109 results on '"Van Neste L"'
Search Results
2. Development of a prognostic risk model for clear cell renal cell carcinoma by systematic evaluation of DNA methylation markers
- Author
-
Joosten, S. C., Odeh, S. N. O., Koch, A., Buekers, N., Aarts, M. J. B., Baldewijns, M. M. L. L., Van Neste, L., van Kuijk, S., Schouten, L. J., van den Brandt, P. A., Tjan-Heijnen, V. C., van Engeland, M., and Smits, K. M.
- Published
- 2021
- Full Text
- View/download PDF
3. A conformational variant of p53 (U-p53AZ) as blood-based biomarker for the prediction of the onset of symptomatic Alzheimer’s disease
- Author
-
Piccirella S, Daniela Uberti, Christopher Fowler, Chengjie Xiong, Colin L. Masters, Van Neste L, Kinnon P, James D. Doecke, and Jurgen Fripp
- Subjects
Oncology ,Apolipoprotein E ,medicine.medical_specialty ,Receiver operating characteristic ,business.industry ,Retrospective cohort study ,medicine.disease ,Asymptomatic ,Internal medicine ,Cohort ,medicine ,Biomarker (medicine) ,Dementia ,medicine.symptom ,Alzheimer's disease ,business - Abstract
BackgroundOngoing research seeks to identify blood-based biomarkers able to predict the onset and progression of Alzheimer’s disease (AD). A potential biomarker is the unfolded conformational variant of p53, previously observed in individuals in the prodromal and clinical AD stages. In this retrospective study, we compare diagnostic and prognostic performances of measures of the amyloid β load with those of a conformational variant of U-p53 in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort.MethodsImmunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing in plasma samples from the AIBL study identified the clinically relevant AZ 284®peptide, representing a measure of the U-p53 conformational variant (U-p53AZ). Based on U-p53AZquantification via IP/LC electrospray ionisation-coupled MS/MS (AlzoSure®Predict test) on 515 samples from 482 individuals from the AIBL cohort, the predictive performance of U-p53AZwas assessed and compared with amyloid load as measured by amyloid β-positron emission tomography (Aβ-PET). Its predictive performance was determined at 36, 54, 72 and 90 months following baseline assessment.ResultsU-p53AZwas able to identify individuals with AD dementia with an area under the receiver operating characteristic curve (AUC) of 99%. U-p53AZoutperformed the conventional Aβ-PET measures in predicting the onset of AD dementia both from preclinical (AUC=98%) and prodromal stages (AUC=89%), even 90 months prior to onset (AUC=99%). Additionally, the estimated predictive performance of U-p53AZwas superior (AUC ≥98%) to other risk factors (i.e., gender, Aβ-PET andAPOEε4 allele status) in identifying individuals at high risk for progression to AD.ConclusionThese findings support use of U-p53AZas blood-based biomarker predicting if individuals, at both asymptomatic and MCI stages, would progress to AD at least six years prior to the onset of clinical AD dementia.
- Published
- 2021
4. A Conformational Variant of p53 (U-p53AZ) as Blood-Based Biomarker for the Prediction of the Onset of Symptomatic Alzheimer's Disease.
- Author
-
Piccirella, Simona, Van Neste, L., Fowler, C., Masters, C. L., Fripp, J., Doecke, J. D., Xiong, C., Uberti, D., and Kinnon, P.
