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Rosalind A Eeles,
Ali Amin Al Olama,
Sara Benlloch,
Edward J Saunders,
Daniel A Leongamornlert,
Malgorzata Tymrakiewicz,
Maya Ghoussaini,
Craig Luccarini,
Joe Dennis,
Sarah Jugurnauth-Little, [......],
Sofia Maia,
Paula Paulo,
Ethan Lange,
Kathleen A Cooney,
Antonis C Antoniou,
Daniel Vincent,
François Bacot,
Daniel C Tessier,
Zsofia Kote-Jarai,
Douglas F Easton
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ABSTRACT: Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.
Nature Genetics 03/2013; 45(4):385-391. · 35.53 Impact Factor
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Ali Amin Al Olama,
Zsofia Kote-Jarai,
Fredrick R Schumacher,
Fredrik Wiklund,
Sonja I Berndt,
Sara Benlloch,
Graham G Giles,
Gianluca Severi,
David E Neal,
Freddie C Hamdy, [......],
Shintaro Narita,
Guang-Wen Cao,
Chavdar Slavov,
Vanio Mitev,
Stephen Chanock,
Henrik Gronberg,
Christopher A Haiman,
Peter Kraft,
Douglas F Easton,
Rosalind A Eeles
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ABSTRACT: Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four genome-wide association studies (GWAS) including 5,953 cases of aggressive PrCa and 11,463 controls (men without PrCa). We computed association tests for ~2.6M SNPs and followed up the most significant SNPs by genotyping 49,121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa (OR=1.12 (95% CI 1.03-1.21), P=1.4x10(-8)). This report describes a genetic variant which is associated with aggressive prostate cancer, which is a type of prostate cancer associated with a poorer prognosis.
Human Molecular Genetics 10/2012; · 7.64 Impact Factor
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Zsofia Kote-Jarai,
Ali Amin Al Olama,
Graham G Giles,
Gianluca Severi,
Johanna Schleutker,
Maren Weischer,
Daniele Campa,
Elio Riboli,
Tim Key,
Henrik Gronberg, [......],
James Farnham,
Heiko Muller,
Dietrich Rothenbacher,
Norihiko Tsuchiya,
Shintaro Narita,
Guang-Wen Cao,
Chavdar Slavov,
Vanio Mitev,
Douglas F Easton,
Rosalind A Eeles
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ABSTRACT: Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ∼25% of the familial risk in this disease, have now been identified.
Nature Genetics 01/2011; 43(8):785-91. · 35.53 Impact Factor
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ABSTRACT: The purpose of this study was to compare apparent diffusion coefficients, metabolic ratios, and vascularity values within histologically defined prostate tumors with those in nontumor tissue to determine which functional parameter or combination of parameters is best for differentiating tumor from nontumor tissue.
Twenty patients due for prostatectomy underwent endorectal MRI at 1.5 T. Transverse T2-weighted, diffusion-weighted, 2D chemical shift, and dynamic contrast-enhanced images were acquired. After prostatectomy, the gland was sectioned transversely. Fresh slices and stained whole-mount sections with histologically defined tumor outlines were photographed. The tumor outlines were mapped onto images, and the apparent diffusion coefficient (ADC), choline-to-citrate (Cho/cit) ratio, and vascularity of the histologically defined tumor, normal peripheral zone, and central gland were quantitatively measured. Area under the receiver operating characteristics (ROC) curve (A(z)) was used to determine the sensitivity and specificity of parameter combinations in cancer detection.
In tumor regions larger than 1 cm(2), the Cho/cit ratio was higher in tumor than in nontumor tissue (p < 0.001), in the peripheral zone alone (p = 0.007), and in the central gland alone (p = 0.005). ADC was lower and tumor vascularity greater in tumor than in nontumor tissue (ADC, p = 0.003; initial area under the gadolinium plasma concentration-time curve [initial gadolinium AUC], p = 0.012; forward rate constant [K(trans)], p = 0.011; return rate constant [k(ep)], p = 0.036). No single parameter had a significantly greater A(z) (ADC, 0.71; Cho/cit ratio, 0.79; initial gadolinium AUC, 0.60; K(trans), 0.62; k(ep), 0.65). Pairs of parameters, however, did increase A(z): ADC and initial gadolinium AUC (A(z) = 0.94) versus ADC (p = 0.001) and initial gadolinium AUC (p < 0.001); ADC and Cho/cit ratio (A(z) = 0.94) versus ADC (p = 0.001) and Cho/cit ratio (not significant); and Cho/cit ratio and initial gadolinium AUC (A(z) = 0.88) versus Cho/cit ratio (not significant) and initial gadolinium AUC (p < 0.001). All three functional techniques together had an A(z) of 0.95, showing no further improvement.
