Publications by authors named "Christopher S Foster"

67 Publications

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Lancet Oncol 2021 11 19;22(11):1618-1631. Epub 2021 Oct 19.

University Hospital Southampton, Southampton, UK; Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.

Background: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants.

Methods: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual.

Findings: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0).

Interpretation: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings.

Funding: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(21)00522-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576477PMC
November 2021

Diversity and inclusion for the All of Us research program: A scoping review.

PLoS One 2020 1;15(7):e0234962. Epub 2020 Jul 1.

National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.

The All of Us Research Program (All of Us) is a national effort to accelerate health research by exploring the relationship between lifestyle, environment, and genetics. It is set to become one of the largest research efforts in U.S. history, aiming to build a national resource of data from at least one million participants. All of Us aims to address the need for more diversity in research and set the stage for that diversity to be leveraged in precision medicine research to come. This paper describes how the program assessed demographic characteristics of participants who have enrolled in other U.S. biomedical research cohorts to better understand which groups are traditionally represented or underrepresented in biomedical research. We 1) reviewed the enrollment characteristics of national cohort studies like All of Us, and 2) surveyed the literature, focusing on key diversity categories essential to the program's enrollment aims. Based on these efforts, All of Us emphasizes enrollment of racial and ethnic minorities, and has formally designated the following additional groups as historically underrepresented: individuals-with inadequate access to medical care; under the age of 18 or over 65; with an annual household income at or below 200% of the federal poverty level; who have a cognitive or physical disability; have less than a high school education or equivalent; are intersex; identify as a sexual or gender minority; or live in rural or non-metropolitan areas. Research accounting for wider demographic variability is critical. Only by ensuring diversity and by addressing the very barriers that limit it, can we position All of Us to better understand and tackle health disparities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234962PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329113PMC
September 2020

Anti-metastatic effect of ranolazine in an in vivo rat model of prostate cancer, and expression of voltage-gated sodium channel protein in human prostate.

Prostate Cancer Prostatic Dis 2019 12 20;22(4):569-579. Epub 2019 Mar 20.

Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.

Background: Voltage-gated Na channels (VGSCs) are functionally upregulated in rat and human prostate cancer (PCa) where channel activity promotes cellular invasiveness in vitro and metastasis in vivo. Ranolazine is a clinically used VGSC inhibitor/anti-anginal drug, which has been shown previously to inhibit breast cancer metastasis in vivo.

Methods: Using the Dunning model of rat PCa, the effect of ranolazine applied systemically (by gavage) was tested on the development of primary tumours and metastases following subcutaneous inoculation of Mat-LyLu cells into Copenhagen rats. In addition, human prostate tissue microarrays were used to determine VGSC protein expression in cancerous versus non-cancerous tissue. Several public databases were searched to compare Nav1.7/ SCN9A expression levels in 'normal' vs. PCa tissues.

Results: Ranolazine (2.5 and 5 µM) decreased the number of lung metastases by up to 63%. In contrast, primary tumourigenesis was not affected. Ranolazine also reduced the percentage of cells in the metastases expressing Nav1.7, the main VGSC subtype expressed in PCa, but the expression level was higher. In prostate tissue microarrays, VGSC protein expression was significantly higher in cancerous versus non-cancerous tissue. There was no correlation between the VGSC expression and either prostate-specific antigen or Gleason score. In public databases, little information could be found on Nav1.7 protein expression in PCa. In addition, the database information on Nav1.7 mRNA (SCN9A) expression levels did not correlate with previously reported upregulation in PCa cells and tissues.

Conclusions: The main conclusions were (i) ranolazine inhibited metastasis and (ii) it was a subpopulation of cells with particularly high levels of Nav1.7 protein that reached the metastatic sites. These data extend earlier studies and suggest that Nav1.7 expression could serve as a functional biomarker of metastatic PCa and that VGSC blockers may be useful as anti-metastatic agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41391-019-0128-3DOI Listing
December 2019

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.

Nat Genet 2018 05 16;50(5):682-692. Epub 2018 Apr 16.

The Institute of Cancer Research, London, UK.

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0086-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372064PMC
May 2018

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

Br J Cancer 2018 01 4;118(2):266-276. Epub 2018 Jan 4.

Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 CE, The Netherlands.

Background: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort.

Methods: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV.

Results: 1634 participants had ⩾3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers.

