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The genomic complexity of primary human prostate cancer

Author

Listed:
  • Michael F. Berger

    (The Broad Institute of Harvard and MIT
    Present address: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.)

  • Michael S. Lawrence

    (The Broad Institute of Harvard and MIT)

  • Francesca Demichelis

    (Weill Cornell Medical College
    Institute for Computational Biomedicine, Weill Cornell Medical College)

  • Yotam Drier

    (Weizmann Institute of Science)

  • Kristian Cibulskis

    (The Broad Institute of Harvard and MIT)

  • Andrey Y. Sivachenko

    (The Broad Institute of Harvard and MIT)

  • Andrea Sboner

    (Yale University
    Program in Computational Biology and Bioinformatics, Yale University)

  • Raquel Esgueva

    (Weill Cornell Medical College)

  • Dorothee Pflueger

    (Weill Cornell Medical College)

  • Carrie Sougnez

    (The Broad Institute of Harvard and MIT)

  • Robert Onofrio

    (The Broad Institute of Harvard and MIT)

  • Scott L. Carter

    (The Broad Institute of Harvard and MIT)

  • Kyung Park

    (Weill Cornell Medical College)

  • Lukas Habegger

    (Program in Computational Biology and Bioinformatics, Yale University)

  • Lauren Ambrogio

    (The Broad Institute of Harvard and MIT)

  • Timothy Fennell

    (The Broad Institute of Harvard and MIT)

  • Melissa Parkin

    (The Broad Institute of Harvard and MIT)

  • Gordon Saksena

    (The Broad Institute of Harvard and MIT)

  • Douglas Voet

    (The Broad Institute of Harvard and MIT)

  • Alex H. Ramos

    (The Broad Institute of Harvard and MIT
    Harvard Medical School)

  • Trevor J. Pugh

    (The Broad Institute of Harvard and MIT
    Harvard Medical School
    Dana-Farber Cancer Institute)

  • Jane Wilkinson

    (The Broad Institute of Harvard and MIT)

  • Sheila Fisher

    (The Broad Institute of Harvard and MIT)

  • Wendy Winckler

    (The Broad Institute of Harvard and MIT)

  • Scott Mahan

    (The Broad Institute of Harvard and MIT)

  • Kristin Ardlie

    (The Broad Institute of Harvard and MIT)

  • Jennifer Baldwin

    (The Broad Institute of Harvard and MIT)

  • Jonathan W. Simons

    (The Prostate Cancer Foundation)

  • Naoki Kitabayashi

    (Weill Cornell Medical College)

  • Theresa Y. MacDonald

    (Weill Cornell Medical College)

  • Philip W. Kantoff

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Lynda Chin

    (The Broad Institute of Harvard and MIT
    Harvard Medical School
    Dana-Farber Cancer Institute
    Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute)

  • Stacey B. Gabriel

    (The Broad Institute of Harvard and MIT)

  • Mark B. Gerstein

    (Yale University
    Program in Computational Biology and Bioinformatics, Yale University
    Yale University)

  • Todd R. Golub

    (The Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Howard Hughes Medical Institute
    Center for Cancer Genome Discovery, Dana-Farber Cancer Institute)

  • Matthew Meyerson

    (The Broad Institute of Harvard and MIT
    Harvard Medical School
    Dana-Farber Cancer Institute
    Center for Cancer Genome Discovery, Dana-Farber Cancer Institute)

  • Ashutosh Tewari

    (Institute of Prostate Cancer and Lefrak Center of Robotic Surgery, Weill Cornell Medical College and New York Presbyterian Hospitals)

  • Eric S. Lander

    (The Broad Institute of Harvard and MIT
    Harvard Medical School
    Whitehead Institute for Biomedical Research, 9 Cambridge Center)

  • Gad Getz

    (The Broad Institute of Harvard and MIT)

  • Mark A. Rubin

    (Weill Cornell Medical College)

  • Levi A. Garraway

    (The Broad Institute of Harvard and MIT
    Harvard Medical School
    Dana-Farber Cancer Institute
    Center for Cancer Genome Discovery, Dana-Farber Cancer Institute)

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.

Suggested Citation

  • Michael F. Berger & Michael S. Lawrence & Francesca Demichelis & Yotam Drier & Kristian Cibulskis & Andrey Y. Sivachenko & Andrea Sboner & Raquel Esgueva & Dorothee Pflueger & Carrie Sougnez & Robert , 2011. "The genomic complexity of primary human prostate cancer," Nature, Nature, vol. 470(7333), pages 214-220, February.
    • Handle: RePEc:nat:nature:v:470:y:2011:i:7333:d:10.1038_nature09744
    DOI: 10.1038/nature09744
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    Cited by:

    1. Michael Fraser & Julie Livingstone & Jeffrey L. Wrana & Antonio Finelli & Housheng Hansen He & Theodorus van der Kwast & Alexandre R. Zlotta & Robert G. Bristow & Paul C. Boutros, 2021. "Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Julie Livingstone & Yu-Jia Shiah & Takafumi N. Yamaguchi & Lawrence E. Heisler & Vincent Huang & Robert Lesurf & Tsumugi Gebo & Benjamin Carlin & Stefan Eng & Erik Drysdale & Jeffrey Green & Theodorus, 2021. "The telomere length landscape of prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Yu Chen & Amy Y. Wang & Courtney A. Barkley & Yixin Zhang & Xinyang Zhao & Min Gao & Mick D. Edmonds & Zechen Chong, 2023. "Deciphering the exact breakpoints of structural variations using long sequencing reads with DeBreak," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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