagnosed ccRCC cases, suggesting FGFR2 isoform testing can be used in the diagnosis of RCC subtypes. The finding of a prevalent isoform switch of FGFR2 in a tissue-specific manner holds promise for the future development of FGFR2-IIIc as a distinct early detection biomarker and therapeutic target for ccRCC. Clin Cancer Res; 19(9); 2460–72. ©2013 AACR.</div>

Chromophobe cell

Kidney cancer

10.1158/1078-0432.c.6521414.v1

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Data from Cytoplasmic Sequestration of p27 via AKT Phosphorylation in Renal Cell Carcinoma

Jean Hee Kim Eric Jonasch Angela Alexander John D. Short Shengli Cai

<div>AbstractPurpose: p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC) or how p27 participates in disease progression or response to therapy.Experimental Design: RCC-derived cell lines, primary tumors, and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS), and subcellular localization. RCC-derived cell lines were treated with phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors and effects on p27 localization were assessed. The potential contribution of cytoplasmic p27 to resistance to apoptosis was also evaluated.Results: p27 was elevated in tumors compared with matched controls, and cytoplasmic mislocalization of p27 was associated with increasing tumor grade. Cytoplasmic localization of p27 correlated with phosphorylation at T157, an AKT phosphorylation site in the p27 NLS. In RCC cell lines, activated PI3K/AKT signaling was accompanied by mislocalization of p27. AKT activation and phosphorylation of p27 was associated with resistance to apoptosis, and small interfering RNA knockdown of p27 or relocalization to the nucleus increased apoptosis in RCC cells. Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not.Conclusions: In RCC, p27 is phosphorylated at T157 of the NLS, with increasing tumor grade associated with cytoplasmic p27. PI3K inhibition (which reduces AKT activity) reduces T157 phosphorylation and induces nuclear relocalization of p27, whereas mTOR inhibition does not. Clinical testing of these findings may provide a rational approach for use of mTOR and PI3K/AKT pathway inhibitors in patients with RCC.</div>

LY294002

Wortmannin

10.1158/1078-0432.c.6517134

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MP66-17 PATIENTS PERSPECTIVES ON ADJUVANT THERAPY IN RENAL CELL CARCINOMA

The Journal of Urology (2018)

Dena Battle Hans J. Hammers Eric Jonasch Ithaar Derweesh Daniel J. George

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II1 Apr 2018MP66-17 PATIENTS PERSPECTIVES ON ADJUVANT THERAPY IN RENAL CELL CARCINOMA Dena Battle, Hans Hammers, Eric Jonasch, Ithaar Derweesh, Daniel George, Börje Ljungberg, Axel Bex, and Michael Staehler Dena BattleDena Battle More articles by this author , Hans HammersHans Hammers More articles by this author , Eric JonaschEric Jonasch More articles by this author , Ithaar DerweeshIthaar Derweesh More articles by this author , Daniel GeorgeDaniel George More articles by this author , Börje LjungbergBörje Ljungberg More articles by this author , Axel BexAxel Bex More articles by this author , and Michael StaehlerMichael Staehler More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1889AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES At this point in time, there is no approved adjuvant therapy (AT) for renal cell carcinoma (RCC). The discussion on AT is driven by the pending maturation of overall survival (OS) data for sunitinib in patients at high risk for recurrence. Data on patient's perception of AT are missing. The purpose of this study was to assess the value of specific adjuvant outcome measures to patients with RCC METHODS We conducted a survey-monkey survey in n=450 patients with RCC on the perspective on AT. The survey was promoted via kccure.org, facebook and smartpatients.com. Question were not related to specific results of adjuvant trials but asking only about the attitude towards AT as an intervention. RESULTS Median age was 55.6 years (17-82 years) and 56.4% of the patients were female. 73.6% of the patients underwent nephrectomy as primary therapy, while 22.0% had a partial nephrectomy. 76.4% of the patients had clear cell RCC. 39.1% had recurrence of RCC and 35.3% were receiving systemic therapy for metastatic RCC. 63.1% of patients would use AT if it prolonged OS, followed by 60.1% if AT prolonged disease free survival (DFS), 42.7% if AT demonstrated acceptable toxicity, and 36.7% if guaranteed insurance coverage and efficacy. Experience with systemic therapy was correlated with a wish for a prolonged OS (p<0.0001). Patients with a history of systemic therapy rely on the physician's recommendation in contrast to patients without a history of systemic therapy (p<0.0001). The recurrence status, age, initial stage and type of surgery had no influence on the patients' decisions.28.0% of the patients would need more information prior to their decision, 24.2% would only take AT with a proven OS benefit, 16.9% would use AT if there was moderate toxicity, 13.6% would use AT independent of the associated toxicity level, 8.2% would only use AT without any toxicity. 3.8% of the patients would not use AT. Patients on systemic therapy had a significant higher acceptance of toxicity (p<0.0001). CONCLUSIONS Patients are willing to use AT to achieve OS and DFS benefits, and place lower emphasis on toxicity. These data provide an important perspective on patient perceptions of AT, and emphasize the need for patient education on harms and benefits of AT. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e875 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Dena Battle More articles by this author Hans Hammers More articles by this author Eric Jonasch More articles by this author Ithaar Derweesh More articles by this author Daniel George More articles by this author Börje Ljungberg More articles by this author Axel Bex More articles by this author Michael Staehler More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Adjuvant Therapy