Conclusions: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/bjc.2017.429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785754PMC
January 2018

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

PLoS Genet 2017 Sep 25;13(9):e1007001. Epub 2017 Sep 25.

Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1007001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628936PMC
September 2017

Pathological Concordance between Prostate Biopsies and Radical Prostatectomy Using Transperineal Sector Mapping Biopsies: Validation and Comparison with Transrectal Biopsies.

Urol Int 2017 29;99(2):168-176. Epub 2017 Jul 29.

Department of Urology, King's College Hospital, London, UK.

Background/Aims/Objectives: Our aim was to evaluate the accuracy of systematic transperineal sector mapping biopsy (TPSMB) in predicting Gleason score (GS) at radical prostatectomy (RP), to compare its accuracy with standard transrectal ultrasound-guided biopsies (TRUS) and to establish the clinical impact of discordance between biopsies and RP on subsequent surgical management.

Methods: Two hundred fifty-five patients from 2008 to 2013 who underwent RP following TPSMB (n = 204) or TRUS (n = 51), were included in this retrospective multi-institutional study. Concordance between biopsies and RPs GS was assessed both as percentages and with Cohen's Kappa coefficient. All mismatches between biopsies and RP were assessed for significance by 3 urologists using the Delphi method.

Results: No differences were present among the groups. Concordance between biopsy and RP GS was 75.49% for TPSMB and 64.70% for TRUS. Kappa coefficient was 0.42 and 0.39 respectively. The Delphi method showed lower clinical impact of GS discordances for TPSMB with 7.8% of patients having significant change, thus being potentially more suitable for other treatment modalities, compared to TRUS (13.7%).

Conclusions: TPSMB had a higher accuracy for predicting the GS grade at RP showing superior GS concordance compared with standard TRUS. TPSMB provides an effective technique for systematic prostate biopsy to evaluate overall prostate cancer GS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000471491DOI Listing
June 2018

Identification of FBXL4 as a Metastasis Associated Gene in Prostate Cancer.

Sci Rep 2017 07 11;7(1):5124. Epub 2017 Jul 11.

Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.

Prostate cancer is the most common cancer among western men, with a significant mortality and morbidity reported for advanced metastatic disease. Current understanding of metastatic disease is limited due to difficulty of sampling as prostate cancer mainly metastasizes to bone. By analysing prostate cancer bone metastases using high density microarrays, we found a common genomic copy number loss at 6q16.1-16.2, containing the FBXL4 gene, which was confirmed in larger series of bone metastases by fluorescence in situ hybridisation (FISH). Loss of FBXL4 was also detected in primary tumours and it was highly associated with prognostic factors including high Gleason score, clinical stage, prostate-specific antigen (PSA) and extent of disease, as well as poor patient survival, suggesting that FBXL4 loss contributes to prostate cancer progression. We also demonstrated that FBXL4 deletion is detectable in circulating tumour cells (CTCs), making it a potential prognostic biomarker by 'liquid biopsy'. In vitro analysis showed that FBXL4 plays a role in regulating the migration and invasion of prostate cancer cells. FBXL4 potentially controls cancer metastasis through regulation of ERLEC1 levels. Therefore, FBXL4 could be a potential novel prostate cancer suppressor gene, which may prevent cancer progression and metastasis through controlling cell invasion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-05209-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505985PMC
July 2017

Neonatal Nav1.5 protein expression in normal adult human tissues and breast cancer.

Pathol Res Pract 2017 Aug 6;213(8):900-907. Epub 2017 Jun 6.

Imperial College London, Department of Life Sciences, Neuroscience Solutions to Cancer Research Group, South Kensington Campus, London SW7 2AZ, UK; Cyprus International University, Biotechnology Research Centre, Haspolat, Lefkosa, North Cyprus, Cyprus. Electronic address:

Expression of the neonatal splice variant of the voltage-gated sodium channel α-subunit (VGSC) subtype Nav1.5 (nNav1.5), encoded by the gene SCN5A, was shown earlier to be upregulated in human breast cancer (BCa), both in vitro and in vivo. Channel activity promoted BCa invasion of Matrigelin vitro and metastasis in vivo. Consequently, expression of nNav1.5 has been proposed as a functional biomarker of BCa cells with metastatic potential. Here, we have determined immunohistochemically both nNav1.5 and total VGSC (tVGSC) protein expression in a range of adult human tissues. Some VGSC protein was expressed in normal colon, small intestine, stomach, prostate, bladder and breast. As expected, high levels of VGSC protein were expressed in brain, skeletal muscle and cardiac muscle. On the other hand, nNav1.5 protein was not expressed in any of the normal tissues tested except breast where a low-level of protein was present. In comparison to normal breast, nNav1.5 protein expression in BCa was consistently widespread and occurred at a significantly higher level. We also questioned whether there was any relationship between the nNav1.5 protein expression and the estrogen receptor (ERα) status of BCa and obtained the following results. First, all cases lacking nNav1.5 were positive for ERα. Second, in all ERα-negative tissues, nNav1.5 protein was expressed in plasma membrane. Third, however, in ERα-positive cases, nNav1.5 protein expression was observed in both plasma membrane and cytoplasm. In conclusion, nNav1.5 protein has a restricted expression pattern among human tissues. High level expression occurs in BCa and associates with ERα status. These results further support the proposition that nNav1.5 is a novel biomarker of metastatic BCa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prp.2017.06.003DOI Listing
August 2017

A novel DNA methylation score accurately predicts death from prostate cancer in men with low to intermediate clinical risk factors.

Oncotarget 2016 Nov;7(44):71833-71840

Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK.

Clinically aggressive disease behavior is difficult to predict in men with low to intermediate clinical risk prostate cancer and methylation biomarkers may be a valuable adjunct for assessing the management of these patients. We set to evaluate the utility of DNA methylation to identify high risk disease in men currently considered as low or intermediate risk. DNA was extracted from formalin-fixed paraffin-embedded transurethral prostate resection tissues collected during the years 1990-96 in a watchful-waiting cohort of men in the UK. The primary end point was death of prostate cancer, assessed by reviewing cancer registry records from 2009. Methylation was quantified by pyrosequencing assays for six genes (HSPB1, CCND2, TIG1, DPYS, PITX2, and MAL) with established biomarker value in prostate cancer. A novel prognostic methylation score was developed by multivariate Cox modelling using the six methylation biomarkers in 385 men with low-and-intermediate clinical risk variables and its prognostic value compared to two previously defined clinically-derived risk scores. Methylation score was the most significant variable in univariate and bivariate analysis in men with low-to-intermediate CAPRA risk score. When combined with CAPRA score the hazard ratio was 2.02; 95% confidence interval, 1.40-2.92. For a methylation score sensitivity of 83% the specificity was 44%, while the maximum achieved sensitivity by CAPRA was 68% at a specificity of 44%. The derived methylation score is a strong predictor of aggressive prostate cancer that could have an important role in directing the management of patients with low-to-intermediate risk disease. The estimated areas under the curve (AUC) at 10 years of follow-up were 0.62 (95% CI: 0.51, 0.70) and 0.74 (95% CI: 0.65, 0.82) for CAPRA, and combined (CAPRA + methylation) risk score (CRS) respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.12377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342126PMC
November 2016

Transcriptome sequencing of human breast cancer reveals aberrant intronic transcription in amplicons and dysregulation of alternative splicing with major therapeutic implications.

Int J Oncol 2016 01 30;48(1):130-44. Epub 2015 Oct 30.

Molecular Pathology Laboratory, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, Faculty of Health and Life Sciences, University of Liverpool, Royal Liverpool University Hospital, Liverpool L69 3GA, UK.

Advances in genomic and transcriptome sequencing are revealing the massive scale of previously unrecognised alterations occurring during neoplastic transformation. Breast cancers are genetically and phenotypically heterogeneous. Each of the three major subtypes [ERBB2 amplified, estrogen receptor (ESR)-positive and triple-negative] poses diagnostic and therapeutic challenges. Here we show, using high-resolution next-generation transcriptome sequencing, that in all three breast cancer subtypes, but not matched controls, there was significant overexpression of transcripts from intronic and untranslated regions in addition to exons from specific genes, particularly amplified oncogenes and hormone receptors. For key genes ERBB2 and ESR1, we demonstrate that overexpression is linked to the production of highly modified and truncated splice variants in tumours, but not controls, correlated with tumour subtype. Translation of these tumour-specific splice variants generates truncated proteins with altered subcellular locations and functions, modifying the phenotype, affecting tumour biology, and targeted antitumour therapies. In contrast, tumour suppressors TP53, BRCA1/2 and NF1 did not show intronic overexpression or truncated splice variants in cancers. These findings emphasize the detection of intronic as well as exonic changes in the transcriptional landscapes of cancers have profound therapeutic implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ijo.2015.3222DOI Listing
January 2016

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Nat Genet 2015 Apr 2;47(4):367-372. Epub 2015 Mar 2.

