Publications by authors named "Glen Kristiansen"

441 Publications

Diagnosis of "cribriform" prostatic adenocarcinoma: an interobserver reproducibility study among urologic pathologists with recommendations.

Am J Cancer Res 2021 15;11(8):3990-4001. Epub 2021 Aug 15.

Department of Pathology, Tufts Medical Center Boston, MA, USA.

Accurate diagnosis of cribriform Gleason pattern 4 (CrP4) prostate adenocarcinoma (PCa) is important due to its independent association with adverse clinical outcomes and as a growing body of evidence suggests that it impacts clinical decision making in PCa management. To identify reproducible features for diagnosis of CrP4, we assessed interobserver agreement among 27 experienced urologic pathologists of 60 digital images from 44 radical prostatectomies (RP) that represented a broad spectrum of potential CrP4. The following morphologic features were correlated with the consensus diagnosis (defined as 75% agreement) for each image: partial vs. transluminal glandular bridging, intraglandular stroma, <12 vs. ≥12 lumina, well vs. poorly formed lumina, mucin (mucinous fibroplasia, extravasation, or extracellular pool), size (compared to benign glands and number of lumina), number of attachments with gland border by tumor cells forming a "glomeruloid-like" pattern, a clear luminal space along the periphery of gland occupying <50% of glandular circumference, central nerve, dense (cell mass occupying >50% of luminal space) vs. loose, and regular vs. irregular contour. Interobserver reproducibility for the overall diagnostic agreement was fair (k=0.40). Large CrP4 had better agreement (k=0.49) compared to small CrP4 (k=0.40). Transluminal bridging, dense cellular proliferation, a clear luminal space along the periphery of gland occupying <50% of gland circumference, lack of intraglandular mucin, and lack of contact between the majority of intraglandular cells with stroma were significantly associated with consensus for CrP4. In contrast, partial bridging, majority of intraglandular cells in contact with stroma, mucinous fibroplasia, only one attachment to the gland border by tumor cells forming a "glomeruloid-like" pattern, and a clear luminal space along the periphery of gland accounting for >50% of the glandular circumference were associated with consensus against CrP4. In summary, we identified reproducible morphological features for and against CrP4 diagnosis, which could be used to refine and standardize the diagnostic criteria for CrP4.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414383PMC
August 2021

Extrahepatic Surgery in Cirrhosis Significantly Increases Portal Pressure in Preclinical Animal Models.

Front Physiol 2021 20;12:720898. Epub 2021 Aug 20.

Department of Internal Medicine 1, Center for Cirrhosis and Portal Hypertension Bonn (CCB), University Hospital Bonn, Bonn, Germany.

Liver cirrhosis is a relevant comorbidity with increasing prevalence. Postoperative decompensation and development of complications in patients with cirrhosis remains a frequent clinical problem. Surgery has been discussed as a precipitating event for decompensation and complications of cirrhosis, but the underlying pathomechanisms are still obscure. The aim of this study was to analyze the role of abdominal extrahepatic surgery in cirrhosis on portal pressure and fibrosis in a preclinical model. Compensated liver cirrhosis was induced using tetrachlormethane (CCL4) inhalation and bile duct ligation (BDL) models in rats, non-cirrhotic portal hypertension by partial portal vein ligation (PPVL). Intestinal manipulation (IM) as a model of extrahepatic abdominal surgery was performed. 2 and 7 days after IM, portal pressure was measured . Hydroxyproline measurements, Sirius Red staining and qPCR measurements of the liver were performed for evaluation of fibrosis development and hepatic inflammation. Laboratory parameters of liver function in serum were analyzed. Portal pressure was significantly elevated 2 and 7 days after IM in both models of cirrhosis. In the non-cirrhotic model the trend was the same, while not statistically significant. In both cirrhotic models, IM shows strong effects of decompensation, with significant weight loss, elevation of liver enzymes and hypoalbuminemia. 7 days after IM in the BDL group, Sirius red staining and hydroxyproline levels showed significant progression of fibrosis and significantly elevated mRNA levels of hepatic inflammation compared to the respective control group. A progression of fibrosis was not observed in the CCL4 model. In animal models of cirrhosis with continuous liver injury (BDL), IM increases portal pressure, and development of fibrosis. Perioperative portal pressure and hence inflammation processes may be therapeutic targets to prevent post-operative decompensation in cirrhosis.
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http://dx.doi.org/10.3389/fphys.2021.720898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418541PMC
August 2021

promoter hypomethylation is a negative prognostic biomarker at initial diagnosis but predicts response and favorable outcome to anti-PD-1 based immunotherapy in clear cell renal cell carcinoma.

J Immunother Cancer 2021 Aug;9(8)

Center for Integrated Oncology Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), Bonn, Germany

Background: In metastatic clear cell renal cell carcinoma (ccRCC), different combination therapies, each including anti-PD-1 immune checkpoint blockade (ICB), are applied as first-line treatment. Robust predictive biomarkers for rational upfront therapy decisions are lacking, although they are urgently needed. Recently, we showed that promoter methylation predicts response to ICB in melanoma. Here, we aimed to investigate methylation in ccRCC and its utility to serve as a predictive biomarker for anti-PD-1 based ICB in metastatic ccRCC.

Methods: methylation was analyzed with regard to transcriptional gene activity (mRNA expression), intratumoral immune cell composition, and clinical course in two ccRCC cohorts obtained from The Cancer Genome Atlas (TCGA cohort, n=533) and the University Hospital Bonn (UHB Non-ICB Cohort, n=116). In addition, methylation as well as CD8 T cell infiltrates and PD-L1 expression were evaluated in pre-treatment samples from a multicenter cohort (RCC-ICB Cohort, n=71). Patients included in the RCC-ICB Cohort were treated with either first line anti-PD-1 based combination therapy (n=25) or monotherapy post-tyrosine kinase inhibition in second line or later. Analyses were performed with regard to treatment response according to RECIST, progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) following treatment initiation.

