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Intern
    Onkologische Forschung

    Panel-NGS in Adrenocortical Carcinoma

    Precision medicine in adrenocortical carcinoma – Molecular signature for prognostication and targeted therapy (collaboration among Endocrinology, Pathology, Human Genetics and Bioinformatics Unit CCC)

    Summary:

    Adrenocortical carcinoma (ACC) is a rare disease with poor prognosis and limited treatment options. This project aims to improve patient care by establishing a better prognostic score and identification of new drugable targets.

    Following first experience with exome sequencing in benign endocrine tumors (Beuschlein 2014, Reincke 2015, Calebiro 2016), we characterized (as part of two international consortia) large series of fresh frozen tumor material of ACC samples using comprehensive "multiple omic strategies" (Assie 2014, Zheng 2016). To apply these results for clinical use, we recently investigated the molecular signature of more than 100 formalin-fixed paraffin-embedded ACC tumor samples using targeted next generation sequencing (for mutations and copy number variations) and pyrosequencing (for methylation in promoter regions of selected genes). With this approach, we identified a restricted number of molecular alterations (i.e. total number of mutations, alterations in Wnt/β catenin and/or Rb/p53 pathways, and high methylation pattern) that might significantly improve the prognostic stratification of patients with ACC. In addition, we could pinpoint potential drugable events, which are particularly required for patients with advanced disease (manuscript in preparation).

    The current project aims to validate our ACC-specific combined score in an independent prospective series of patients by using a customized gene panel. Moreover, we intend to establish a reliable method for the isolation and sequencing of circulating tumor DNA for the early detection of disease recurrences (liquid biopsy). Our study will pave the way toward a precision medicine approach for patients with ACC.

    Recent Publications

    Altieri B, Sbiera S, Della Casa S, Weigand I, Wild V, Steinhauer S, Fadda G, Kocot A, Bekteshi M, Mambretti EM, Rosenwald A, Pontecorvi A, Fassnacht M, Ronchi CL. Livin/BIRC7 expression as malignancy marker in adrenocortical tumors. Oncotarget. 2017 8(6):9323-9338

    Assié G, Letouzé E, Fassnacht M, Jouinot A, Luscap W, Barreau O, Omeiri H, Rodriguez S, Perlemoine K, René-Corail F, Elarouci N, Sbiera S, Kroiss M, Allolio B, Waldmann J, Quinkler M, Mannelli M, Mantero F, Papathomas T, De Krijger R, Tabarin A, Kerlan V, Baudin E, Tissier F, Dousset B, Groussin L, Amar L, Clauser E, Bertagna X, Ragazzon B, Beuschlein F, Libé R, de Reyniès A, Bertherat J. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet. 2014 46(6):607-12. 

    Beuschlein F*, Fassnacht M*, Assié G*, Calebiro D*, Stratakis CA, Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR, Schaak K, Schmittfull A, Schwarzmayr T, Barreau O, Vezzosi D, Rizk-Rabbin M, Zabel U, Szarek E, Salpea P, Forlino A, Vetro A, Zuffardi O, Kisker C, Diener S, Meitinger T, Lohse MJ, Reincke M, Bertherat J, Strom TM, Allolio B. 2014 Constitutive Activation of PRKACA in Adrenal Cushing's Syndrome. N Engl J Med 370(11):1019-28

    Calebiro D, Grassi ES, Eszlinger M, Ronchi CL, Godbole A, Bathon K, Guizzardi F, de Filippis T, Krohn K, Jaeschke H, Schwarzmayr T, Bircan R, Gozu HI, Sancak S, Niedziela M, Strom TM, Fassnacht M, Persani L, Paschke R. 2016. Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas. J Clin Invest. 126(9):3383-8

    Fassnacht M, Berruti A, Baudin E, Demeure MJ, Gilbert J, Haak H, Kroiss M, Quinn DI, Hesseltine E, Ronchi CL, Terzolo M, Choueiri TK, Poondru S, Fleege T, Rorig R, Chen J, Stephens AW, Worden F, Hammer GD. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol. 2015 16(4):426-35.

    Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardière C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Müller HH, Skogseid B; the FIRM-ACT Study Group. 2012 Combination Chemotherapy in Advanced Adrenocortical Carcinoma. N Engl J Med. 366 (23): 2189-97

    Henning JEK, Deutschbein T, Altieri B, Steinhauer S, Kircher S, Sbiera S, Wild V, Schlötelburg W, Kroiss M, Perotti P, Rosenwald A, Berruti A, Fassnacht M, Ronchi CL. Gemcitabine-Based Chemotherapy in Adrenocortical Carcinoma: A Multicenter Study of Efficacy and Predictive Factors. J Clin Endocrinol Metab. 2017 102(11):4323-4332. 

    Laufs V, Altieri B, Sbiera S, Kircher S, Steinhauer S, Beuschlein F, Quinkler M, Willenberg HS, Rosenwald A, Fassnacht M, Ronchi CL. ERCC1 as predictive biomarker to platinum-based chemotherapy in adrenocortical carcinomas. Eur J Endocrinol. 2018 178(2):183-190

    Libé R, Borget I, Ronchi CL, Zaggia B, Kroiss M, Kerkhofs T, Bertherat J, Volante M, Quinkler M, Chabre O, Bala M, Tabarin A, Beuschlein F, Vezzosi D, Deutschbein T, Borson-Chazot F, Hermsen I, Stell A, Fottner C, Leboulleux S, Hahner S, Mannelli M, Berruti A, Haak H, Terzolo M, Fassnacht M, Baudin E; ENSAT network.  Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study. Ann Oncol. 2015 26(10):2119-25.

    Reincke M*, Sbiera S*, Hayakawa A, Theodoropoulou M, Osswald A, Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K, Saeki Y, Tanaka K, Wieland T, Graf E, Saeger W, Ronchi CL, Allolio B, Buchfelder M, Strom TM, Fassnacht M*, Komada M*. 2015 Mutations in the deubiquitinase gene USP8 cause Cushing's disease. Nat Genet. 47(1):31-8

    Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA, Lerario AM, Else T, Knijnenburg TA, Ciriello G, Kim S, Assie G, Morozova O, Akbani R, Shih J, Hoadley KA, Choueiri TK, Waldmann J, Mete O, Robertson AG, Wu HT, Raphael BJ, Shao L, Meyerson M, Demeure MJ, Beuschlein F, Gill AJ, Sidhu SB, Almeida MQ, Fragoso MCBV, Cope LM, Kebebew E, Habra MA, Whitsett TG, Bussey KJ, Rainey WE, Asa SL, Bertherat J, Fassnacht M, Wheeler DA; Cancer Genome Atlas Research Network, Hammer GD, Giordano TJ, Verhaak RGW. Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma. Cancer Cell. 2016 30(2):363. 

    Kontakt

    Comprehensive Cancer Center Mainfranken
    Haus C16
    Josef-Schneider Str. 6
    97080 Würzburg

    Tel.: +49 931 201-35350
    Fax: +49 931 201-35359
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