Department of Radiation Oncology, University of Toronto, Toronto, Canada.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380509PMC
April 2015

DNA methylation of PITX2 predicts poor survival in men with prostate cancer.

Biomark Med 2014 ;8(9):1143-50

Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts & London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK.

Aim: We investigated if methylation of candidate genes can be useful for predicting prostate cancer (PCa) specific death.

Patients & Methods: Methylation of PITX2, WNT5a, SPARC, EPB41L3 and TPM4 was investigated in a 1:2 case-control cohort comprising 45 men with cancer of Gleason score ≤ 7 who died (cases), and 90 men who were alive or died of other causes with survival time longer than the cases (controls). A univariate conditional logistic regression model was fitted by maximizing the likelihood of DNA methylation of each gene versus the primary end point.

Results: A 10% increase in methylation of PITX2 was associated with PCa related death with OR 1.56 (95% CI: 1.17-2.08; p = 0.005).

Conclusion: Our study strengthens prior findings that PITX2 methylation is useful as a biomarker of poor outcome of PCa and in addition we also suggest that it may be particularly useful in men with low Gleason score.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/bmm.14.41DOI Listing
July 2015

Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.

Elife 2014 Oct 1;3. Epub 2014 Oct 1.

Children's Brain Tumour Research Centre, University of Nottingham, Nottingham, United Kingdom.

Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.02935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371858PMC
October 2014

DNA methylation gene-based models indicating independent poor outcome in prostate cancer.

BMC Cancer 2014 Sep 6;14:655. Epub 2014 Sep 6.

Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.

Background: Prostate cancer has a variable clinical behaviour with frequently unpredictable outcome. DNA methylation plays an important role in determining the biology of cancer but prognostic information is scanty. We assessed the potential of gene-specific DNA methylation changes to predict death from prostate cancer in a cohort of untreated men in the UK.

Methods: This was a population-based study in which cases were identified from six cancer registries in Great Britain. DNA was extracted from formalin-fixed paraffin wax-embedded transurethral prostate resection tissues collected during 1990-96 from men with clinically-localised cancer who chose not to be treated for at least 6 months following diagnosis. The primary end point was death from prostate cancer. Outcomes were determined through medical records and cancer registry records. Pyrosequencing was used to quantify methylation in 13 candidate genes with established or suggested roles in cancer. Univariate and multivariate Cox models were used to identify possible predictors for prostate cancer-related death.

Results: Of 367 men, 99 died from prostate cancer during a median of 9.5 years follow-up (max = 20). Univariately, 12 genes were significantly associated with prostate cancer mortality, hazard ratios ranged between 1.09 and 1.28 per decile increase in methylation. Stepwise Cox regression modelling suggested that the methylation of genes HSPB1, CCND2 and DPYS contributed objective prognostic information to Gleason score and PSA with respect to cancer-related death during follow-up (p = 0.006).

Conclusion: Methylation of 13 genes was analysed in 367 men with localised prostate cancer who were conservatively treated and stratified with respect to death from prostate cancer and those who survived or died of other causes. Of the 13 genes analysed, differential methylation of HSPB1, CCND2 and DPYS provided independent prognostic information. Assessment of gene-methylation may provide independent objective information that can be used to segregate prostate cancers at diagnosis into predicted behavioural groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2407-14-655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162944PMC
September 2014

Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study.

Eur Urol 2014 Sep 15;66(3):489-99. Epub 2014 Jan 15.

Radboud University Medical Centre, Nijmegen, The Netherlands.

Background: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations.

Objective: To report the first year's screening results for all men at enrollment in the study.

Design, Setting And Participants: We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrollment, and those men with PSA >3 ng/ml were offered prostate biopsy.

Outcome Measurements And Statistical Analysis: PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types.

Results And Limitations: We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups.

Conclusions: The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease.

Patient Summary: In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2014.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105321PMC
September 2014

The expression of C-FABP and PPARγ and their prognostic significance in prostate cancer.