Results: promoter hypomethylation was significantly correlated with mRNA expression, lymphocyte infiltration, and poor OS in both primary ccRCC cohorts (TCGA: HR 0.30 (95% CI 0.18 to 0.49), p<0.001; UHB Non-ICB: HR 0.35 (95% CI 0.16 to 0.75), p=0.007). In contrast, promoter hypomethylation predicted response and, accordingly, favorable outcomes (PFS and OS) in patients with ICB-treated ccRCC, overcompensating the negative prognostic value of hypomethylation at initial diagnosis. Moreover, in multivariable Cox regression, promoter hypomethylation remained an independent predictor of improved outcome in ICB-treated ccRCC after co-adjustment of the International Metastatic Renal Cell Carcinoma Database Consortium score (HR 3.00 (95% CI 1.47 to 6.28), p=0.003).

Conclusions: Our study suggests methylation as a powerful predictive biomarker for immunotherapy response in metastatic RCC.
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http://dx.doi.org/10.1136/jitc-2021-002949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395367PMC
August 2021

Myoglobin, expressed in brown adipose tissue of mice, regulates the content and activity of mitochondria and lipid droplets.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Aug 10:159026. Epub 2021 Aug 10.

Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland. Electronic address:

The identification of novel physiological regulators that stimulate energy expenditure through brown adipose tissue (BAT) activity in substrate catalysis is of utmost importance to understand and treat metabolic diseases. Myoglobin (MB), known to store or transport oxygen in heart and skeletal muscles, has recently been found to bind fatty acids with physiological constants in its oxygenated form (i.e., MBO). Here, we investigated the in vivo effect of MB expression on BAT activity. In particular, we studied mitochondrial function and lipid metabolism as essential determinants of energy expenditure in this tissue. We show in a MB-null (MBko) mouse model that MB expression in BAT impacts on the activity of brown adipocytes in a twofold manner: i) by elevating mitochondrial density plus maximal respiration capacity, and through that, by stimulating BAT oxidative metabolism along with the organelles` uncoupled respiration; and ii) by influencing the free fatty acids pool towards a palmitate-enriched composition and shifting the lipid droplet (LD) equilibrium towards higher counts of smaller droplets. These metabolic changes were accompanied by the up-regulated expression of thermogenesis markers UCP1, CIDEA, CIDEC, PGC1-α and PPAR-α in the BAT of MB wildtype (MBwt) mice. Along with the emergence of the "browning" BAT morphology, MBwt mice exhibited a leaner phenotype when compared to MBko littermates at 20 weeks of age. Our data shed novel insights into MB's role in linking oxygen and lipid-based thermogenic metabolism. The findings suggest potential new strategies of targeting the MB pathway to treat metabolic disorders related to diminishing energy expenditure.
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http://dx.doi.org/10.1016/j.bbalip.2021.159026DOI Listing
August 2021

The signal transducer CD24 suppresses the germ cell program and promotes an ectodermal rather than mesodermal cell fate in embryonal carcinomas.

Mol Oncol 2021 Jul 22. Epub 2021 Jul 22.

Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany.

Testicular germ cell tumors (GCTs) are stratified into seminomas and nonseminomas. Seminomas share many histological and molecular features with primordial germ cells, whereas the nonseminoma stem cell population-embryonal carcinoma (EC)-is pluripotent and thus able to differentiate into cells of all three germ layers (teratomas). Furthermore, ECs are capable of differentiating into extra-embryonic lineages (yolk sac tumors, choriocarcinomas). In this study, we deciphered the molecular and (epi)genetic mechanisms regulating expression of CD24, a highly glycosylated signaling molecule upregulated in many cancers. CD24 is overexpressed in ECs compared with other GCT entities and can be associated with an undifferentiated pluripotent cell fate. We demonstrate that CD24 can be transactivated by the pluripotency factor SOX2, which binds in proximity to the CD24 promoter. In GCTs, CD24 expression is controlled by epigenetic mechanisms, that is, histone acetylation, since CD24 can be induced by the application histone deacetylase inhibitors. Vice versa, CD24 expression is downregulated upon inhibition of histone methyltransferases, E3 ubiquitin ligases, or bromodomain (BRD) proteins. Additionally, three-dimensional (3D) co-cultivation of EC cells with microenvironmental cells, such as fibroblasts, and endothelial or immune cells, reduced CD24 expression, suggesting that crosstalk with the somatic microenvironment influences CD24 expression. In a CRISPR/Cas9 deficiency model, we demonstrate that CD24 fulfills a bivalent role in differentiation via regulation of homeobox, and phospho- and glycoproteins; that is, it is involved in suppressing the germ cell/spermatogenesis program and mesodermal/endodermal differentiation, while poising the cells for ectodermal differentiation. Finally, blocking CD24 by a monoclonal antibody enhanced sensitivity toward cisplatin in EC cells, including cisplatin-resistant subclones, highlighting CD24 as a putative target in combination with cisplatin.
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http://dx.doi.org/10.1002/1878-0261.13066DOI Listing
July 2021

Fibroblast activation protein inhibitor (FAPi) positive tumour fraction on PET/CT correlates with Ki-67 in liver metastases of neuroendocrine tumours.

Nuklearmedizin 2021 Jul 13. Epub 2021 Jul 13.

Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany.