The combination of two functional parameters is associated with significant improvement in prostate cancer detection over use of any parameter alone. Use of a third parameter does not increase the rate of detection.
American Journal of Roentgenology 12/2009; 193(6):1583-91. · 2.78 Impact Factor
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Ali Amin Al Olama,
Zsofia Kote-Jarai,
Graham G Giles,
Michelle Guy,
Jonathan Morrison,
Gianluca Severi,
Daniel A Leongamornlert,
Malgorzata Tymrakiewicz,
Sameer Jhavar,
Ed Saunders, [......],
Christopher J Woodhouse, Alan Thompson,
Tim Christmas,
Chris Ogden,
Colin Cooper,
Jenny L Donovan,
Freddie C Hamdy,
David E Neal,
Rosalind A Eeles,
Douglas F Easton
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ABSTRACT: Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility.
Nature Genetics 09/2009; 41(10):1058-60. · 35.53 Impact Factor
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Rosalind A Eeles,
Zsofia Kote-Jarai,
Ali Amin Al Olama,
Graham G Giles,
Michelle Guy,
Gianluca Severi,
Kenneth Muir,
John L Hopper,
Brian E Henderson,
Christopher A Haiman, [......],
Manuel Luedeke,
Klara Stefflova,
Anna M Ray,
Ethan M Lange,
Jim Farnham,
Humera Khan,
Chavdar Slavov,
Atanaska Mitkova,
Guangwen Cao,
Douglas F Easton
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ABSTRACT: Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)).
Nature Genetics 09/2009; 41(10):1116-21. · 35.53 Impact Factor
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ABSTRACT: New in vitro models of castration-resistant prostate cancer (CRPC) are urgently required.
Trans-rectal needle biopsies (TRBP) of the prostate were performed for research purposes on progressing CRPC patients who had not received prior treatment to the prostate. Biopsies were immediately digested with collagenase and plated onto collagen-coated flasks with a feeder layer of 3T6 cells and cultured in cytokine-supplemented keratinocyte serum-free medium.
Biopsies from 25 patients were collected and one of these, following an initial period of crisis, spontaneously immortalized. A series of cell lines called Bob were then established from a clone that survived CD133-selection followed by 4 weeks under adhesion-independent conditions in methylcellulose. Gains and losses previously described in clinical prostate tumors, most notably loss of 8(p) and gain of 8(q), were identified on comparative genomic hybridization and long-term growth in culture, survival in methylcellulose and invasion through matrigel confirmed the malignant phenotype of Bob. Furthermore, Bob expressed high levels of p53 and markers of early differentiation, including K8, prostatic acid phosphatase and prostate stem cell antigen. There was, however, no in vivo growth and ERG and ETV1 were not rearranged. Growth in serum permitted some differentiation.
This is the first spontaneously immortalized prostate cancer cell line to be established from a TRBP of a patient with CRPC. Bob is a novel pre-clinical model for functional studies in CRPC and especially for studying the CRPC "basal" phenotype.
The Prostate 07/2009; 69(14):1507-20. · 3.48 Impact Factor
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Michelle Guy,
Zsofia Kote-Jarai,
Graham G Giles,
Ali Amin Al Olama,
Sarah K Jugurnauth,
Shani Mulholland,
Daniel A Leongamornlert,
Stephen M Edwards,
Jonathan Morrison,
Helen I Field, [......],
Tim Christmas,
Chris Ogden,
Cyril Fisher,
Charles Jameson,
Colin S Cooper,
Dallas R English,
John L Hopper,
David E Neal,
Douglas F Easton,
Rosalind A Eeles
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ABSTRACT: There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.
Asian Journal of Andrology 01/2009; 11(1):49-55. · 1.52 Impact Factor
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Sameer Jhavar,
Daniel Brewer,
Sandra Edwards,
Zsofia Kote-Jarai,
Gerhardt Attard,
Jeremy Clark,
Penny Flohr,
Timothy Christmas, Alan Thompson,
Matthew Parker, [......],
Christopher Ogden,
Cyril Fisher,
Gyula Kovacs,
Cathy Corbishley,
Charles Jameson,
Andy Norman,
Johann De-Bono,
Anders Bjartell,
Rosalind Eeles,
Colin S. Cooper
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ABSTRACT: OBJECTIVE
To integrate the mapping of ERG alterations with the collection of expression microarray (EMA) data, as previous EMA analyses have failed to consider the genetic heterogeneity and complex patterns of ERG alteration frequently found in cancerous prostates.MATERIALS AND METHODS
We determined genome-wide expression levels with GeneChip Human Exon 1.0 ST arrays (Affymetrix, Santa Clara, CA, USA) using RNA prepared from 35 specimens of prostate cancer from 28 prostates.RESULTSThe expression profiles showed clustering, in unsupervised hierarchical analyses, into two distinct prostate cancer categories, with one group strongly associated with indicators of poor clinical outcome. The two categories are not tightly linked to ERG status. By analysis of the data we identified a subgroup of cancers lacking ERG rearrangements that showed an outlier pattern of SPINK1 mRNA expression. There was a major distinction between ERG rearranged and non-rearranged cancers that involves the levels of expression of genes linked to exposure to β-oestradiol, and to retinoic acid.CONCLUSIONS
Expression profiling of prostate cancer samples containing single patterns of ERG alterations can provide novel insights into the mechanism of prostate cancer development, and support the view that factors other than ERG status are the major determinants of poor clinical outcome.