Int J Oncol 2014 Jan 5;44(1):265-75. Epub 2013 Nov 5.

Molecular Pathology Laboratory, Department of Molecular and Clinical Cancer Medicine, Liverpool University, Liverpool, L69 3GA, UK.

The purpose of this study was to test the hypothesis that cooperative interaction between cutaneous fatty acid-binding protein (C-FABP) and peroxisome proliferator-activated receptors (PPAR) promotes the malignant progression of human prostate cancer. The expression of C-FABP, PPARβ/δ and PPARγ was measured by western blot analysis in prostate cell lines and by immunohistochemical staining in tissue sections of benign prostatic hyperplasia (BPH) and prostatic carcinomas. The correlation between the expression of PPARs and C-FABP was assessed. The significance of increased expression of these proteins was analysed with respect to prognosis and compared with those of alternative biomarkers. The expression levels of C-FABP and PPARγ in prostate cancer cell lines and the cytoplasm and nuclei of carcinoma tissues were significantly (Student's t-test, p<0.05) higher compared to those in benign cell lines and BPH tissues. The raised expression level of C-FABP and PPARγ was significantly correlated with the increased combined Gleason scores (GS) of the carcinomas. Enhanced expression of cytoplasmic C-FABP significantly correlated with increased nuclear PPARγ (Student's t-test, p<0.005). While expression of PPARβ/δ in carcinomas did not correlate with patient outcome, the increased levels of both C-FABP and PPARγ were associated with shorter patient survival. Multivariate analysis indicated that C-FABP was independently associated with patient survival, whereas PPARγ was confounded by C-FABP in predicting patient survival. Thus, the increased C-FABP may interact with PPARγ in a coordinated mechanism to facilitate malignant progression in prostatic cancer. Both C-FABP and PPARγ are suitable as prognostic factors to predict the clinical outcome of prostatic cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ijo.2013.2166DOI Listing
January 2014

A novel cutaneous Fatty Acid-binding protein-related signaling pathway leading to malignant progression in prostate cancer cells.

Genes Cancer 2013 Jul;4(7-8):297-314

Molecular Pathology Laboratory, Department of Molecular and Clinical Cancer Medicine, the University of Liverpool, Liverpool, UK.

Cutaneous fatty acid-binding protein (C-FABP), a cancer promoter and metastasis inducer, is overexpressed in the majority of prostatic carcinomas. Investigation of molecular mechanisms involved in tumor-promoting activity of C-FABP has established that there is a fatty acid-initiated signaling pathway leading to malignant progression of prostatic cancer cells. Increased C-FABP expression plays an important role in this novel signaling pathway. Thus, when C-FABP expression is increased, excessive amounts of fatty acids are transported into the nucleus where they act as signaling molecules to stimulate their nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ). The activated PPARγ then modulates the expression of its downstream target regulatory genes, which eventually lead to enhanced tumor expansion and aggressiveness caused by an overgrowth of cells with reduced apoptosis and an increased angiogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1947601913499155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807643PMC
July 2013

Mantle cell lymphoma involving the prostate with features of granulomatous prostatitis: a case report.

Int J Surg Pathol 2012 Dec 18;20(6):610-2. Epub 2012 Jun 18.

Royal Liverpool University Hospital, Liverpool, UK.

A case of mantle cell lymphoma involving the prostate is reported. This was associated with scattered histiocytes and features of granulomatous prostatitis. This demonstrates that histiocytes are seen in mantle cell lymphoma in unusual sites and raises the possibility of a pathogenetic association with granulomatous prostatitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1066896912444923DOI Listing
December 2012

Morphology and antigen expression profile of pulmonary neuroendocrine cells in reactive proliferations and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH).

Histopathology 2011 Oct;59(4):751-62

Department of Pathology, Royal Liverpool University Hospital University of Liverpool, UK.

Aims: To compare the morphology and antigenic profile of pulmonary neuroendocrine cells (PNECs) proliferating as a reaction to pulmonary injury with those proliferating in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) in which carcinoids develop.