Aim: Gallium-68-labelled inhibitors of the fibroblast activation protein (FAPi) enable positron emission tomography/computed tomography (PET/CT) imaging of fibroblast activation. We evaluated if [Ga]Ga-DATA5 m.SA.FAPi PET/CT is related to Ki-67 as a marker of tumour aggressiveness in patients with liver metastases of NET.

Methods: Thirteen patients with liver metastases of a histologically confirmed NET who underwent PET/CT with [Ga]Ga-DATA5 m.SA.FAPi, [18F]FDG and [Ga]Ga-DOTA-TOC were retrospectively analyzed. PET-positive liver tumour volumes were segmented for calculation of volume, SUVmax and PET-positive tumour fraction (TF). PET parameters were correlated with Ki-67.

Results: FDG correlated positively (rho = 0.543, p < 0.05) and DOTATOC correlated negatively (rho = -0.618, p < 0.05) with Ki-67, the correlation coefficients were in the moderate range. There was no significant correlation between FAPi and Ki-67 (rho = 0.382, p > 0.05). FAPi correlated positively (rho = 0.770, p < 0.01) and DOTATOC correlated negatively (rho = -0.828, p < 0.01) with Ki-67, both significantly with high correlation coefficients. FDG also correlated significantly with Ki-67, with a moderate correlation coefficient (rho = 0.524, p < 0.05). The ratio FAPi:DOTATOC showed a significant and strong correlation with Ki-67 (rho = 0.808, p < 0.01).

Conclusion: The ratio FAPi:DOTATOC might serve as a clinical parameter for the assessment of dedifferentiation and aggressiveness of liver metastases in patients with NET. [Ga]Ga-DATA5 m.SA.FAPi might hold potential for identification of high-risk patients. Further studies are warranted to evaluate its prognostic significance in comparison to [F]FDG in patients with NET.
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http://dx.doi.org/10.1055/a-1521-8604DOI Listing
July 2021

No evidence to support the impact of migration background on treatment response rates and cancer survival: a retrospective matched-pair analysis in Germany.

BMC Cancer 2021 May 10;21(1):526. Epub 2021 May 10.

Department of Integrated Oncology, CIO Bonn, Center for Integrated Oncology ABCD, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

Background: Immigration has taken the central stage in world politics, especially in the developed countries like Germany, where the continuous flow of immigrants has been well documented since 1960s. Strikingly, emerging data suggest that migrant patients have a poorer response to the treatment and lower survival rates in their new host country, raising concerns about health disparities. Herein, we present our investigation on the treatment response rate and cancer survival in German patients with and without an immigrant background that were treated at our comprehensive cancer center in Germany.

Methods: Initially, we considered 8162 cancer patients treated at the Center for Integrated Oncology (CIO), University Hospital Bonn, Germany (April 2002-December 2015) for matched-pair analysis. Subsequently, the German patients with a migration background and those from the native German population were manually identified and catalogued using a highly specific name-based algorithm. The clinical parameters such as demographic characteristics, tumor characteristics, defined staging criteria, and primary therapy were further adjusted. Using these stringent criteria, a total of 422 patients (n = 211, Germans with migration background; n = 211, native German population) were screened to compare for the treatment response and survival rates (i.e., 5-year overall survival, progression-free survival, and time to progression).

Results: Compared to the cohort with migration background, the cohort without migration background was slightly older (54.9 vs. 57.9 years) while having the same sex distribution (54.5% vs. 55.0% female) and longer follow-up time (36.9 vs. 42.6 months). We did not find significant differences in cancer survival (5-year overall survival, P = 0.771) and the response rates (Overall Remission Rate; McNemar's test, P = 0.346) between both collectives.

Conclusion: Contrary to prior reports, we found no significant differences in cancer survival between German patients with immigrant background and native German patients. Nevertheless, the advanced treatment protocols implemented at our comprehensive cancer center may possibly account for the low variance in outcome. To conduct similar studies with a broader perspective, we propose that certain risk factors (country-of-origin-specific infections, dietary habits, epigenetics for chronic diseases etc.) should be considered, specially in the future studies that will recruit new arrivals from the 2015 German refugee crisis.
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http://dx.doi.org/10.1186/s12885-021-08141-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108356PMC
May 2021

CircEHD2, CircNETO2 and CircEGLN3 as Diagnostic and Prognostic Biomarkers for Patients with Renal Cell Carcinoma.

Cancers (Basel) 2021 Apr 30;13(9). Epub 2021 Apr 30.

Department of Urology, University Hospital Bonn, 53127 Bonn, Germany.

Background: Circular RNA (circRNA) plays an important role in the carcinogenesis of various tumors. It is assumed that circRNAs have a high tissue and tumor specificity, thus they are discussed as cancer biomarkers. The knowledge about circRNAs in clear cell renal carcinoma (ccRCC) is limited so far, and thus we studied the expression profile of seven circRNAs (circCOL5A1, circEHD2, circEDEM2, circEGNL3, circNETO2, circSCARB1, circSOD2) in a cohort of ccRCC patients.

Methods: Fresh-frozen normal and cancerous tissues were prospectively collected from patients with ccRCC undergoing partial/radical nephrectomy. Total RNA was isolated from 121 ccRCC and 91 normal renal tissues, and the circRNA expression profile was determined using quantitative real-time PCR.

Results: circEHD2, circENGLN3, and circNETO2 were upregulated in ccRCC compared with non-malignant renal tissue. circENGLN3 expression was highly discriminative between normal and cancerous tissue. None of the circRNAs was correlated with clinicopathological parameters. High circEHD2 and low circNETO2 levels were an independent predictor of a shortened progression-free survival, cancer-specific survival, and overall survival in patients with ccRCC undergoing nephrectomy.

