Prostate Cancer Genomics and Transcriptomics

Functional analysis of coding and noncoding RNA in prostate cancer

In the framework of the ICGC project "The Genomes of Early Onset Prostate Cancers", we sequenced the transcriptomes (mRNA and miRNA) of 140 patient samples. To increase our understanding of processes contributing to prostate cancer progression, we have analyzed selected candidates from these signatures using cellular assays and RNA interference methodologies.

Selected Publications
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  • Angeles AK, Heckmann D, Flosdorf N, Duensing S, Sültmann H. The ERG-regulated LINC00920 promotes prostate cancer cell survival via the 14-3-3ε- FOXO pathway. Molecular Cancer Research 18(10):1545-1559, 2020
  • Gerhauser C, Favero F, Risch T, Simon R, Feuerbach L, Assenov Y, Heckmann D, Sidiropoulos N, Waszak SM, Hübschmann D, Urbanucci A, Girma EG, Kuryshev V, Klimczak LJ, Saini N, Stütz AM, Weichenhan D, Böttcher LM, Toth R, Hendriksen JD, Koop C, Lutsik P, Matzk S, Warnatz HJ, Amstislavskiy V, Feuerstein C, Raeder B, Bogatyrova O, Schmitz EM, Hube-Magg C, Kluth M, Huland H, Graefen M, Lawerenz C, Henry GH, Yamaguchi TN, Malewska A, Meiners J, Schilling D, Reisinger E, Eils R, Schlesner M, Strand DW, Bristow RG, Boutros PC, von Kalle C, Gordenin D, Sültmann H, Brors B, Sauter G, Plass C, Yaspo ML, Korbel JO, Schlomm T, Weischenfeldt J. Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories. Cancer Cell 34(6):996-1011, 2018
  • Angeles AK, Bauer S, Ratz L, Klauck SM, Sültmann H. Genome-Based Classification and Therapy of Prostate Cancer. Diagnostics (Basel) 8(3):62, 2018. Review.
  • Ratz L, Laible M, Kacprzyk LA, Wittig-Blaich SM, Tolstov Y, Duensing S, Altevogt P, Klauck SM, Sültmann H. TMPRSS2:ERG gene fusion variants induce TGF-ß signaling and epithelial to mesenchymal transition in human prostate cancer cells. Oncotarget 8(15):25115-25130, 2017
  • Pickl JMA, Tichy D, Kuryshev VY, Tolstov Y, Falkenstein M, Schüler J, Reidenbach D, Hotz-Wagenblatt A, Kristiansen G, Roth W, Hadaschik B, Hohenfellner M, Duensing S, Heckmann D, Sültmann H. Ago-RIP-Seq identifies Polycomb repressive complex I member CBX7 as a major target of miR-375 in prostate cancer progression. Oncotarget 7(37):59589-59603, 2016

Cooperations: Depts. of Urology and Molecular Urooncology at Heidelberg University Medical Center; Div. of Biostatistics, DKFZ

Support: German Federal Ministry for Education and Research (BMBF) in the program for medical genome research (NGFNplus); Institute for Medical Genome Research and Systems Biology, (IMGuS), Vienna, Austria; Austrian National Foundation; Austria Wirtschaftsservice GmbH.

Translational Genomics of Lung Cancer

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Lung cancer is the main cause of mortality among all malignancies in western countries. The prognosis of the disease is very poor. Thus, better diagnostic tools and more efficient and specific therapies are urgently required. We are analyzing the roles of genes and miRNAs in therapy resistance and perform mutation typing and Panel/exome sequencing of plasma DNA (Liquid biopsy) to monitor tumor progression and therapy.

Selected Publications:

  • Dietz S, Christopoulos P, Yuan Z, Gu L, Volckmar A-L, Ogrodnik SJ, Angeles AK, Dalle Fratte C, Zemojtel T, Schneider MA, Kazdal D, Endris V, Meister M, Muley T, Cecchin E, Reck M, Schlesner M, Thomas M, Stenzinger A, Sültmann H. Longitudinal therapy monitoring of ALK-positive non-small cell lung cancer by copy number profiling combined with targeted sequencing of cell-free DNA. EBioMedicine 62:103103, 2020
  • Dietz S, Lifshitz A, Kazdal D, Harms A, Endris V, Winter H, Stenzinger A, Warth A, Sill M, Tanay A, Sültmann H. Global DNA methylation reflects spatial heterogeneity and molecular evolution of lung adenocarcinomas. Int J Cancer 144(5):1061-1072, 2019
  • Dietz S, Harms A, Endris V, Eichhorn F, Kriegsmann M, Longuespée R, Stenzinger A, Sültmann H, Warth A, Kazdal D. Spatial distribution of EGFR and KRAS mutation frequencies correlates with histological growth patterns of lung adenocarcinomas. Int J Cancer 141(9):1841-1848, 2017
  • Riediger AL, Dietz S, Schirmer U, Meister M, Heinzmann-Groth I, Schneider M, Muley T, Thomas M, Sültmann H. Mutation analysis of circulating plasma DNA to determine response to EGFR tyrosine kinase inhibitor therapy of lung adenocarcinoma patients. Sci Rep 6:33505, 2016
  • Dietz S, Schirmer U, Mercé C, Kuryshev V, von Bubnoff N, Dahl E, Meister M, Muley T, Thomas M, Sültmann H. Low input whole-exome sequencing to determine the representation of the tumor exome in circulating DNA of non-small cell lung cancer patients. PLoS One 11(8):e0161012, 2016
  • Hülsmann H, Rolff J, Bender C, Jarahian M, Korf U, Herwig R, Fröhlich H, Thomas M, Merk J, Sültmann H, Kuner R. Activation of AMP-activated protein kinase (AMPK) sensitizes lung cancer cells and H1299 xenografts to Erlotinib. Lung Cancer 86(2):151-157, 2014
  • Kaduthanam S, Gade S, Meister M, Brase JC, Johannes M, Dienemann H, Warth A, Schnabel PA, Herth FJ, Sültmann H, Muley T, Kuner R. Serum miR-142-3p is associated with early relapse in operable lung adenocarcinoma patients. Lung Cancer S0169-5002(13):23-28, 2013

Cooperations: Thoraxklinik Heidelberg; Div. of Vertebrate Genomics, Max-Planck-Institute for Molecular Genetics, Berlin; Dept. of Pathology at Heidelberg University Medical Center; EPO GmbH, Berlin-Buch

Support: German Federal Ministry for Education and Research (BMBF) in the funding programs German Centers for Lung Research (DZL), Medical Systems Biology (PREDICT), and eBio (EPITREAT).

Genomics of Diseases

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Our genomics expertise is utilized in cooperative projects aiming at the analysis of genes and biological processes in diverse diseases. For example, we have contributed to the characterization of spatial and molecular heterogeneity of renal cell cancers, to the molecular analysis of exosome contents in mouse models and to the identification of the receptor for Hepatitis B viruses entering mammalian cells.

Selected Publications:

  • Dietz S, Sültmann H, Du Y, Reisinger E, Riediger AL, Volckmar AL, Stenzinger A, Schlesner M, Jäger D, Hohenfellner M, Duensing S, Grüllich C, Pahernik S. Patient-specific molecular alterations are associated with metastatic clear cell renal cell cancer progressing under tyrosine kinase inhibitor therapy. Oncotarget 8(43):74049-74057, 2017
  • Hoefflin R, Lahrmann B, Warsow G, Hübschmann D, Spath C, Walter B, Chen X, Hofer L, Macher-Goeppinger S, Tolstov Y, Korzeniewski N, Duensing A, Grüllich C, Jäger D, Perner S, Schönberg G, Nyarangi-Dix J, Isaac S, Hatiboglu G, Teber D, Hadaschik B, Pahernik S, Roth W, Eils R, Schlesner M, Sültmann H, Hohenfellner M, Grabe N, Duensing S. Spatial niche formation but not malignant progression is a driving force for intratumoral heterogeneity. Nat Commun 7:ncomms11845, 2016
  • Ridder K, Sevko A, Heide J, Dams M, Rupp A, Macas J, Starmann J, Tjwa M, Plate K, Sültmann H, Altevogt P, Umansky P, Momma S. Myeloid derived suppressor cells are the principal target for tumor-derived microvesicles in vivo. Oncoimmunology 4(6):e1008371, 2015
  • Zhang Z, Filzmayer C, Ni Y, Sültmann H, Mutz P, Hiet M-S, Vondran FWR, Bartenschlager R, Urban S. Hepatitis D Virus replication is sensed by MDA5 and induces IFN-β/λ responses in hepatocytes. J Hepatol 69(1):25-35, 2018

Cooperations: Depts. of Urology and Molecular Urooncology at Heidelberg University Medical Center; Institute for Neurology (Edinger Institute), Frankfurt; Hepatitis B Research Group, Heidelberg University

Support: DKFZ intramural funding; German Federal Ministry for Education and Research (BMBF) in the German Cancer Consortium (DKTK).

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