Methods And Results: The morphology and expression of a range of antigens including markers of epithelial differentiation [cytokeratins, thyroid transcription factor (TTF)-1], neuroendocrine antigens [neural cell adhesion molecule (NCAM), chromogranin, protein gene product (PGP) 9.5, neurone-specific enolase (NSE), synaptophysin], peptide products [gastrin-releasing peptide (GRP), calcitonin, calcitonin gene-related peptide (CGRP)] and inactivator [common acute lymphoblastic leukaemia antigen (CALLA)] and antigens involved in cell proliferation and death (p53, p16, p27, Rb, Bcl-2, c-kit, Ki67) were studied in four cases of reactive PNEC proliferation and seven cases of DIPNECH. Proliferation was more florid in DIPNECH. There was no major shift in antigen expression with proliferation in either group apart from CALLA, which was expressed only by proliferating cells and not by solitary PNECs. There were differences between the groups in expression of p53, p16 and Ki67, which were seen more consistently and earlier in proliferation in DIPNECH.

Conclusions: These data suggest that there are early and fundamental differences in cell kinetics between the reactive PNEC proliferation that occurs in response to pulmonary injury and that seen in the pre-neoplastic condition of DIPNECH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-2559.2011.03992.xDOI Listing
October 2011

siRNA knockdown of ribosomal protein gene RPL19 abrogates the aggressive phenotype of human prostate cancer.

PLoS One 2011 22;6(7):e22672. Epub 2011 Jul 22.

Section of Cellular Pathology and Molecular Genetics, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.

We provide novel functional data that posttranscriptional silencing of gene RPL19 using RNAi not only abrogates the malignant phenotype of PC-3M prostate cancer cells but is selective with respect to transcription and translation of other genes. Reducing RPL19 transcription modulates a subset of genes, evidenced by gene expression array analysis and Western blotting, but does not compromise cell proliferation or apoptosis in-vitro. However, growth of xenografted tumors containing the knocked-down RPL19 in-vivo is significantly reduced. Analysis of the modulated genes reveals induction of the non-malignant phenotype principally to involve perturbation of networks of transcription factors and cellular adhesion genes. The data provide evidence that extra-ribosomal regulatory functions of RPL19, beyond protein synthesis, are critical regulators of cellular phenotype. Targeting key members of affected networks identified by gene expression analysis raises the possibility of therapeutically stabilizing a benign phenotype generated by modulating the expression of an individual gene and thereafter constraining a malignant phenotype while leaving non-malignant tissues unaffected.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022672PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3142177PMC
December 2011

Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study.

Lancet Oncol 2011 Mar;12(3):245-55

Cancer Research UK Centre of Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, St Bartholomew's Medical School, Queen Mary University of London, London, UK.

Background: Optimum management of clinically localised prostate cancer presents unique challenges because of the highly variable and often indolent natural history of the disease. To predict disease aggressiveness, clinicians combine clinical variables to create prognostic models, but the models have limited accuracy. We assessed the prognostic value of a predefined cell cycle progression (CCP) score in two cohorts of patients with prostate cancer.

Methods: We measured the expression of 31 genes involved in CCP with quantitative RT-PCR on RNA extracted from formalin-fixed paraffin-embedded tumour samples, and created a predefined score and assessed its usefulness in the prediction of disease outcome. The signature was assessed retrospectively in a cohort of patients from the USA who had undergone radical prostatectomy, and in a cohort of randomly selected men with clinically localised prostate cancer diagnosed by use of a transurethral resection of the prostate (TURP) in the UK who were managed conservatively. The primary endpoint was time to biochemical recurrence for the cohort of patients who had radical prostatectomy, and time to death from prostate cancer for the TURP cohort.

Findings: After prostatectomy, the CCP score was useful for predicting biochemical recurrence in the univariate analysis (hazard ratio for a 1-unit change [doubling] in CCP 1·89; 95% CI 1·54-2·31; p=5·6×10(-9)) and the best multivariate analysis (1·77, 1·40-2·22; p=4·3×10(-6)). In the best predictive model (final multivariate analysis), the CCP score and prostate-specific antigen (PSA) concentration were the most important variables and were more significant than any other clinical variable. In the TURP cohort, the CCP score was the most important variable for prediction of time to death from prostate cancer in both univariate analysis (2·92, 2·38-3·57, p=6·1×10(-22)) and the final multivariate analysis (2·57, 1·93-3·43; p=8·2×10(-11)), and was stronger than all other prognostic factors, although PSA concentration also added useful information. Heterogeneity in the hazard ratio for the CCP score was not noted in any case for any clinical variables.

Interpretation: The results of this study provide strong evidence that the CCP score is a robust prognostic marker, which, after additional validation, could have an essential role in determining the appropriate treatment for patients with prostate cancer.