Conclusions: The analysis of circRNAs may provide diagnostic and prognostic information. Thus, circRNAs could help to optimize the individual treatment and ultimately improve ccRCC patients' survival.
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http://dx.doi.org/10.3390/cancers13092177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124893PMC
April 2021

Zona Pellucida Protein 2 (ZP2) Is Expressed in Colon Cancer and Promotes Cell Proliferation.

Cancers (Basel) 2021 Apr 7;13(8). Epub 2021 Apr 7.

Neuro- and Tumor Cell Biology Group, Department of Nuclear Medicine, Venusberg-Campus 1, University Hospital of Bonn, 53127 Bonn, Germany.

Background: Zona pellucida protein ZP2 has been identified as a new colon tumor biomarker. Its transcripts were specifically expressed in four out of four human colon cancer cell lines and enhanced in about 60% of primary colon cancer tissues when compared to matched healthy ones. ZP2 down-regulation by siRNA led to a decreased proliferation rate, EXOSC5 transcript, cyclin D1 protein level, and ERK1/2 phosphorylation state.

Methods: Sensitivity and quantitative expression analysis of ZP2 transcripts in tumor and matched normal colon tissue was performed with respective cDNA preparations. Silencing RNA effects on colon cancer cells were examined by q-PCR, western blot, and proliferation rate experiments.

Results: In a significant portion of 69 primary colon tumor samples, the molecule showed a low but specific expression, which revealed a sensitivity value of around 90% and a specificity value of 30% when matched to the respective normal counterparts. Down-regulation of ZP2 protein by siRNA led to a decreased proliferation rate, EXOSC5 and cyclin D1 level, and phosphorylation state of ERK1/2. ZP2 has also been found to be a cell membrane-bound protein.

Conclusion: ZP2 shows an enhanced expression level in colon cancer tissue and, thus, can be used as a diagnostic tool, albeit in combination with other biomarkers. Its character as a membrane protein makes ZP2 even a potential target molecule for tumor therapy, especially as it positively affects colon cancer cell proliferation.
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http://dx.doi.org/10.3390/cancers13081759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067760PMC
April 2021

Tumor Infiltrating Neutrophils Are Frequently Found in Adenocarcinomas of the Biliary Tract and Their Precursor Lesions with Possible Impact on Prognosis.

J Pers Med 2021 Mar 23;11(3). Epub 2021 Mar 23.

Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany.

Biliary tract cancer (BTC) is characterized by an intense stromal reaction and a complex landscape of infiltrating immune cells. Evidence is emerging that tumor-infiltrating neutrophils (TINs) have an impact on carcinogenesis and tumor progression. TINs have also been associated with outcomes in various solid malignant tumors but their possible clinical role in BTC is largely unknown. Tissue samples from patients with sporadic BTC ("spBTC" cohort, = 53) and BTC in association with primary sclerosing cholangitis ("PSC-BTC" cohort, = 7) were collected. Furthermore, tissue samples from 27 patients with PSC who underwent liver transplantation ("PSC-LTX" cohort) were investigated. All specimens were assessed for TIN density in invasive and precancerous lesions (biliary intraepithelial neoplasia, BilIN). Most spBTC showed low TIN density (LD, 61%). High TIN density (HD) was detected in 16% of the tumors, whereas 23% were classified as intermediate density (ID); the majority of both HD and ID groups were in T1-T2 tumors (83% and 100%, = 0.012). TIN density in BilIN lesions did not significantly differ among the three groups. The HD group had a mean overall survival (OS) of 53.5 months, whereas the mean OS in the LD and ID groups was significantly shorter (LD 29.5 months vs. ID 24.6 months, log-rank < 0.05). The results of this study underline the possible prognostic relevance of TINs in BTC and stress the complexity of the immune cell landscape in BTC. The prognostic relevance of TINs suggests a key regulator role in inflammation and immune landscape in BTC.
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http://dx.doi.org/10.3390/jpm11030233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004909PMC
March 2021

Cardiac Myeloid Sarcoma: Multimodal Imaging and Histopathologic Findings.

Radiol Cardiothorac Imaging 2021 Feb 11;3(1):e200540. Epub 2021 Feb 11.

Department of Diagnostic and Interventional Radiology (A.I., D.D., J.A.L.) and Department of Pathology (G.K.), University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; and Quantitative Imaging Laboratory Bonn (QILaB), Bonn, Germany (A.I., D.D., J.A.L.).

Supplemental material is available for this article.
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http://dx.doi.org/10.1148/ryct.2021200540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977984PMC
February 2021

N -Methyladenosine (m A) readers are dysregulated in renal cell carcinoma.

Mol Carcinog 2021 05 23;60(5):354-362. Epub 2021 Mar 23.

Klinik und Poliklinik für Urologie und Kinderurologie, Universitätsklinikum Bonn, Bonn, Germany.

