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

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

doi:10.1016/j.ccr.2013.01.002

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

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 HutterRolf 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

244 Citations (Scopus)

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.

Original language	English
Journal	Cancer Cell
Volume	23
Issue number	2
Pages (from-to)	159-70
Number of pages	12
ISSN	1535-6108
DOIs	https://doi.org/10.1016/j.ccr.2013.01.002
Publication status	Published - 11 Feb 2013
Externally published	Yes

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10.1016/j.ccr.2013.01.002

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Weischenfeldt, J., Simon, R., Feuerbach, L., Schlangen, K., Weichenhan, D., Minner, S., Wuttig, D., Warnatz, H-J., Stehr, H., Rausch, T., Jäger, N., Gu, L., Bogatyrova, O., Stütz, A. M., Claus, R., Eils, J., Eils, R., Gerhäuser, C., Huang, P-H., ... Schlomm, T. (2013). Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell, 23(2), 159-70. https://doi.org/10.1016/j.ccr.2013.01.002

Weischenfeldt, J, Simon, R, Feuerbach, L, Schlangen, K, Weichenhan, D, Minner, S, Wuttig, D, Warnatz, H-J, Stehr, H, Rausch, T, Jäger, N, Gu, L, Bogatyrova, O, Stütz, AM, Claus, R, Eils, J, Eils, R, Gerhäuser, C, Huang, P-H, Hutter, B, Kabbe, R, Lawerenz, C, Radomski, S, Bartholomae, CC, Fälth, M, Gade, S, Schmidt, M, Amschler, N, Haß, T, Galal, R, Gjoni, J, Kuner, R, Baer, C, Masser, S, von Kalle, C, Zichner, T, Benes, V, Raeder, B, Mader, M, Amstislavskiy, V, Avci, M, Lehrach, H, Parkhomchuk, D, Sultan, M, Burkhardt, L, Graefen, M, Huland, H, Kluth, M, Krohn, A, Sirma, H, Stumm, L, Steurer, S, Grupp, K, Sültmann, H, Sauter, G, Plass, C, Brors, B, Yaspo, M-L, Korbel, JO & Schlomm, T 2013, 'Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer', Cancer Cell, vol. 23, no. 2, pp. 159-70. https://doi.org/10.1016/j.ccr.2013.01.002

@article{47ed0163a57c40798843690be9bcb574,

title = "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.",

keywords = "Adult, Aged, Aged, 80 and over, Computational Biology, Gene Rearrangement, Genomics, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Oncogene Proteins, Fusion, Prostatic Neoplasms, Receptors, Androgen, Serine Endopeptidases, Trans-Activators",

author = "Joachim Weischenfeldt and Ronald Simon and Lars Feuerbach and Karin Schlangen and Dieter Weichenhan and Sarah Minner and Daniela Wuttig and Hans-J{\"o}rg Warnatz and Henning Stehr and Tobias Rausch and Natalie J{\"a}ger and Lei Gu and Olga Bogatyrova and St{\"u}tz, {Adrian M} and Rainer Claus and J{\"u}rgen Eils and Roland Eils and Clarissa Gerh{\"a}user and Po-Hsien Huang and Barbara Hutter and Rolf Kabbe and Christian Lawerenz and Sylwester Radomski and Bartholomae, {Cynthia C} and Maria F{\"a}lth and Stephan Gade and Manfred Schmidt and Nina Amschler and Thomas Ha{\ss} and Rami Galal and Jovisa Gjoni and Ruprecht Kuner and Constance Baer and Sawinee Masser and {von Kalle}, Christof and Thomas Zichner and Vladimir Benes and Benjamin Raeder and Malte Mader and Vyacheslav Amstislavskiy and Meryem Avci and Hans Lehrach and Dmitri Parkhomchuk and Marc Sultan and Lia Burkhardt and Markus Graefen and Hartwig Huland and Martina Kluth and Antje Krohn and H{\"u}seyin Sirma and Laura Stumm and Stefan Steurer and Katharina Grupp and Holger S{\"u}ltmann and Guido Sauter and Christoph Plass and Benedikt Brors and Marie-Laure Yaspo and Korbel, {Jan O} and Thorsten Schlomm",

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doi = "10.1016/j.ccr.2013.01.002",

language = "English",

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journal = "Cancer Cell",

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T1 - Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer

AU - Weischenfeldt, Joachim

AU - Simon, Ronald

AU - Feuerbach, Lars

AU - Schlangen, Karin

AU - Weichenhan, Dieter

AU - Minner, Sarah

AU - Wuttig, Daniela

AU - Warnatz, Hans-Jörg

AU - Stehr, Henning

AU - Rausch, Tobias

AU - Jäger, Natalie

AU - Gu, Lei

AU - Bogatyrova, Olga

AU - Stütz, Adrian M

AU - Claus, Rainer

AU - Eils, Jürgen

AU - Eils, Roland

AU - Gerhäuser, Clarissa

AU - Huang, Po-Hsien

AU - Hutter, Barbara

AU - Kabbe, Rolf

AU - Lawerenz, Christian

AU - Radomski, Sylwester

AU - Bartholomae, Cynthia C

AU - Fälth, Maria

AU - Gade, Stephan

AU - Schmidt, Manfred

AU - Amschler, Nina

AU - Haß, Thomas

AU - Galal, Rami

AU - Gjoni, Jovisa

AU - Kuner, Ruprecht

AU - Baer, Constance

AU - Masser, Sawinee

AU - von Kalle, Christof

AU - Zichner, Thomas

AU - Benes, Vladimir

AU - Raeder, Benjamin

AU - Mader, Malte

AU - Amstislavskiy, Vyacheslav

AU - Avci, Meryem

AU - Lehrach, Hans

AU - Parkhomchuk, Dmitri

AU - Sultan, Marc

AU - Burkhardt, Lia

AU - Graefen, Markus

AU - Huland, Hartwig

AU - Kluth, Martina

AU - Krohn, Antje

AU - Sirma, Hüseyin

AU - Stumm, Laura

AU - Steurer, Stefan

AU - Grupp, Katharina

AU - Sültmann, Holger

AU - Sauter, Guido

AU - Plass, Christoph

AU - Brors, Benedikt

AU - Yaspo, Marie-Laure

AU - Korbel, Jan O

AU - Schlomm, Thorsten

PY - 2013/2/11

Y1 - 2013/2/11

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Computational Biology

KW - Gene Rearrangement

KW - Genomics

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Male

KW - Middle Aged

KW - Oncogene Proteins, Fusion

KW - Prostatic Neoplasms

KW - Receptors, Androgen

KW - Serine Endopeptidases

KW - Trans-Activators

U2 - 10.1016/j.ccr.2013.01.002

DO - 10.1016/j.ccr.2013.01.002

M3 - Journal article

C2 - 23410972

SN - 1535-6108

VL - 23

SP - 159

EP - 170

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

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

Abstract

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