Intern
Krebsforschung

Adrenokortikales Karzinom

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 NEJM 2014, Reincke Nat Gen 2015, Calebiro Nat Comm 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 Nat Gen 2014, Zheng Cancer Cell 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 (Lippert JCEM 2018). In addition, we could pinpoint potential drugable events, which are particularly required for patients with advanced disease (Liang Front Endo 2020). We also investigate biomarkers that predict clinical outcome to immunotherapies in ACC.

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 are establishing a reliable method for the isolation and sequencing of circulating tumor DNA for the early detection of disease recurrences (liquid biopsy). Furthermore, we perform – together with the NCT in Heidelberg – whole genome sequencing in ACC to identify drugable targets for individual patients. Our study will pave the way toward a precision medicine approach for patients with ACC.

Recent Publications

Horak P, Heining C, Kreutzfeldt S, Hutter B, Mock A, Hüllein J, Fröhlich M, Uhrig S, Jahn A, Rump A, Gieldon L, Möhrmann L, Hanf D, Teleanu V, Heilig CE, Lipka DB, Allgäuer M, Ruhnke L, Laßmann A, Endris V, Neumann O, Penzel R, Beck K, Richter D, Winter U, Wolf S, Pfütze K, Geörg C, Meißburger B, Buchhalter I, Augustin M, Aulitzky WE, Hohenberger P, Kroiss M, Schirmacher P, Schlenk RF, Keilholz U, Klauschen F, Folprecht G, Bauer S, Siveke JT, Brandts CH, Kindler T, Boerries M, Illert AL, von Bubnoff N, Jost PJ, Spiekermann K, Bitzer M, Schulze-Osthoff K, von Kalle C, Klink B, Brors B, Stenzinger A, Schröck E, Hübschmann D, Weichert W, Glimm H, Fröhling S. Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers.

Cancer Discov. 2021 Nov;11(11):2780-2795. doi: 10.1158/2159-8290.CD-21-0126. Marquardt A, Landwehr LS, Ronchi CL, di Dalmazi G, Riester A, Kollmannsberger P, Altieri B, Fassnacht M, Sbiera S. Identifying New Potential Biomarkers in Adrenocortical Tumors Based on mRNA Expression Data Using Machine Learning. Cancers (Basel). 2021 Sep 17;13(18):4671. doi: 10.3390/cancers13184671.

Kimpel O, Bedrose S, Megerle F, Berruti A, Terzolo M, Kroiss M, Mai K, Dekkers OM, Habra MA, Fassnacht M. 2021 Adjuvant platinum-based chemotherapy in radically resected adrenocortical carcinoma: a cohort study. Br J Cancer. 2021 Oct;125(9):1233-1238.

Landwehr LS, Schreiner J, Appenzeller S, Kircher S, Herterich S, Sbiera S, Fassnacht M, Kroiss M, Weigand I. A novel patient-derived cell line of adrenocortical carcinoma shows a pathogenic role of germline MUTYH mutation and high tumour mutational burden. Eur J Endocrinol. 2021 May 4;184(6):823-835

Fassnacht M, Assie G, Baudin E, Eisenhofer G, de la Fouchardiere C, Haak HR, de Krijger R, Porpiglia F, Terzolo M, Berruti A. 2020. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 31(11):1476-1490

Voronina N, Wong JKL, Hübschmann D, Hlevnjak M, Uhrig S, Heilig CE, Horak P, Kreutzfeldt S, Mock A, Stenzinger A, Hutter B, Fröhlich M, Brors B, Jahn A, Klink B, Gieldon L, Sieverling L, Feuerbach L, Chudasama P, Beck K, Kroiss M, Heining C, Möhrmann L, Fischer A, Schröck E, Glimm H, Zapatka M, Lichter P, Fröhling S, Ernst A. The landscape of chromothripsis across adult cancer types. Nat Commun. 2020 May 8;11(1):2320. doi: 10.1038/s41467-020-16134-7.

Jouinot A, Lippert J, Fassnacht M, de La Villeon B, Septier A, Neou M, Perlemoine K, Appenzeller S, Sibony M, Gaujoux S, Dousset B, Libe R, Groussin L, Ronchi CL, Assié G, Bertherat J. 2020. Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma. Endocr Connect. 2020 Jul;9(7):705-714. doi: 10.1530/EC-20-0228

Landwehr LS, Altieri B, Schreiner J, Sbiera I, Weigand I, Kroiss M, Fassnacht M, Sbiera S. 2020. Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma. J Immunother Cancer. 2020 May;8(1):e000469.

Liang R, Weigand I, Lippert J, Kircher S, Altieri B, Steinhauer S, Hantel C, Rost S, Rosenwald A, Kroiss M, Fassnacht M, Sbiera S, Ronchi CL. 2020. Targeted Gene Expression Profile Reveals CDK4 as Therapeutic Target for Selected Patients With Adrenocortical Carcinoma. Front Endocrinol (Lausanne). 2020 Apr 16;11:219. doi: 10.3389/fendo.2020.00219. eCollection 2020.

Sun N, Kunzke T, Sbiera S, Kircher S, Feuchtinger A, Aichler M, Herterich S, Ronchi CL, Weigand I, Schlegel N, Waldmann J, Candida Villares Fragoso M, Whitsett TG, Gill AJ, Fassnacht M, Walch A, Kroiss M. 2019 Prognostic Relevance of Steroid Sulfation in Adrenocortical Carcinoma Revealed by Molecular Phenotyping Using High-Resolution Mass Spectrometry Imaging. Clin Chem. 65(10):1276-1286

Assié G, Jouinot A, Fassnacht M, Libé R, Garinet S, Jacob L, Hamzaoui N, Neou M, Sakat J, de La Villéon B, Perlemoine K, Ragazzon B, Sibony M, Tissier F, Gaujoux S, Dousset B, Sbiera S, Ronchi CL, Kroiss M, Korpershoek E, De Krijger R, Waldmann J, Quinkler M, Haissaguerre M, Tabarin A, Chabre O, Luconi M, Mannelli M, Groussin L, Bertagna X, Baudin E, Amar L, Coste J, Beuschlein F, Bertherat J. 2019. Value of Molecular Classification for Prognostic Assessment of Adrenocortical Carcinoma. JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1558. [Epub ahead of print]