N -Methyladenosine (m A) is the most common modification of messenger RNA (mRNA) in mammals. It critically influences RNA metabolism and plays an essential role in virtually all types of bioprocesses including gene expression, tissue development, self-renewal and differentiation of stem cells, stress response and circadian clock control. It plays a crucial role in carcinogenesis and could be used as a prognostic and a diagnostic tool and as a target for new anticancer therapies. m A modification is dynamically and reversibly regulated by three types of proteins. Methyltransferases, so-called "writers" add a methyl group to the adenosine, which can be removed by demethylases, also called "erasers." m A-specific RNA-binding proteins, from here on referred to as "readers," preferentially bind to the m A site and mediate biological functions, such as translation, splicing or decay of RNA. In this study, we examined the expression of the six m A readers HNRNPA2B1, HNRNPC, YTHDC1 and YTHDF1-3 in clear cell renal carcinoma (ccRCC). We show that on mRNA level the expression of all six m A readers is significantly downregulated compared to normal renal tissue and on protein level five out of six readers are dysregulated. Lower levels of some m A readers are correlated with advanced stage and grade as well as associated with a shorter overall, progression-free and cancer-specific survival. In summary, we could show that m A readers are dysregulated in ccRCC and might therefore act as a tumor marker, could give further information on the individual prognosis and be a target of innovative cancer therapy.
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http://dx.doi.org/10.1002/mc.23297DOI Listing
May 2021

Case report: Breast metastasis in a prostate cancer patient.

Nuklearmedizin 2021 Aug 18;60(4):302-303. Epub 2021 Mar 18.

Klinik und Poliklinik für Nuklearmedizin, Universitätsklinikum Bonn, Bonn, Germany.

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http://dx.doi.org/10.1055/a-1310-3633DOI Listing
August 2021

Repression Leads to Enhanced NOTCH Signaling in Fusion Positive Prostate Cancer Cells.

Cancers (Basel) 2021 Feb 25;13(5). Epub 2021 Feb 25.

Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany.

About 50% of prostate cancer (PCa) tumors are (T2E) fusion-positive (T2E+), but the role of T2E in PCa progression is not fully understood. We were interested in investigating epigenomic alterations associated with T2E+ PCa. Using different sequencing cohorts, we found several transcripts of the cluster to be repressed in T2E+ PCa. This repression correlated strongly with enhanced expression of NOTCH and several of its target genes in TCGA and ICGC PCa RNA-seq data. We corroborated these findings using a cellular model with inducible T2E expression. Overexpression of in vitro led to silencing of genes associated with NOTCH signaling (, ) and . Interestingly, overexpression led to the repression of , a negative regulator of the transcription factor , the primary effector of NOTCH signaling, and promoted cell proliferation by repressing the cell cycle inhibitor p21. Inhibition of NOTCH as well as knockdown of reduced the oncogenic properties of PCa cell lines. Using tissue microarray analysis encompassing 533 human PCa cores, ERG-positive areas exhibited significantly increased expression. Taken together, our data suggest that an epigenomic regulatory network enhances NOTCH signaling and thereby contributes to the oncogenic properties of T2E+ PCa.
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http://dx.doi.org/10.3390/cancers13050964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975324PMC
February 2021

Management of Germ Cell Tumours of the Testes in Adult Patients: German Clinical Practice Guideline, PART II - Recommendations for the Treatment of Advanced, Recurrent, and Refractory Disease and Extragonadal and Sex Cord/Stromal Tumours and for the Management of Follow-Up, Toxicity, Quality of Life, Palliative Care, and Supportive Therapy.

Urol Int 2021 22;105(3-4):181-191. Epub 2021 Jan 22.

II. Medical Clinic and Polyclinic, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Objectives: We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects.

Materials And Methods: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements.

Results: Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy.

Conclusion: Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.
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http://dx.doi.org/10.1159/000511245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006578PMC
July 2021

DNA Promoter Methylation and ERG Regulate the Expression of CD24 in Prostate Cancer.

Am J Pathol 2021 04 22;191(4):618-630. Epub 2021 Jan 22.

Institute of Pathology, Center for Integrated Oncology, University of Bonn, Bonn, Germany; Center for Integrated Oncology Aachen/Bonn/Cologne/Dusseldorf, Bonn, Germany. Electronic address:

CD24 is overexpressed in many human cancers and is a driver of tumor progression. Herein, molecular mechanisms leading to up-regulation of CD24 in prostate cancer were studied. DNA methylation of the CD24 gene promoter at four loci using quantitative methylation-specific PCR was evaluated. Expression of CD24 in tumor tissues was studied by immunohistochemistry. To corroborate the results in vitro, ERG-inducible LNCaP TMPRSS2:ERG (T2E) cells and luciferase promoter assays were used. DNA methylation of the CD24 promoter was significantly higher in tumors than in benign tissue and was associated with biochemical recurrence-free survival, tumor grade, and stage. CD24 mRNA and protein expression were significantly higher in T2E-positive, ERG-overexpressing, and/or PTEN-deficient cases. Higher levels of CD24 protein expression conferred shorter biochemical recurrence-free survival, and these observations were confirmed using The Cancer Genome Atlas prostate adenocarcinoma data. In silico analysis of the CD24 promoter revealed an ERG binding site in between the DNA methylation sites. ERG overexpression led to a strong induction of CD24 mRNA and protein expression. Luciferase promoter assays using the wild-type and mutated ERG binding site within the CD24 promoter showed ERG-dependent activation. Collectively, our results suggest that promoter DNA methylation of the CD24 gene and T2E fusion status are factors involved in the up-regulation of CD24 in patients with prostate cancer.
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http://dx.doi.org/10.1016/j.ajpath.2020.12.014DOI Listing
April 2021

Otoferlin is a prognostic biomarker in patients with clear cell renal cell carcinoma: A systematic expression analysis.

Int J Urol 2021 04 19;28(4):424-431. Epub 2021 Jan 19.

Department of Urology, University Hospital Bonn, Bonn, Germany.

Objectives: To comprehensively investigate the role of otoferlin as a prognostic and diagnostic biomarker in clear cell renal cell carcinoma.

