TY - JOUR
T1 - The role of genetic markers in the management of prostate cancer
AU - Choudhury, Atish D.
AU - Eeles, Rosalind
AU - Freedland, Stephen J.
AU - Isaacs, William B.
AU - Pomerantz, Mark M.
AU - Schalken, Jack A.
AU - Tammela, Teuvo L.J.
AU - Visakorpi, Tapio
N1 - Funding Information:
Financial disclosures: Dean A. Tripp certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Atish D. Choudhury is supported by a US National Institutes of Health (NIH) T-32 Training Grant, the Anne Huber Foster Fellowship, the Prostate Cancer Foundation Young Investigator Award and the US Department of Defense Physician Scientist Training Award. Rosalind Eeles is supported by Cancer Research UK Grant C5047/A7357, the US NIH Cancer Post-GWAS initiative grant number 1 U19 CA 148537-01 (GAME_ON initiative), The European Commission's Seventh Framework Programme grant agreement number 223175 (HEALTH-F2-2009-223175), and support from the US NIH National Institute for Health Research to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden Foundation NHS Trust, The Institute of Cancer Research and The Everyman Campaign, Prostate Action, The Orchid Cancer Appeal, The National Cancer Research Network UK, and The National Cancer Research Institute UK. Mark M. Pomerantz is supported by the Prostate Cancer Foundation Young Investigator Award. Tapio Visakorpi is supported by the Academy of Finland, the Cancer Society of Finland, the Reino Lahtikari Foundation, the Sigrid Juselius Foundation, European Union, TEKES, and the Medical Research Fund of Tampere University Hospital.
PY - 2012/10
Y1 - 2012/10
N2 - Context: Despite widespread screening for prostate cancer (PCa) and major advances in the treatment of metastatic disease, PCa remains the second most common cause of cancer death for men in the Western world. In addition, the use of prostate-specific antigen testing has led to the diagnosis of many potentially indolent cancers, and aggressive treatment of these cancers has caused significant morbidity without clinical benefit in many cases. The recent discoveries of inherited and acquired genetic markers associated with PCa initiation and progression provide an opportunity to apply these findings to guide clinical decision making. Objective: In this review, we discuss the potential use of genetic markers to better define groups of men at high risk of developing PCa, to improve screening techniques, to discriminate indolent versus aggressive disease, and to improve therapeutic strategies in patients with advanced disease. Evidence acquisition: PubMed-based literature searches and abstracts through January 2012 provided the basis for this literature review. We also examined secondary sources from reference lists of retrieved articles and data presented at recent congresses. Cited review articles are only from the years 2007-2012, favoring more recent discussions because of the rapidly changing field. Original research articles were curated based on favoring large sample sizes, independent validation, frequent citations, and basic science directly related to potentially clinically relevant prognostic or predictive markers. In addition, all authors on the manuscript evaluated and interpreted the data acquired. Evidence synthesis: We address the use of inherited genetic variants to assess risk of PCa development, risk of advanced disease, and duration of response to hormonal therapies. The potential for using urine measurements such as prostate cancer antigen 3 (PCA3) RNA and the transmembrane protease, serine 2 v-ets erythroblastosis virus E26 oncogene homolog (avian) (TMPRSS2-ERG) gene fusion to aid screening is discussed. Multiple groups have developed gene expression signatures from primary prostate tumors correlating with poor prognosis, and attempts to improve and standardize these signatures as diagnostic tests are presented. Massive sequencing efforts are underway to define important somatic genetic alterations (amplifications, deletions, point mutations, translocations) in PCa, and these alterations hold great promise as prognostic markers and for predicting response to therapy. We provide a rationale for assessing genetic markers in metastatic disease for guiding choice of therapy and for stratifying patients in clinical trials, and discuss challenges in clinical trial design incorporating the use of these markers. Conclusions: The use of genetic markers has the potential to aid disease screening, improve prognostic discrimination, and prediction of response to treatment. However, most markers have not been prospectively validated for providing useful prognostic or predictive information or improvement upon clinicopathologic parameters already in use. Significant efforts are underway to develop these research findings into clinically useful diagnostic tests in order to improve clinical decision making.
AB - Context: Despite widespread screening for prostate cancer (PCa) and major advances in the treatment of metastatic disease, PCa remains the second most common cause of cancer death for men in the Western world. In addition, the use of prostate-specific antigen testing has led to the diagnosis of many potentially indolent cancers, and aggressive treatment of these cancers has caused significant morbidity without clinical benefit in many cases. The recent discoveries of inherited and acquired genetic markers associated with PCa initiation and progression provide an opportunity to apply these findings to guide clinical decision making. Objective: In this review, we discuss the potential use of genetic markers to better define groups of men at high risk of developing PCa, to improve screening techniques, to discriminate indolent versus aggressive disease, and to improve therapeutic strategies in patients with advanced disease. Evidence acquisition: PubMed-based literature searches and abstracts through January 2012 provided the basis for this literature review. We also examined secondary sources from reference lists of retrieved articles and data presented at recent congresses. Cited review articles are only from the years 2007-2012, favoring more recent discussions because of the rapidly changing field. Original research articles were curated based on favoring large sample sizes, independent validation, frequent citations, and basic science directly related to potentially clinically relevant prognostic or predictive markers. In addition, all authors on the manuscript evaluated and interpreted the data acquired. Evidence synthesis: We address the use of inherited genetic variants to assess risk of PCa development, risk of advanced disease, and duration of response to hormonal therapies. The potential for using urine measurements such as prostate cancer antigen 3 (PCA3) RNA and the transmembrane protease, serine 2 v-ets erythroblastosis virus E26 oncogene homolog (avian) (TMPRSS2-ERG) gene fusion to aid screening is discussed. Multiple groups have developed gene expression signatures from primary prostate tumors correlating with poor prognosis, and attempts to improve and standardize these signatures as diagnostic tests are presented. Massive sequencing efforts are underway to define important somatic genetic alterations (amplifications, deletions, point mutations, translocations) in PCa, and these alterations hold great promise as prognostic markers and for predicting response to therapy. We provide a rationale for assessing genetic markers in metastatic disease for guiding choice of therapy and for stratifying patients in clinical trials, and discuss challenges in clinical trial design incorporating the use of these markers. Conclusions: The use of genetic markers has the potential to aid disease screening, improve prognostic discrimination, and prediction of response to treatment. However, most markers have not been prospectively validated for providing useful prognostic or predictive information or improvement upon clinicopathologic parameters already in use. Significant efforts are underway to develop these research findings into clinically useful diagnostic tests in order to improve clinical decision making.
KW - GWAS
KW - Gene expression
KW - Genetic markers
KW - Genome-wide association study
KW - Predictive markers
KW - Prognostic markers
KW - Prostate cancer
KW - Screening
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U2 - 10.1016/j.eururo.2012.05.054
DO - 10.1016/j.eururo.2012.05.054
M3 - Review article
C2 - 22695242
AN - SCOPUS:84865693861
SN - 0302-2838
VL - 62
SP - 577
EP - 587
JO - European Urology
JF - European Urology
IS - 4
ER -