Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer.

Abstract

Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic "androgen-type" pathomechanism in EO-PCA.

• Authors: Joachim Weischenfeldt, Ronald Simon, Lars Feuerbach, Karin Schlangen, Dieter Weichenhan, Sarah Minner, Daniela Wuttig, Hans-Jörg Warnatz, Henning Stehr, Tobias Rausch, Natalie Jäger, Lei Gu, Olga Bogatyrova, Adrian M Stütz, Rainer Claus, Jürgen Eils, Roland Eils, Clarissa Gerhäuser, Po-Hsien Huang, Barbara Hutter, Rolf Kabbe, Christian Lawerenz, Sylwester Radomski, Cynthia C Bartholomae, Maria Fälth, Stephan Gade, Manfred Schmidt, Nina Amschler, Thomas Haß, Rami Galal, Jovisa Gjoni, Ruprecht Kuner, Constance Baer, Sawinee Masser, Christof von Kalle, Thomas Zichner, Vladimir Benes, Benjamin Raeder, Malte Mader, Vyacheslav Amstislavskiy, Meryem Avci, Hans Lehrach, Dmitri Parkhomchuk, Marc Sultan, Lia Burkhardt, Markus Graefen, Hartwig Huland, Martina Kluth, Antje Krohn, Hüseyin Sirma, Laura Stumm, Stefan Steurer, Katharina Grupp, Holger Sültmann, Guido Sauter, Christoph Plass, Benedikt Brors, Marie-Laure Yaspo, Jan O Korbel, Thorsten Schlomm
• Journal: Cancer cell (Cancer Cell) Vol. 23 Issue 2 Pg. 159-70 (Feb 11 2013) ISSN: 1878-3686 [Electronic] United States
• PMID: 23410972 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• AR protein, human
• ERG protein, human
• Oncogene Proteins, Fusion
• Receptors, Androgen
• Trans-Activators
• Transcriptional Regulator ERG
• Serine Endopeptidases
• TMPRSS2 protein, human

Topics

• Adult
• Aged
• Aged, 80 and over
• Computational Biology
• Gene Rearrangement
• Genomics
• High-Throughput Nucleotide Sequencing
• Humans
• Male
• Middle Aged
• Oncogene Proteins, Fusion (genetics)
• Prostatic Neoplasms (genetics)
• Receptors, Androgen (genetics)
• Serine Endopeptidases (genetics)
• Trans-Activators (genetics)
• Transcriptional Regulator ERG