Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories

Clarissa Gerhauser; Francesco Favero; Thomas Risch; Ronald Simon; Lars Feuerbach; Yassen Assenov; Doreen Heckmann; Nikos Sidiropoulos; Sebastian M. Waszak; Daniel Hübschmann; Alfonso Urbanucci; Etsehiwot G. Girma; Vladimir Kuryshev; Leszek J. Klimczak; Natalie Saini; Adrian M. Stütz; Dieter Weichenhan; Lisa Marie Böttcher; Reka Toth; Josephine D. Hendriksen; Christina Koop; Pavlo Lutsik; Sören Matzk; Hans Jörg Warnatz; Vyacheslav Amstislavskiy; Clarissa Feuerstein; Benjamin Raeder; Olga Bogatyrova; Eva Maria Schmitz; Claudia Hube-Magg; Martina Kluth; Hartwig Huland; Markus Graefen; Chris Lawerenz; Gervaise H. Henry; Takafumi N. Yamaguchi; Alicia Malewska; Jan Meiners; Daniela Schilling; Eva Reisinger; Roland Eils; Matthias Schlesner; Douglas W. Strand; Robert G. Bristow; Paul C. Boutros; Christof von Kalle; Dmitry Gordenin; Holger Sültmann; Benedikt Brors; Guido Sauter; Christoph Plass; Marie Laure Yaspo; Jan O. Korbel; Thorsten Schlomm; Joachim Weischenfeldt

doi:10.1016/j.ccell.2018.10.016

Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories

Clarissa Gerhauser, Francesco Favero, Thomas Risch, Ronald Simon, Lars Feuerbach, Yassen Assenov, Doreen Heckmann, Nikos Sidiropoulos, Sebastian M. Waszak, Daniel Hübschmann, Alfonso Urbanucci, Etsehiwot G. Girma, Vladimir Kuryshev, Leszek J. Klimczak, Natalie Saini, Adrian M. Stütz, Dieter Weichenhan, Lisa Marie Böttcher, Reka Toth, Josephine D. HendriksenChristina Koop, Pavlo Lutsik, Sören Matzk, Hans Jörg Warnatz, Vyacheslav Amstislavskiy, Clarissa Feuerstein, Benjamin Raeder, Olga Bogatyrova, Eva Maria Schmitz, Claudia Hube-Magg, Martina Kluth, Hartwig Huland, Markus Graefen, Chris Lawerenz, Gervaise H. Henry, Takafumi N. Yamaguchi, Alicia Malewska, Jan Meiners, Daniela Schilling, Eva Reisinger, Roland Eils, Matthias Schlesner, Douglas W. Strand, Robert G. Bristow, Paul C. Boutros, Christof von Kalle, Dmitry Gordenin, Holger Sültmann, Benedikt Brors, Guido Sauter, Christoph Plass, Marie Laure Yaspo, Jan O. Korbel^*, Thorsten Schlomm, Joachim Weischenfeldt

^*Corresponding author for this work

60 Citations (Scopus)

Abstract

Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples. Gerhauser et al. molecularly characterize prostate cancers diagnosed before 56 years old, which reveals an APOBEC-driven mutational process and identifies an aggressive subgroup with increased expression of ESRP1. They develop a framework to predict the order of somatic alterations and clinical outcome.

Original language	English
Journal	Cancer Cell
Volume	34
Issue number	6
Pages (from-to)	996-1011.e8
Number of pages	24
ISSN	1535-6108
DOIs	https://doi.org/10.1016/j.ccell.2018.10.016
Publication status	Published - 2018

Keywords

APOBEC
cancer genomics
early-onset cancer
epigenetic risk-score
mutational processes
prostate cancer
structural variants
tumor evolution
tumor evolution prediction

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Gerhauser, C., Favero, F., Risch, T., Simon, R., Feuerbach, L., Assenov, Y., Heckmann, D., Sidiropoulos, N., Waszak, S. M., Hübschmann, D., Urbanucci, A., Girma, E. G., Kuryshev, V., Klimczak, L. J., Saini, N., Stütz, A. M., Weichenhan, D., Böttcher, L. M., Toth, R., ... Weischenfeldt, J. (2018). Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories. Cancer Cell, 34(6), 996-1011.e8. https://doi.org/10.1016/j.ccell.2018.10.016

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 2018, 'Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories', Cancer Cell, vol. 34, no. 6, pp. 996-1011.e8. https://doi.org/10.1016/j.ccell.2018.10.016