- Published
- 2022
- Full Text
- View/download PDF
5. Transcriptional regulation of Wnt inhibitory factor-1 by Miz-1/c-Myc
- Author
-
Licchesi, J D F, Van Neste, L, Tiwari, V K, Cope, L, Lin, X, Baylin, S B, and Herman, J G
- Published
- 2010
- Full Text
- View/download PDF
6. Re-expression of CXCL14, a common target for epigenetic silencing in lung cancer, induces tumor necrosis
- Author
-
Tessema, M, Klinge, D M, Yingling, C M, Do, K, Van Neste, L, and Belinsky, S A
- Published
- 2010
- Full Text
- View/download PDF
7. 383 Multicenter validation study of a urine-based molecular biomarker algorithm to predict high-grade prostate cancer
- Author
-
Hendriks, R.J., primary, Dijkstra, S., additional, Trooskens, G., additional, Van Criekinge, W., additional, Cornel, E.B., additional, Jannink, S.A., additional, De Jong, H., additional, Hessels, D., additional, Smit, F.P., additional, Melchers, W.J.G., additional, Leyten, G.H.J.M., additional, De Reijke, T.M., additional, Vergunst, H., additional, Kil, P., additional, Knipscheer, B.C., additional, Hulsbergen-Van De Kaa, C.A., additional, Mulders, P.F.A., additional, Van Oort, I.M., additional, Van Neste, L., additional, and Schalken, J.A., additional
- Published
- 2016
- Full Text
- View/download PDF
8. MC13-0087 Epigenetic assay detects early stage non-small cell lung cancer in sputum
- Author
-
Van Neste, L., primary, Moreau, F., additional, Kelley, M.J., additional, Belinsky, S.A., additional, Bigley, J., additional, and Van Criekinge, W., additional
- Published
- 2013
- Full Text
- View/download PDF
9. 55: Early Methylation of SYNE1 in Colorectal Cancer: Implications for Stool-Based Colorectal Cancer Screening
- Author
-
Dhir, M., primary, Glockner, S., additional, Van Neste, L., additional, Schuebel, K., additional, Baylin, S., additional, and Ahuja, N., additional
- Published
- 2009
- Full Text
- View/download PDF
10. High content image cytometry in the context of subnuclear organization
- Author
-
De Vos, W. H., primary, Van Neste, L., additional, Dieriks, B., additional, Joss, G. H., additional, and Van Oostveldt, P., additional
- Published
- 2009
- Full Text
- View/download PDF
11. In vitro validation of -secretase inhibitors alone or in combination with other anti-cancer drugs for the treatment of T-cell acute lymphoblastic leukemia
- Author
-
De Keersmaecker, K., primary, Lahortiga, I., additional, Mentens, N., additional, Folens, C., additional, Van Neste, L., additional, Bekaert, S., additional, Vandenberghe, P., additional, Odero, M. D., additional, Marynen, P., additional, and Cools, J., additional
- Published
- 2008
- Full Text
- View/download PDF
12. PubMeth: a cancer methylation database combining text-mining and expert annotation
- Author
-
Ongenaert, M., primary, Van Neste, L., additional, De Meyer, T., additional, Menschaert, G., additional, Bekaert, S., additional, and Van Criekinge, W., additional
- Published
- 2007
- Full Text
- View/download PDF
13. Relation between telomerase activity, hTERT and telomere length for intracranial tumours
- Author
-
Maes, L., primary, Van Neste, L., additional, Van Damme, K., additional, Kalala, J., additional, De Ridder, L., additional, Bekaert, S., additional, and Cornelissen, M., additional
- Published
- 2007
- Full Text
- View/download PDF
14. High content image cytometry in the context of subnuclear organization
- Author
-
De Vos, W. H., Van Neste, L., Dieriks, B., Joss, G. H., and Van Oostveldt, P.
- Abstract
The organization of proteins in space and time is essential to their function. To accurately quantify subcellular protein characteristics in a population of cells with regard for the stochasticity of events in a natural context, there is a fastgrowing need for imagebased cytometry. Simultaneously, the massive amount of data that is generated by imagecytometric analyses, calls for tools that enable pattern recognition and automated classification. In this article, we present a general approach for multivariate phenotypic profiling of individual cell nuclei and quantification of subnuclear spots using automated fluorescence mosaic microscopy, optimized image processing tools, and supervised classification. We demonstrate the efficiency of our analysis by determination of differential DNA damage repair patterns in response to genotoxic stress and radiation, and we show the potential of data mining in pinpointing specific phenotypes after transient transfection. The presented approach allowed for systematic analysis of subnuclear features in large image data sets and accurate classification of phenotypes at the level of the single cell. Consequently, this type of nuclear fingerprinting shows potential for highthroughput applications, such as functional protein assays or drug compound screening. © 2009 International Society for Advancement of Cytometry
- Published
- 2010
- Full Text
- View/download PDF
15. Cellular distribution of somatogenic receptors and insulin-like growth factor-I mRNA in the rat liver
- Author
-
van Neste, L., primary, Husman, B., additional, Möller, C., additional, Andersson, G., additional, and Norstedt, G., additional
- Published
- 1988
- Full Text
- View/download PDF
16. The (0+)-(0+) beta transition in 156Eu
- Author
-
Van Neste, L., primary, Coussement, R., additional, and Deutsch, J.P., additional
- Published
- 1967
- Full Text
- View/download PDF
17. Second-forbidden contributions to isospin-forbidden (0+)-(0+) beta-transitions
- Author
-
Van Neste, L., primary, Coussement, R., additional, and Deutsch, J.P., additional
- Published
- 1966
- Full Text
- View/download PDF
18. The use of graphite thermometers in heat conductivity experiments below 1° K
- Author
-
Dupré, A., primary, Van Itterbeek, A., additional, Michiels, L., additional, and Van Neste, L., additional
- Published
- 1964
- Full Text
- View/download PDF
19. Second-forbidden contributions to allowed isospin hindered J → J transitions
- Author
-
Coussement, R., primary and Van Neste, L., additional
- Published
- 1967
- Full Text
- View/download PDF
20. The (0+)−(0+) position decay of 66Ga
- Author
-
Van Neste, L., primary, Coussement, R., additional, and Deutsch, J.P., additional
- Published
- 1967
- Full Text
- View/download PDF
21. Genome-Wide Expression Profiling Reveals Downregulation of OTP and CD44 and Upregulation of RET as Indicators of Poor Prognosis in Lung Carcinoids.