George (robot)

10.1016/j.juro.2018.02.1889

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Supplementary Table from Gene Body Methylation of the Lymphocyte-Specific Gene CARD11 Results in Its Overexpression and Regulates Cancer mTOR Signaling

Michael H. McGuire Santosh K. Dasari Hui Yao Yunfei Wen Lingegowda S. Mangala

Supplementary Table from Gene Body Methylation of the Lymphocyte-Specific Gene CARD11 Results in Its Overexpression and Regulates Cancer mTOR Signaling

10.1158/1541-7786.22526660.v1

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Figures S1-S10 from Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape

Zixing Wang Tae Beom Kim Bo Peng José A. Karam Chad J. Creighton

Figure S1. Biphasic histologic components of sarcomatoid renal cell carcinoma. The macrodissected paired epithelioid or carcinomatous (E) and spindled or sarcomatoid (S) components of clear cell RCC (upper panel), Papillary RCC (middle panel), and chromophobe RCC (lower panel). H&E stain, scale bar 200 ï�m. Figure S2. Sarcomatoid ccRCC shows fewer VHL deletions. (A) Clear cell RCC (H&E stain, scale bar 100 Âµm) with (B) Fluorescence in situ hybridization (FISH) image showing paired CEN3q signals (green) and a single VHL signal (red). (C) Sarcomatoid ccRCC (H&E stain, scale bar 100 Âµm) with (D) FISH image showing balanced CEN3q (green) and VHL (red) signals. (E) Box plot showing significantly higher VHL/3q ratios associated with sarcomatoid histology, P<0.008. Figure S3: The smooth scatter plot of signal B versus signal A. Figure S4a: 3p21 and 3p21.1 copy number versus chromosome position. Figure S4b: 3p25 copy number versus chromosome position. Figure S5: Kernel density plots. Each sample per row; left three columns: 3p21; middle three columns: 2q37; and right three columns: 1p1. Figure S6a: Example of more than one peak in the summed signal. Figure S6b: Example of 4 peaks in signals A and B. Figure S7: Density plots of TCGA samples with copy-neutral LOH. Figure S8. VHL and PBRM1 show fewer 2-hit inactivation in sarcomatoid ccRCC. Sarcomatoid ccRCC and ccRCC cases shown in terms of the inactivating "hits" on 3p21-25 genes (VHL, PBRM1, SETD2, BAP1) consisting of mutations or methylation (mutually exclusive for VHL) and deletions. Figure S9. Top activated and inhibited pathways of sarcomatoid samples. Pathways altered by differentially expressed genes between non-sarcomatoid and sarcomatoid samples. The genes selected were differentially expressed in both the TCGA and MD Anderson samples. Figure S10. S- component shows a higher mutational load in sarcomatoid RCC. The total number of non-synonymous mutations in the E- and S- components of sarcomatoid RCC, across all parent RCC subtypes (A) and in clear cell RCC (B).

BAP1

Chromophobe cell

Stain

10.1158/1078-0432.22468044

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Supplementary Methods from Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape

Zixing Wang Tae Beom Kim Bo Peng José A. Karam Chad J. Creighton

Supplemental Methods 1. Exome sequencing pipeline Supplemental Methods 2. RNA seq pipeline Supplemental Methods 3. DNA methylation profiling pipeline Supplemental Methods 4. Fluorescence in situ hybridization Supplemental Methods 5. TCGA samples with possible copy neutral loss of heterozygosity in 3p21 and 3p25 regions

Exome

10.1158/1078-0432.22468035

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Supplementary Figure from Gene Body Methylation of the Lymphocyte-Specific Gene CARD11 Results in Its Overexpression and Regulates Cancer mTOR Signaling

Michael H. McGuire Santosh K. Dasari Hui Yao Yunfei Wen Lingegowda S. Mangala

Supplementary Figure from Gene Body Methylation of the Lymphocyte-Specific Gene CARD11 Results in Its Overexpression and Regulates Cancer mTOR Signaling

10.1158/1541-7786.22526663

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