BJU International 11/2008; 103(9):1256 - 1269. · 2.84 Impact Factor
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ABSTRACT: To compare the accuracy of prostate-specific antigen (PSA) velocity (PSAV) vs PSA doubling time (DT) for predicting the repeat biopsy results in men with localized prostate cancer on active surveillance (AS), as the utility of PSAV vs PSADT in untreated prostate cancer has not been well studied.
Eligible patients had favourable-risk localized prostate cancer (T1/2a, PSA level <or=15 ng/mL, Gleason score <or=3 + 4, and percentage positive biopsy cores <or=50%), and consented to AS between 2002 and 2005. Repeat biopsies were taken after 18-24 months, with adverse histology defined as any of: primary Gleason grade >or=4, >50% cores positive, or initial Gleason score 3 + 3 upgraded to >or=3 + 4. Using all PSA values for the 2 years preceding repeat biopsy, the PSAV and PSADT were calculated using linear regression and the log-slope method (DT = ln2/slope), respectively.
In all, 199 patients were assessable; the median PSAV and PSADT were 0.71 ng/mL/year and 5.29 years, respectively. Fifty-three patients (27%) had adverse histology on repeat biopsy. On univariate analyses, PSAV (P < 0.001) and PSADT (P = 0.019) were associated with adverse histology. The area under the receiver operating characteristic curve for predicting adverse histology was 0.70 and 0.63 for PSAV and PSADT, respectively. The mean difference was 0.07 (95% confidence interval 0.03-0.12; P < 0.001).
PSAV is more accurate than PSADT for predicting adverse histology on repeat biopsies. These data suggest that PSAV should be used in preference to PSADT to describe PSA kinetics in untreated, localized prostate cancer.
BJU International 11/2008; 103(7):872-6. · 2.84 Impact Factor
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ABSTRACT: Outcome data from a prospective study of active surveillance of localised prostate cancer were analysed to identify factors, present at the time of diagnosis, that predict subsequent radical treatment.
Eligible patients had clinical stage T1-T2a, N0-Nx, M0-Mx adenocarcinoma of the prostate with serum PSA<15 ng/ml, Gleason score <or= 7, primary Gleason grade <or= 3, and % positive biopsy cores (pbc) <or= 50%. Monitoring included serial PSA measurement and repeat prostate biopsies. Radical treatment was initiated in the event of biochemical progression (PSA velocity > 1 ng/ml/yr) or histological progression (primary Gleason grade >or= 4, or %pbc > 50%). Multivariate Cox regression analysis of baseline variables was performed with respect to time to radical treatment.
The 326 men recruited from 2002 to 2006 have been followed for a median of 22 mo. Median age was 67 yr, and median initial PSA (iPSA) 6.4 ng/ml. Sixty-five patients (20%) had deferred radical treatment, 16 (5%) changed to watchful waiting because of increasing comorbidity, 7 (2%) died of other causes, and 238 (73%) remain on surveillance. On multivariate Cox regression analysis, the free/total PSA ratio (p<0.001) and clinical T stage (p=0.006) were independent determinants of time to radical treatment.
In addition to established prognostic factors, the free/total PSA ratio may predict time to radical treatment in patients with untreated, localised prostate cancer managed by active surveillance. This possibility warrants further study.
European Urology 03/2008; 54(6):1297-305. · 8.49 Impact Factor
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Rosalind A Eeles,
Zsofia Kote-Jarai,
Graham G Giles,
Ali Amin Al Olama,
Michelle Guy,
Sarah K Jugurnauth,
Shani Mulholland,
Daniel A Leongamornlert,
Stephen M Edwards,
Jonathan Morrison, [......], Alan Thompson,
Tim Christmas,
Chris Ogden,
Cyril Fisher,
Charles Jamieson,
Colin S Cooper,
Dallas R English,
John L Hopper,
David E Neal,
Douglas F Easton
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ABSTRACT: Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at </=60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 x 10(-8) to P = 8.7 x 10(-29)). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3.