Methods: Three independent cohorts were used to study otoferlin in clear cell renal cell carcinoma: The Cancer Genome Atlas cohort (messenger ribonucleic acid expression; clear cell renal cell carcinoma n = 514, normal renal tissue n = 81); study validation cohort (messenger ribonucleic acid expression; clear cell renal cell carcinoma n = 79, normal renal tissue n = 44); and immunohistochemistry cohort (protein expression; clear cell renal cell carcinoma n = 142, normal renal tissue n = 30). Otoferlin gene expressions were extracted from The Cancer Genome Atlas database or determined using quantitative real-time polymerase chain reaction, respectively. Protein expression was assessed using immunohistochemistry staining against otoferlin on tissue microarrays. Correlations between otoferlin messenger ribonucleic acid/protein expression and clinicopathological data/patient survival were statistically tested.

Results: Otoferlin messenger ribonucleic acid expression was significantly upregulated in clear cell renal cell carcinoma compared with normal renal tissue. High expression levels correlated with advanced stage, higher grade and metastatic tumors, accompanied by independent prognostic significance for overall and cancer-specific survival. In contrast, otoferlin protein expression was downregulated in tumor tissue. Although, high otoferlin expression in clear cell renal cell carcinoma was positively correlated with histological grading and independently predictive of a shortened progression-free survival.

Conclusion: Our data suggest otoferlin as an indicator of tumor aggressiveness and as a prognostic biomarker for patients with clear cell renal cell carcinoma, leading to the conclusion that otoferlin could promote the malignancy of clear cell renal cell carcinoma.
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http://dx.doi.org/10.1111/iju.14486DOI Listing
April 2021

Prognostic role of TSPAN1, KIAA1324 and ESRP1 in prostate cancer.

APMIS 2021 Apr 2;129(4):204-212. Epub 2021 Feb 2.

Institute of Pathology, University Hospital Bonn, Bonn, Germany.

The aim of this study was to validate prostate cancer-associated genes on transcript level and to assess the prognostic value of the most promising markers by immunohistochemistry. Based on differentially expressed genes found in a previous study, 84 genes were further validated using mRNA expression data and follow-up information from the Cancer Genome Atlas (TCGA) prostate cancer cohort (n = 497). Immunohistochemistry was used for validation of three genes in an independent, clinically annotated prostatectomy patient cohort (n = 175) with biochemical relapse as endpoint. Also, associations with clinicopathological variables were evaluated. Eleven protein-coding genes from the list of 84 genes were associated with biochemical recurrence-free survival on mRNA expression level in multivariate Cox-analyses. Three of these genes (TSPAN1, ESRP1 and KIAA1324) were immunohistochemically validated using an independent cohort of prostatectomy patients. Both ESRP1 and KIAA1324 were independently associated with biochemical recurrence-free survival. TSPAN1 was univariately prognostic but failed significance on multivariate analysis, probably due to its strong correlation with high Gleason scores. Multistep filtering using the publicly available TCGA cohort, data of an earlier expression profiling study which profiled 3023 cancer-associated transcripts in 42 primary prostate cancer cases, identified two novel candidate prognostic markers (ESRP1 and KIAA1324) of primary prostate cancer for further study.
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http://dx.doi.org/10.1111/apm.13117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986212PMC
April 2021

Management of Germ Cell Tumours of the Testis in Adult Patients. German Clinical Practice Guideline Part I: Epidemiology, Classification, Diagnosis, Prognosis, Fertility Preservation, and Treatment Recommendations for Localized Stages.

Urol Int 2021 7;105(3-4):169-180. Epub 2021 Jan 7.

II. Medical Clinic and Polyclinic, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Introduction: This is the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up on germ cell tumours (GCTs) of the testis in adult patients. We present the guideline content in two publications. Part I covers the topic's background, methods, epidemiology, classification systems, diagnostics, prognosis, and treatment recommendations for the localized stages.

Methods: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search was in March 2018) were provided. Thirty-one experts entitled to vote, rated the final clinical recommendations and statements.

Results: We provide 161 clinical recommendations and statements. We present information on the quality of cancer care and epidemiology and give recommendations for staging and classification as well as for diagnostic procedures. The diagnostic recommendations encompass measures for assessing the primary tumour as well as procedures for the detection of metastases. One chapter addresses prognostic factors. In part I, we separately present the treatment recommendations for germ cell neoplasia in situ, and the organ-confined stages (clinical stage I) of both seminoma and nonseminoma.

Conclusion: Although GCT is a rare tumour entity with excellent survival rates for the localized stages, its management requires an interdisciplinary approach, including several clinical experts. Quality of care is highly related to institutional expertise and can be reassured by established online-based second-opinion boards. There are very few studies on diagnostics with good level of evidence. Treatment of metastatic GCTs must be tailored to the risk according to the International Germ Cell Cancer Collaboration Group classification after careful diagnostic evaluation. An interdisciplinary approach as well as the referral of selected patients to centres with proven experience can help achieve favourable clinical outcomes.
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http://dx.doi.org/10.1159/000510407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006579PMC
July 2021

[Molecular pathology of urogenital tumors : Recommendations from the 2019 International Society of Urological Pathology (ISUP) Consensus Conference].

Pathologe 2021 May 4;42(3):310-318. Epub 2021 Jan 4.

Institut für Pathologie, Universitätsklinikum Bonn, Venusberg-Campus 1, Gebäude 62, 53127, Bonn, Deutschland.