- Author
-
Swarts, D., Van Neste, L., Henfling, M., Van Suylen, R. J., Volante, M., Ramaekers, F., Van Criekinge, W., Van Engeland, M., and Speel, E. J.
- Subjects
- *
LUNG cancer , *CARCINOID , *CHROMAFFIN cell tumors , *NEUROENDOCRINE tumors , *CANCER invasiveness , *IMMUNOHISTOCHEMISTRY - Abstract
Introduction: Lung carcinoids comprise a heterogeneous group of neuroendocrine tumors. Only few parameters have been identified that correlated with poor disease outcome, including 11q22-q25 deletions. New biomarkers are required to further improve diagnosis and prediction of prognosis. Aim(s): To identify differentially expressed genes between carcinoids with a favorable and poor outcome using high resolution gene-expression profiling, and to test their value as prognostic markers. Materials and methods: mRNA of five tumors with a favorable (>5yr survival) and five with a poor (distant metastasis / deceased) disease outcome was labeled and hybridized to 4x44k Agilent arrays, with a human pool expressing 70-80% of genes as a control. Results were validated by qRT-PCR and immunohistochemistry on an independent series of lung carcinoids. Results: Expression profiling revealed amongst others overexpression of the RET oncogene and repression of the homeobox gene OTP and CD44 in the poor prognosis group. In 54 frozen cases, low CD44 (p<0.0001) and OTP (p=0.0013), and high RET (p=0.0035) expression were significantly associated with decreased 15-year survival, outperforming WHO classification. Downregulation of CD44 and OTP expression was confirmed in tumors with a poor prognosis by immunohistochemistry. Conclusion: High resolution expression profiling unmasked new lung carcinoid candidate genes, of which CD44, OTP, and RET efficiently predict poor outcome. [ABSTRACT FROM AUTHOR]
- Published
- 2012
22. A tissue biopsy-based epigenetic multiplex PCR assay for prostate cancer detection
- Author
-
Van Neste Leander, Bigley Joseph, Toll Adam, Otto Gaëtan, Clark James, Delrée Paul, Van Criekinge Wim, and Epstein Jonathan I
- Subjects
GSTP1 ,APC ,RASSF1 ,Methylation ,Epigenetics ,Prostate cancer ,Diagnosis ,Multiplex ,Singleplex ,MSP ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Background PSA-directed prostate cancer screening leads to a high rate of false positive identifications and an unnecessary biopsy burden. Epigenetic biomarkers have proven useful, exhibiting frequent and abundant inactivation of tumor suppressor genes through such mechanisms. An epigenetic, multiplex PCR test for prostate cancer diagnosis could provide physicians with better tools to help their patients. Biomarkers like GSTP1, APC and RASSF1 have demonstrated involvement with prostate cancer, with the latter two genes playing prominent roles in the field effect. The epigenetic states of these genes can be used to assess the likelihood of cancer presence or absence. Results An initial test cohort of 30 prostate cancer-positive samples and 12 cancer-negative samples was used as basis for the development and optimization of an epigenetic multiplex assay based on the GSTP1, APC and RASSF1 genes, using methylation specific PCR (MSP). The effect of prostate needle core biopsy sample volume and age of formalin-fixed paraffin-embedded (FFPE) samples was evaluated on an independent follow-up cohort of 51 cancer-positive patients. Multiplexing affects copy number calculations in a consistent way per assay. Methylation ratios are therefore altered compared to the respective singleplex assays, but the correlation with patient outcome remains equivalent. In addition, tissue-biopsy samples as small as 20 μm can be used to detect methylation in a reliable manner. The age of FFPE-samples does have a negative impact on DNA quality and quantity. Conclusions The developed multiplex assay appears functionally similar to individual singleplex assays, with the benefit of lower tissue requirements, lower cost and decreased signal variation. This assay can be applied to small biopsy specimens, down to 20 microns, widening clinical applicability. Increasing the sample volume can compensate the loss of DNA quality and quantity in older samples.