Funding: Cancer Research UK, Queen Mary University of London, Orchid Appeal, US National Institutes of Health, and Koch Foundation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(10)70295-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091030PMC
March 2011

Suppressing tumourigenicity of prostate cancer cells by inhibiting osteopontin expression.

Int J Oncol 2011 Apr 2;38(4):1083-91. Epub 2011 Feb 2.

Molecular Pathology Laboratory, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, 6th Floor, Duncan Building, Daulby Street, Liverpool L69 3GA, UK.

Expression of osteopontin (OPN) is increased in prostate cancer cells. The possibility of utilising the increased OPN as a target to suppress the tumourigenicity was investigated in this study. Small interference RNAs against OPN were transfected into highly malignant DU145 prostate cancer cells, which express high level of OPN prior to the transfections, to establish OPN-suppressed clones. Compared with the control transfectants generated by scrambled RNA, suppressed expression of OPN significantly inhibited cell invasiveness and anchorage-independent growth. Similar results were obtained from in vivo experiments. OPN-suppressed transfectants produced significant reductions in average sizes of subcutaneous tumours after inoculation into nude mice. When the levels of OPN measured in transfectants before injection were related to tumour sizes, the reduction in tumour sizes was not propotionally related to the inhibition in OPN-levels. However, when the levels of OPN were analysed in the tumour tissues, it was found that the reduced OPN expression levels were significantly associated with the reducing tumour sizes. These results showed that changes in OPN levels had occurred after the transfectants were inoculated in mice. This study suggested while OPN can be an effective target for therapeutic suppression of prostate cancer, more effective way than RNAi is needed to inhibit OPN expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ijo.2011.932DOI Listing
April 2011

Immunohistochemistry for p16, but not Rb or p21, is an independent predictor of prognosis in conservatively treated, clinically localised prostate cancer.

Pathology 2010 ;42(6):519-23

Centre for Molecular Oncology and Imaging, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.

Aims: Treatment decisions are difficult in clinically localised prostate cancer and further biomarkers of aggressive behaviour are required. We investigated the hypothesis that the tissue expression of three cell cycle markers, Rb, p21 and p16, would provide helpful prognostic information in a well characterised series of prostate cancers which were clinically localised and treated conservatively.

Methods: The immunohistochemical staining expression of these markers was assessed in tissue microarrays and correlated with 10 year prostate cancer survival and overall survival and then compared with pathological data including contemporary Gleason score, age, measures of tumour extent and initial serum prostate specific antigen (PSA) level.

Results: Rb overexpression did not show any significant association with Gleason score or prostate cancer survival. p21 protein expression showed a significant association with prostate cancer survival (p = 0.02) and overall survival (p = 0.01) in a univariate model but not in a multivariate model with pathological and serum PSA data. There was a significant association between p16 cytoplasmic expression and prostate cancer survival (HR = 2.52, 95%CI = 1.79-3.55, p < 0.001) and overall survival (HR = 1.54, 95% CI = 1.20-1.98, p = 0.001) in a univariate model. p16 expression remained an independent prognostic factor for prostate cancer survival (HR = 1.50, 95%CI = 1.05-2.14, p = 0.03).

Conclusion: We conclude that p16 cytoplasmic expression can be used as a predictor of outcome in conservatively treated prostate cancer. Rb and p21 show no independent association with outcome and therefore further research is not warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/00313025.2010.508788DOI Listing
January 2011

An improved prognostic model for stage T1a and T1b prostate cancer by assessments of cancer extent.

Mod Pathol 2011 Jan 10;24(1):58-63. Epub 2010 Sep 10.