Comprehensive understanding of molecular principles in cancer and the diversification of oncological therapy promise individual therapeutic concepts, which have not yet found their way into urogenital cancer therapy. In March 2019 the International Society of Urogenital Pathology (ISUP) therefore held a consensus conference on recommendations for molecular diagnostics of genitourinary tumors, which were published in five separate manuscripts and are summarized in this article.In preparation for the conference, a comprehensive survey of current practices for molecular testing of urogenital tumors was carried out by members of the ISUP. At the conference, the results and the corresponding background information were presented by five working groups and recommendations for action for diagnostics were developed. An agreement between 66% of the conference participants was defined as consensus.
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http://dx.doi.org/10.1007/s00292-020-00888-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084837PMC
May 2021

Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status.

Cancers (Basel) 2020 Dec 11;12(12). Epub 2020 Dec 11.

Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany.

Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic or germline variant. However, the underlying mechanism for around 80% of the patients with a family or personal history of DGC and LBC has so far not been elucidated. In this cohort study, patients meeting the 2015 HDGC clinical testing criteria were included, and subsequently, sequencing was performed. Of the 207 patients (161 families) in this study, we detected 21 pathogenic or likely pathogenic variants (PV) in 60 patients (28 families) and one PV in two patients from one family. Sixty-eight percent ( = 141) of patients were female. The overall PV detection rate was 18% (29/161 families). Criterion 1 and 3 of the 2015 HDGC testing criteria yielded the highest detection rate of PVs (21% and 28%). PV carriers and patients without proven PV were compared. Risk of gastric cancer (GC) (38/62 61% vs. 102/140 73%) and age at diagnosis (40 ± 13 years vs. 44 ± 12 years) were similar between the two groups. However, GC was more advanced in gastrectomy specimens of patients without PV (81% vs. 26%). LBC prevalence in female carriers of a PV was 20% ( = 8/40). Clinical phenotypes differed strongly between families with the same PV. Emphasis should be on detecting more causative genes predisposing for HDGC and improve the management of patients without a proven pathogenic germline variant.
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http://dx.doi.org/10.3390/cancers12123726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763201PMC
December 2020

Downstream Neighbor of SON (DONSON) Expression Is Enhanced in Phenotypically Aggressive Prostate Cancers.

Cancers (Basel) 2020 Nov 19;12(11). Epub 2020 Nov 19.

Department of Urology, University Hospital Bonn, 53127 Bonn, Germany.

Downstream neighbor of Son (DONSON) plays a crucial role in cell cycle progression and in maintaining genomic stability, but its role in prostate cancer (PCa) development and progression is still underinvestigated. Methods: DONSON mRNA expression was analyzed with regard to clinical-pathological parameters and progression using The Cancer Genome Atlas (TCGA) and two publicly available Gene Expression Omnibus (GEO) datasets of PCa. Afterwards, DONSON protein expression was assessed via immunohistochemistry on a comprehensive tissue microarray (TMA). Subsequently, the influence of a DONSON-knockdown induced by the transfection of antisense-oligonucleotides on proliferative capacity and metastatic potential was investigated. DONSON was associated with an aggressive phenotype in the PCa TCGA cohort, two GEO PCa cohorts, and our PCa TMA cohort as DONSON expression was particularly strong in locally advanced, metastasized, and dedifferentiated carcinomas. Thus, DONSON expression was notably upregulated in distant and androgen-deprivation resistant metastases. In vitro, specific DONSON-knockdown significantly reduced the migration capacity in the PCa cell lines PC-3 and LNCaP, which further suggests a tumor-promoting role of DONSON in PCa. In conclusion, the results of our comprehensive expression analyses, as well as the functional data obtained after DONSON-depletion, lead us to the conclusion that DONSON is a promising prognostic biomarker with oncogenic properties in PCa.
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http://dx.doi.org/10.3390/cancers12113439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699366PMC
November 2020

CTLA4 promoter methylation predicts response and progression-free survival in stage IV melanoma treated with anti-CTLA-4 immunotherapy (ipilimumab).

Cancer Immunol Immunother 2021 Jun 16;70(6):1781-1788. Epub 2020 Nov 16.

Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Venusberg-Campus, 53127, Bonn, Germany.

Anti-CTLA-4-antibodies can induce long-lasting tumor remissions. However, only a few patients respond, necessitating the development of predictive companion biomarkers. Increasing evidence suggests a major role of epigenetics, including DNA methylation, in immunology and resistance to immune checkpoint blockade. Here, we tested CTLA4 promoter methylation and CTLA-4 protein expression as predictive biomarkers for response to anti-CTLA-4 immunotherapy. We identified retrospectively N = 30 stage IV melanoma patients treated with single-agent anti-CTLA-4 immunotherapy (ipilimumab). We used quantitative methylation-specific PCR and immunohistochemistry to quantify CTLA4 methylation and protein expression in pre-treatment samples. CTLA4 methylation was significantly higher in progressive as compared to responding tumors and significantly associated with progression-free survival. A subset of infiltrating lymphocytes and tumor cells highly expressed CTLA-4. However, CTLA-4 protein expression did not predict response to treatment. We conclude that CTLA4 methylation is a predictive biomarker for response to anti-CTLA-4 immunotherapy.
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http://dx.doi.org/10.1007/s00262-020-02777-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139923PMC
June 2021

Mitophagy-associated genes PINK1 and PARK2 are independent prognostic markers of survival in papillary renal cell carcinoma and associated with aggressive tumor behavior.

Sci Rep 2020 11 2;10(1):18857. Epub 2020 Nov 2.

