Do low-grade and low-volume prostate cancers bear the hallmarks of malignancy?

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Abstract

Prostate cancer is generally multifocal and consists of a dominant focus-measured by tumour volume and deemed the index lesion-and one or more separate, secondary tumour foci of smaller volume. Much laboratory and clinical evidence has shown that we need to rethink how we regard low-grade and low-volume prostate lesions. In this Personal View, we discuss why small, low-grade Gleason pattern prostate lesions, which are currently designated as prostate cancer, could be regarded as non-malignant. These lesions either do not meet the criteria of the hallmarks of cancer or robust evidence that they do so is absent, by contrast with large lesions with a high Gleason grade, which seem to cause most metastatic disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Most cited references 74

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The Hallmarks of Cancer

Douglas Hanahan, Robert Weinberg (2000)

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The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma.

Jonathan Epstein, William Allsbrook, Mahul B Amin … (2005)

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The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer

Catherine S. Grasso, Yi-Mi Wu, Dan R Robinson … (2012)

Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC) 1 . As less is known about the role of mutations 2–4 , here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment naïve, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1, which define a subtype of ETS fusionnegative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in ~1/3 of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Further, we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with AR, which is required for AR-mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signaling and increases tumour growth. Proteins that physically interact with AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX, and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study.