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PMID: 21307934 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

The genomic complexity of primary human prostate cancer.

Nature ·Vol. 470 ·No. 7333 ·2011-02-10 ·Pages 214-20

Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AY, Sboner A, Esgueva R, Pflueger D, Sougnez C, Onofrio R, Carter SL, Park K, Habegger L, Ambrogio L, Fennell T, Parkin M, Saksena G, Voet D, Ramos AH, Pugh TJ, Wilkinson J, Fisher S, Winckler W, Mahan S, Ardlie K, Baldwin J, Simons JW, Kitabayashi N, MacDonald TY, Kantoff PW, Chin L, Gabriel SB, Gerstein MB, Golub TR, Meyerson M, Tewari A, Lander ES, Getz G, Rubin MA, Garraway LA

Abstract

Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.

MeSH Terms
Adaptor Proteins, Signal Transducing Carrier Proteins/genetics Case-Control Studies Cell Adhesion Molecules/genetics Chromatin/genetics,metabolism Chromosome Aberrations Chromosome Breakpoints Epigenesis, Genetic/genetics Gene Expression Regulation, Neoplastic Genome, Human/genetics Guanylate Kinases Humans Male PTEN Phosphohydrolase/genetics,metabolism Prostatic Neoplasms/genetics Recombination, Genetic/genetics Signal Transduction/genetics Transcription, Genetic
Chemicals
Adaptor Proteins, Signal Transducing CADM2 protein, human Carrier Proteins Cell Adhesion Molecules Chromatin Guanylate Kinases MAGI2 protein, human PTEN Phosphohydrolase PTEN protein, human
Authors & Affiliations
41 authors, click to expand affiliations / ORCID
Berger Michael F
The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Lawrence Michael S
Demichelis Francesca
Drier Yotam
Cibulskis Kristian
Sivachenko Andrey Y
Sboner Andrea
Esgueva Raquel
Pflueger Dorothee
Sougnez Carrie
Onofrio Robert
Carter Scott L
Park Kyung
Habegger Lukas
Ambrogio Lauren
Fennell Timothy
Parkin Melissa
Saksena Gordon
Voet Douglas
Ramos Alex H
Pugh Trevor J
Wilkinson Jane
Fisher Sheila
Winckler Wendy
Mahan Scott
Ardlie Kristin
Baldwin Jennifer
Simons Jonathan W
Kitabayashi Naoki
MacDonald Theresa Y
Kantoff Philip W
Chin Lynda
Gabriel Stacey B
Gerstein Mark B
Golub Todd R
Meyerson Matthew
Tewari Ashutosh
Lander Eric S
Getz Gad
Rubin Mark A
Garraway Levi A
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature09744
Published
2011-02-10
Pages
214-20
Language
English
Region
England
NLM ID
0410462
PMCID
PMC3075885
Subset
IM
Grants
NCI NIH HHS · P50 CA090381 · United States
NHGRI NIH HHS · U54 HG003067 · United States
NCI NIH HHS · R33 CA126674-03 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · 2 P50 CA090381-11 · United States
NIH HHS · DP2 OD002750 · United States
NCI NIH HHS · R33 CA126674 · United States
NIH HHS · DP2 OD002750-01 · United States
External Links
PubMed source DOI: 10.1038/nature09744 PMC Full Text View journal details
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