Institute of Pathology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

The aim of this study was to investigate the mitophagy-related genes PINK1 and PARK2 in papillary renal cell carcinoma and their association with prognosis. In silico data of PINK1 and PARK2 were analyzed in TCGA cohorts of papillary renal cell carcinoma comprising 290 tumors and 33 corresponding non-neoplastic renal tissues. Protein expression data from a cohort of 95 papillary renal cell carcinoma patients were analyzed and associated with clinical-pathological parameters including survival. PINK1 and PARK2 were significantly downregulated in papillary renal cell carcinoma at transcript and protein levels. Reduced transcript levels of PINK1 and PARK2 were negatively associated with overall survival (p < 0.05). At the protein level, PARK2 and PINK1 expression were positively correlated (correlation coefficient 0.286, p = 0.04) and reduced PINK1 protein expression was prognostic for shorter survival. Lower PINK1 protein levels were found in tumors with metastases at presentation and in tumors of higher pT-stages. The multivariate analysis revealed mRNA expression of PINK1 and PARK2 as well as PINK1 protein expression as independent prognostic factors for shorter overall survival. The downregulation of PINK1 is a strong predictor of poor survival in papillary renal cell carcinoma. Immunohistochemical PINK1 expression in resected pRCC should be considered as an additional prognostic marker for routine practice.
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http://dx.doi.org/10.1038/s41598-020-75258-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608557PMC
November 2020

Detection of AR-V7 in primary prostate cancer.

Cancer Treat Res Commun 2021 24;28:100230. Epub 2020 Oct 24.

Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany; Department of Urology, University Hospital Heidelberg, National Center for Tumor Diseases (NCT) Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.ctarc.2020.100230DOI Listing
October 2020

Cultivation of Clear Cell Renal Cell Carcinoma Patient-Derived Organoids in an Air-Liquid Interface System as a Tool for Studying Individualized Therapy.

Front Oncol 2020 22;10:1775. Epub 2020 Sep 22.

Institute of Pathology, University Hospital Bonn, Bonn, Germany.

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer accounting for 80% of all renal cancers as well as the majority of renal cancer-associated deaths. During the last decade, the treatment paradigm for ccRCC has radically changed. In particular, the recent development of immune checkpoint inhibitors (ICI) has led to an increased overall survival in the metastatic setting. Moreover, novel immune therapies targeting the tumor microenvironment have been developed. In this rapidly evolving treatment landscape, precise tools for personalized cancer therapy are needed. Here, we collected fresh tissue from 42 patients who underwent surgical resection for renal cell carcinoma. Part of the tissue was used to obtain formalin-fixed, paraffin-embedded samples or RNA. The remaining tissue was minced and cultured in a collagen-based three-dimensional, air-liquid interface (ALI) culture system. The generated patient-derived tumor organoids (ALI PDOs) were characterized by immunohistochemistry staining and RNA sequencing to validate their close similarity to the matched tumor. Immune cells and stromal cells within the microenvironment could be identified. Finally, we treated 10 ALI PDOs with the commonly used targeted cancer drug cabozantinib or the ICI nivolumab. Interestingly, we observed varying responses of ALI PDOs to these treatments and future studies are needed to investigate whether the ALI PDO approach could inform about treatment responses in patients. In conclusion, this three-dimensional ccRCC culture model represents a promising, facile tool for monitoring tumor responses to different types of therapies in a controlled manner, yet, still preserves the key features of the tumor of origin.
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http://dx.doi.org/10.3389/fonc.2020.01775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537764PMC
September 2020

CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8 T Cells.

Immunity 2020 10;53(4):805-823.e15

Institute of Pathology, University Hospital Bonn, University of Bonn, Bonn, Germany.

The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8 TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226 TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226CD8 T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.
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http://dx.doi.org/10.1016/j.immuni.2020.09.010DOI Listing
October 2020

Comprehensive Analysis of the ATP-binding Cassette Subfamily B Across Renal Cancers Identifies ABCB8 Overexpression in Phenotypically Aggressive Clear Cell Renal Cell Carcinoma.

Eur Urol Focus 2020 Sep 30. Epub 2020 Sep 30.

Department of Urology, University Hospital Bonn, Bonn, Germany; Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany. Electronic address:

Background: ATP-binding cassette (ABC) transporters play a crucial role in the development of multidrug resistance in diverse cancer entities.

Objective: Our study was designed to comprehensively analyze the ABC subfamily B (ABCB) in renal cell carcinoma (RCC) using The Cancer Genome Atlas (TCGA) datasets.

Design, Setting, And Participants: We performed systematic survival analyses of ABCB1-10 using the TCGA datasets for clear cell, papillary, and chromophobe RCC.

Outcome Measurements And Statistical Analysis: Results were validated via quantitative polymerase chain reaction in a clear cell RCC (ccRCC) cohort containing 152 samples. Afterward, ABCB8 protein expression was assessed in a tissue microarray RCC cohort (n = 144) by immunohistochemistry with subsequent quantitative image analysis. In vitro, antisense oligonucleotide-induced ABCB8 knockdowns were established in ACHN and CAKI1 following functional analyses.

Results And Limitations: Various ABCB members have prognostic value among the three most occurring RCC subtypes. Of note, ABCB8 was identified as the most prognostic ABCB gene in the RCC TCGA cohorts. Further, ABCB8 proved to be an independent predictor of shortened cancer-specific survival in three independent cohorts. In vitro, specific ABCB8 knockdown reduced viability and migration capacity in ACHN and CAKI1.

Conclusions: ABCB8 was identified as a promising prognostic biomarker. Functional analyses suggest a tumor-promoting role of ABCB8 in ccRCC.

Patient Summary: In this study, the transporter gene ABCB8 proved to be a risk predictor of a worse clinical course in clear cell renal cell carcinoma. In the renal cell carcinoma cell culture model, depletion of this gene led to a reduction in the malignant potential, and inhibition of this gene may therefore possess a therapeutic value.
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http://dx.doi.org/10.1016/j.euf.2020.09.007DOI Listing
September 2020
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