Nature Genetics 03/2008; 40(3):316-21. · 35.53 Impact Factor
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Sameer Jhavar,
Alison Reid,
Jeremy Clark,
Zsofia Kote-Jarai,
Timothy Christmas, Alan Thompson,
Christopher Woodhouse,
Christopher Ogden,
Cyril Fisher,
Cathy Corbishley,
Johann De-Bono,
Rosalind Eeles,
Daniel Brewer,
Colin Cooper
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ABSTRACT: Translocation of TMPRSS2 to the ERG gene, found in a high proportion of human prostate cancer, results in overexpression of the 3'-ERG sequences joined to the 5'-TMPRSS2 promoter. The studies presented here were designed to test the ability of expression analysis on GeneChip Human Exon 1.0 ST arrays to detect 5'-TMPRSS2-ERG-3' hybrid transcripts encoded by this translocation. Monitoring the relative expression of each ERG exon revealed altered transcription of the ERG gene in 15 of a series of 27 prostate cancer samples. In all cases, exons 4 to 11 exhibited enhanced expression compared with exons 2 and 3. This pattern of expression indicated that the most abundant hybrid transcripts involve fusions to ERG exon 4, and RT-PCR analyses confirmed the joining of TMPRSS2 exon 1 to ERG exon 4 in all 15 cases. The exon expression patterns also indicated that TMPRSS2-ERG fusion transcripts commonly contain deletion of ERG exon 8. Analysis of gene-level data from the arrays allowed the identification of genes whose expression levels significantly correlated with the presence of the translocation. These studies demonstrate that expression analyses using exon arrays represent a valuable approach for detecting ETS gene translocation in prostate cancer, in parallel with analyses of gene expression profiles.
Journal of Molecular Diagnostics 02/2008; 10(1):50-7. · 3.58 Impact Factor
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ABSTRACT: Active surveillance for early prostate cancer is a policy of close monitoring with radical treatment targeted at cases with evidence of disease progression. There is no consensus on the need for or optimum timing of repeat biopsies as part of active surveillance.
In a prospective cohort study of active surveillance 119 patients with untreated localized prostate cancer (T1/2a), prostate specific antigen less than 15 ng/ml, Gleason score 3 + 4 or less and 50% or less positive cores underwent repeat biopsy after 18 to 24 months. Histological disease progression was defined as primary Gleason grade 4 or greater, greater than 50% positive cores or a Gleason score increase from 6 or less to 7 or greater. The risk of histological disease progression was analyzed with respect to baseline clinical factors.
Median patient age was 66 years and median initial prostate specific antigen was 6.6 ng/ml. Histological disease progression was seen in 33 of 119 cases (28%). On multivariate analysis prostate specific antigen density (p = 0.002) and maximum percent involvement of any core (p = 0.04) were significant independent determinants of histological disease progression. Progression was seen in 22 of 40 cases (55%) with prostate specific antigen density 0.2 ng/ml/ml or greater and greater than 15% maximum involvement of any core. Progression was seen in 2 of 33 cases (6%) with prostate specific antigen density less than 0.2 ng/ml/ml and 15% or less maximum involvement of any core.
Repeat biopsy should be an integral part of active surveillance for untreated localized prostate cancer. Immediate repeat biopsy should be considered in patients who elect active surveillance but who have prostate specific antigen density greater than 0.2 ng/ml/ml. These findings must be validated in a cohort of patients with extended biopsies at diagnosis and followup.
The Journal of Urology 10/2007; 178(3 Pt 1):833-7. · 3.75 Impact Factor
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Sameer Jhavar,
J Bartlett,
Gyula Kovacs,
Cathy Corbishley,
D Dearnaley,
Rosalind Eeles,
V Khoo,
R Huddart,
A Horwich, Alan Thompson,
Andy Norman,
Daniel Brewer,
Colin S Cooper,
C Parker
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ABSTRACT: Active surveillance provides a unique opportunity to study biomarkers of prostate cancer behaviour, although only small volumes of tumor tissue are typically available. We have evaluated a technique for constructing tissue microarrays (TMAs) from needle biopsies for assessing immunohistochemical markers in localized prostate cancer managed by active surveillance. TMAs were constructed from diagnostic prostate biopsies for 60 patients with localized prostatic adenocarcinoma in a prospective cohort study of active surveillance. Radical treatment was recommended for a prostate-specific antigen (PSA) velocity greater than 1 ng ml(-1) per year or adverse histology in repeat biopsies, defined as Gleason score > or =4+3 or >50% of cores involved. Sections from the TMAs were stained with H&E, P63/AMACR and Ki-67. Time to radical treatment was analysed with respect to clinical characteristics and Ki-67 LI. At a median follow up of 36 months, 25/60 (42%) patients had received radical treatment. On univariate ana
Prostate cancer and prostatic diseases. 12(2):143-7.