@article{87c2358ff8ee42a0a8a56507782cb235,

title = "Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories",

abstract = "Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples. Gerhauser et al. molecularly characterize prostate cancers diagnosed before 56 years old, which reveals an APOBEC-driven mutational process and identifies an aggressive subgroup with increased expression of ESRP1. They develop a framework to predict the order of somatic alterations and clinical outcome.",

keywords = "APOBEC, cancer genomics, early-onset cancer, epigenetic risk-score, mutational processes, prostate cancer, structural variants, tumor evolution, tumor evolution prediction",

author = "Clarissa Gerhauser and Francesco Favero and Thomas Risch and Ronald Simon and Lars Feuerbach and Yassen Assenov and Doreen Heckmann and Nikos Sidiropoulos and Waszak, {Sebastian M.} and Daniel H{\"u}bschmann and Alfonso Urbanucci and Girma, {Etsehiwot G.} and Vladimir Kuryshev and Klimczak, {Leszek J.} and Natalie Saini and St{\"u}tz, {Adrian M.} and Dieter Weichenhan and B{\"o}ttcher, {Lisa Marie} and Reka Toth and Hendriksen, {Josephine D.} and Christina Koop and Pavlo Lutsik and S{\"o}ren Matzk and Warnatz, {Hans J{\"o}rg} and Vyacheslav Amstislavskiy and Clarissa Feuerstein and Benjamin Raeder and Olga Bogatyrova and Schmitz, {Eva Maria} and Claudia Hube-Magg and Martina Kluth and Hartwig Huland and Markus Graefen and Chris Lawerenz and Henry, {Gervaise H.} and Yamaguchi, {Takafumi N.} and Alicia Malewska and Jan Meiners and Daniela Schilling and Eva Reisinger and Roland Eils and Matthias Schlesner and Strand, {Douglas W.} and Bristow, {Robert G.} and Boutros, {Paul C.} and {von Kalle}, Christof and Dmitry Gordenin and Holger S{\"u}ltmann and Benedikt Brors and Guido Sauter and Christoph Plass and Yaspo, {Marie Laure} and Korbel, {Jan O.} and Thorsten Schlomm and Joachim Weischenfeldt",

year = "2018",

doi = "10.1016/j.ccell.2018.10.016",

language = "English",

volume = "34",

pages = "996--1011.e8",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

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T1 - Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories

AU - Gerhauser, Clarissa

AU - Favero, Francesco

AU - Risch, Thomas

AU - Simon, Ronald

AU - Feuerbach, Lars

AU - Assenov, Yassen

AU - Heckmann, Doreen

AU - Sidiropoulos, Nikos

AU - Waszak, Sebastian M.

AU - Hübschmann, Daniel

AU - Urbanucci, Alfonso

AU - Girma, Etsehiwot G.

AU - Kuryshev, Vladimir

AU - Klimczak, Leszek J.

AU - Saini, Natalie

AU - Stütz, Adrian M.

AU - Weichenhan, Dieter

AU - Böttcher, Lisa Marie

AU - Toth, Reka

AU - Hendriksen, Josephine D.

AU - Koop, Christina

AU - Lutsik, Pavlo

AU - Matzk, Sören

AU - Warnatz, Hans Jörg

AU - Amstislavskiy, Vyacheslav

AU - Feuerstein, Clarissa

AU - Raeder, Benjamin

AU - Bogatyrova, Olga

AU - Schmitz, Eva Maria

AU - Hube-Magg, Claudia

AU - Kluth, Martina

AU - Huland, Hartwig

AU - Graefen, Markus

AU - Lawerenz, Chris

AU - Henry, Gervaise H.

AU - Yamaguchi, Takafumi N.

AU - Malewska, Alicia

AU - Meiners, Jan

AU - Schilling, Daniela

AU - Reisinger, Eva

AU - Eils, Roland

AU - Schlesner, Matthias

AU - Strand, Douglas W.

AU - Bristow, Robert G.

AU - Boutros, Paul C.

AU - von Kalle, Christof

AU - Gordenin, Dmitry

AU - Sültmann, Holger

AU - Brors, Benedikt

AU - Sauter, Guido

AU - Plass, Christoph

AU - Yaspo, Marie Laure

AU - Korbel, Jan O.

AU - Schlomm, Thorsten

AU - Weischenfeldt, Joachim

PY - 2018

Y1 - 2018

N2 - Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples. Gerhauser et al. molecularly characterize prostate cancers diagnosed before 56 years old, which reveals an APOBEC-driven mutational process and identifies an aggressive subgroup with increased expression of ESRP1. They develop a framework to predict the order of somatic alterations and clinical outcome.

AB - Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples. Gerhauser et al. molecularly characterize prostate cancers diagnosed before 56 years old, which reveals an APOBEC-driven mutational process and identifies an aggressive subgroup with increased expression of ESRP1. They develop a framework to predict the order of somatic alterations and clinical outcome.

KW - APOBEC

KW - cancer genomics

KW - early-onset cancer

KW - epigenetic risk-score

KW - mutational processes

KW - prostate cancer

KW - structural variants

KW - tumor evolution

KW - tumor evolution prediction

U2 - 10.1016/j.ccell.2018.10.016

DO - 10.1016/j.ccell.2018.10.016

M3 - Journal article

C2 - 30537516

AN - SCOPUS:85057262396

SN - 1535-6108

VL - 34

SP - 996-1011.e8

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories

Abstract

Keywords

UN SDGs

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