Centre for Molecular Oncology and Imaging, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Treatment decisions on prostate cancer diagnosed by trans-urethral resection (TURP) of the prostate are difficult. The current TNM staging system for pT1 prostate cancer has not been re-evaluated for 25 years. Our objective was to optimise the predictive power of tumor extent measurements in TURP of the prostate specimens. A total of 914 patients diagnosed by TURP of the prostate between 1990 and 1996, managed conservatively were identified. The clinical end point was death from prostate cancer. Diagnostic serum prostate-specific antigen (PSA) and contemporary Gleason grading was available. Cancer extent was measured by the percentage of chips infiltrated by cancer. Death rates were compared by univariate and multivariate proportional hazards models, including baseline PSA and Gleason score. The percentage of positive chips was highly predictive of prostate cancer death when assessed as a continuous variable or as a grouped variable on the basis of and including the quintiles, quartiles, tertiles and median groups. In the univariate model, the most informative variable was a four group-split (≤10%, >10-25%, >25-75% and >75%); (HR=2.08, 95% CI=1.8-2.4, P<0.0001). The same was true in a multivariate model (ΔX(2) (1 d.f.)=15.0, P=0.0001). The current cutoff used by TNM (<=5%) was sub-optimal (ΔX(2) (1 d.f.)=4.8, P=0.023). The current TNM staging results in substantial loss of information. Staging by a four-group subdivision would substantially improve prognostication in patients with early stage disease and also may help to refine management decisions in patients who would do well with conservative treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/modpathol.2010.182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853363PMC
January 2011

Measurements of cancer extent in a conservatively treated prostate cancer biopsy cohort.

Virchows Arch 2010 Nov 9;457(5):547-53. Epub 2010 Sep 9.

Centre for Molecular Oncology and Imaging, Queen Mary University of London, UK.

The optimal method for measuring cancer extent in prostate biopsy specimens is unknown. Seven hundred forty-four patients diagnosed between 1990 and 1996 with prostate cancer and managed conservatively were identified. The clinical end point was death from prostate cancer. The extent of cancer was measured in terms of number of cancer cores (NCC), percentage of cores with cancer (PCC), total length of cancer (LCC) and percentage length of cancer in the cores (PLC). These were correlated with prostate cancer mortality, in univariate and multivariate analysis including Gleason score and prostate-specific antigen (PSA). All extent of cancer variables were significant predictors of prostate cancer death on univariate analysis: NCC, hazard ration (HR) = 1.15, 95% confidence interval (CI) = 1.04-1.28, P = 0.011; PPC, HR = 1.01, 95% CI = 1.01-1.02, P < 0.0001; LCC, HR = 1.02, 95% CI = 1.01-1.03, P = 0.002; PLC, HR = 1.01, 95% CI = 1.01-1.02, P = 0.0001. In multivariate analysis including Gleason score and baseline PSA, PCC and PLC were both independently significant P = 0.004 and P = 0.012, respectively, and added further information to that provided by PSA and Gleason score, whereas NNC and LCC were no longer significant (P = 0.5 and P = 0.3 respectively). In a final model, including both extent of cancer variables, PCC was the stronger, adding more value than PLC (χ² (1df) = 7.8, P = 0.005, χ² (1df) = 0.5, P = 0.48 respectively). Measurements of disease burden in needle biopsy specimens are significant predictors of prostate-cancer-related death. The percentage of positive cores appeared the strongest predictor and was stronger than percentage length of cancer in the cores.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00428-010-0971-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853376PMC
November 2010

Pathology: coming in from the cold.

Cell Tissue Bank 2011 Feb 8;12(1):25-7. Epub 2010 Sep 8.

Division of Pathology, Liverpool University, Duncan Building, Daulby Street, Liverpool, UK.

Following the UK's organ retention scandals that occurred a decade ago, politicians unleashed a deluge of well-intentioned but naïve and unnecessarily burdensome regulations that have progressively stymied human tissue-based research, stifling development of improved diagnostic and prognostic tests as well as discovery of new treatments based on sound knowledge of human-specific biology. For the UK to maintain a leading role in medical research, more sensible levels of regulation need to be introduced that recognise differences between tissue from donors who have passed-away and surgical tissue that is surplus to diagnostic requirements and that otherwise will be incinerated. While it is important to reassure the public that research using their tissues will be conducted within an approved ethical framework, it is equally important to ensure that, as hospital staff and academic researchers, we are able to fulfil our unwritten covenant with patients to do our utmost to seek better diagnostic assays and more predictive prognostic indicators, while collaborating with our colleagues in academia and industry and hence bring hope to patients with illnesses for which no effective treatments are yet available. There is a clear case for introducing an opt-out system as the default to allow all surplus surgical tissues to be immediately available for research, concomitant with an education campaign. This is the optimal and most ethical approach to ensure the wishes of the vast majority of patients are respected by allowing their residual surgical tissues and relevant clinical information to be made available for research without the current levels of obstruction and hindrance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10561-010-9211-7DOI Listing
February 2011
-->