Integrative Genomic Analyses Reveal an Androgen-Driven Somatic Alteration Landscape in Early-Onset Prostate Cancer

Weischenfeldt, Joachim; Simon, Ronald; Feuerbach, Lars; Schlangen, Karin; Weichenhan, Dieter; Minner, Sarah; Wuttig, Daniela; Warnatz, Hans-Jörg; Stehr, Henning; Rausch, Tobias; Jäger, Natalie; Gu, Lei; Bogatyrova, Olga; Stütz, Adrian M.; Claus, Rainer; Eils, Jürgen; Eils, Roland; Gerhäuser, Clarissa; Huang, Po Hsien; Hutter, Barbara; Kabbe, Rolf; Lawerenz, Christian; Radomski, Sylwester; Bartholomae, Cynthia C.; Fälth, Maria; Gade, Stephan; Schmidt, Manfred; Amschler, Nina; Hass, Thomas; Galal, Rami; Gjoni, Jovisa; Kuner, Ruprecht; Baer, Constance; Masser, Sawinee; Kalle, Christof von; Zichner, Thomas; Beneš, Vladimír; Raeder, Benjamin; Mäder, Malte; Amstislavskiy, Vyacheslav; Avci, Meryem; Lehrach, Hans; Parkhomchuk, Dmitri; Sultan, Marc; Burkhardt, Lia; Graefen, Markus; Huland, Hartwig; Kluth, Martina; Krohn, Antje; Sirma, Hüseyin; Stumm, Laura; Steurer, Stefan; Grupp, Katharina; Sültmann, Holger; Sauter, Guido; Plass, Christoph; Brors, Benedikt; Yaspo, Marie Laure; Korbel, Jan O.; Schlomm, Thorsten

doi:10.1016/j.ccr.2013.01.002

Cited by 294 publications

(395 citation statements)

References 56 publications

(84 reference statements)

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“…We have previously used a break-apart FISH probe to demonstrate presence of PTEN breakage in 4% (including cases with simultaneous deletion of the remaining allele) of prostate cancers using a large prostate cancer prognosis tissue microarray containing a single tissue microarray core per donor tumor. 16 The results of our current heterogeneity study suggest that PTEN breakage may be much more frequent (18%), but may be a transient event during the development of complete PTEN loss. This assumption is based on the observation that all tumor foci with PTEN rearrangements also had tissue spots with partial and/or complete deletion of the broken PTEN allele, which can only be explained by initial PTEN breakage and subsequent deletion of chromosomal material flanking the breakpoint.…”

Section: Discussionmentioning

confidence: 62%

“…Next-generation sequencing studies performed by us 16 and others 22 revealed that PTEN can be disrupted by chromosomal breakage, resulting in partial deletions, inversions or translocations. We have previously used a break-apart FISH probe to demonstrate presence of PTEN breakage in 4% (including cases with simultaneous deletion of the remaining allele) of prostate cancers using a large prostate cancer prognosis tissue microarray containing a single tissue microarray core per donor tumor.…”

Section: Discussionmentioning

confidence: 99%

“…This assumption was based on the low overall rate of PTEN breaks (1%) in tumors without simultaneous deletion. 16 Accordingly, the PTEN FISH status was available from 1008 (53%) tissue spots. Reasons for analysis failure included missing tissue spots on the tissue microarray sections (n ¼ 111), lack of unequivocal tumor cells in the tissue spots (n ¼ 501) or insufficient hybridization for both FISH probe sets (n ¼ 270).…”

Section: Technical Issuesmentioning

confidence: 99%

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Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer

et al. 2014

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TMPRSS2:ERG fusions, in combination with deletion of the phosphatase and tensin homolog (PTEN) tumor suppressor, have been suggested to cooperatively drive tumor progression in prostate cancer. We utilized a novel heterogeneity tissue microarray containing samples from 10 different tumor blocks of 189 prostatectomy specimens to study heterogeneity of genomic PTEN alterations in individual foci. PTEN alterations were found in 48/123 (39%) analyzable individual tumor foci, including 40 foci with deletions, 7 with deletion and rearrangement, and 1 focus with rearrangement only. PTEN was homogeneously aberrant in only 4 (8%) and heterogeneously in 44 (92%) of the foci. We found a specific sequence of molecular events from PTEN breakage followed by deletion of DNA sequences flanking the breakpoint, resulting in homozygous deletion. The observation that 16 of 19 foci with homogeneous ERG positivity had focal PTEN alterations but none of 10 foci with PTEN alterations had focal ERG positivity (Po0.0001) suggests that PTEN alterations typically develop subsequent to ERG fusions. We demonstrate a high level of intratumoral heterogeneity of PTEN alterations with deletions and rearrangements that challenges potential PTEN routine diagnosis testing in biopsies. The observation that PTEN alterations develop subsequent to ERG fusion strongly suggests that ERG expression may directly drive development of PTEN aberrations.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Technical Issuesmentioning

confidence: 99%

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Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer

et al. 2014

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“…In the past decades several drivers for prostate cancer and progression were identified at the genomic, transcriptional and protein-level [119,[173][174][175][176][177][178][179][180][181][182]. The acquisition of these driver mutations and subsequent tumor progression could either follow a linear pathway or a molecular diversity model as suggested by Rubin et al, 2011 [178].…”

Section: Genetic Drivers Signaling and Microenvironment In Prostate mentioning

confidence: 99%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

101

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KEYWORDS:Cancer metabolism, metabolic therapy, tissue specific metabolism, genetic drivers, epigenetic drivers, microenvironment, Warburg effect, reverse Warburg effect, mixed Warburg effect, triple-negative breast cancer, estrogen receptor positive breast cancer; prostate cancer, liver cancer, gluconeogenesis, fatty acid metabolism, glucose metabolism, glutamine metabolism, serine metabolism, metabolic normalization, metabolic depletion ABSTRACTTargeting the metabolism of cancer cells has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor positive breast cancer, early and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g. Warburg versus reverse Warburg metabolism). Yet, for each of the cancers their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion.

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“…Global gene expression profiling further shows that the AR is one of several genes to be consistently up-regulated in castrationresistant prostate cancer (CRPC) (7,8), which directly underscores the significance of androgen signaling in disease progression. Additionally, recent integrative genomic analysis revealed a significant enrichment of androgen signaling in early-onset prostate cancers, but not in elderly onset prostate cancers (9), further highlighting the significance of AR across the prostate tumorigenesis spectrum. The phosphatidylinositol (3,4,5)-phosphate kinase (PI3K) signaling pathway plays a critical role in human tumorigenesis, including prostate cancer (10).…”

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confidence: 99%