- Published
- 2012
- Full Text
- View/download PDF
23. The (0 +)−(0 +) position decay of 66Ga
- Author
-
Van Neste, L., Coussement, R., and Deutsch, J.P.
- Published
- 1967
- Full Text
- View/download PDF
24. The (0 +)-(0 +) beta transition in 156Eu
- Author
-
Van Neste, L., Coussement, R., and Deutsch, J.P.
- Published
- 1967
- Full Text
- View/download PDF
25. Second-forbidden contributions to isospin-forbidden (0 +)-(0 +) beta-transitions
- Author
-
Van Neste, L., Coussement, R., and Deutsch, J.P.
- Published
- 1966
- Full Text
- View/download PDF
26. SECOND-FORBIDDEN CONTRIBUTIONS TO ALLOWED ISOSPIN HINDERED J $Yields$ J TRANSITIONS.
- Author
-
Van Neste, L
- Published
- 1967
- Full Text
- View/download PDF
27. THE USE OF GRAPHITE THERMOMETERS IN HEAT CONDUCTIVITY EXPERIMENTS BELOW 1 K
- Author
-
Van Neste, L
- Published
- 1964
- Full Text
- View/download PDF
28. Development and Optimization of a Subtraction-Normalized Immunocyte Profiling Signature for Prostate Cancer Active Surveillance Risk Stratification.
- Author
-
Van Neste L, Henao R, Wojno KJ, Signes J, DeHart J, Busta A, Marriott E, Willing M, Argentini A, Hurley PM, Korman H, Hafron J, Putzi M, Pieczonka CM, Karsh LI, Morris DS, Kassis AI, and Kantoff PW
- Subjects
- Male, Humans, Leukocytes, Mononuclear pathology, Watchful Waiting, Biopsy, Risk Assessment, Prostate-Specific Antigen, Prostatic Neoplasms pathology
- Abstract
Purpose: Less invasive decision support tools are desperately needed to identify occult high-risk disease in men with prostate cancer (PCa) on active surveillance (AS). For a variety of reasons, many men on AS with low- or intermediate-risk disease forgo the necessary repeat surveillance biopsies needed to identify potentially higher-risk PCa. Here, we describe the development of a blood-based immunocyte transcriptomic signature to identify men harboring occult aggressive PCa. We then validate it on a biopsy-positive population with the goal of identifying men who should not be on AS and confirm those men with indolent disease who can safely remain on AS. This model uses subtraction-normalized immunocyte transcriptomic profiles to risk-stratify men with PCa who could be candidates for AS., Materials and Methods: Men were eligible for enrollment in the study if they were determined by their physician to have a risk profile that warranted prostate biopsy. Both training (n = 1017) and validation cohort (n = 1198) populations had blood samples drawn coincident to their prostate biopsy. Purified CD2
+ and CD14+ immune cells were obtained from peripheral blood mononuclear cells, and RNA was extracted and sequenced. To avoid overfitting and unnecessary complexity, a regularized regression model was built on the training cohort to predict PCa aggressiveness based on the National Comprehensive Cancer Network PCa guidelines. This model was then validated on an independent cohort of biopsy-positive men only, using National Comprehensive Cancer Network unfavorable intermediate risk and worse as an aggressiveness outcome, identifying patients who were not appropriate for AS., Results: The best final model for the AS setting was obtained by combining an immunocyte transcriptomic profile based on 2 cell types with PSA density and age, reaching an AUC of 0.73 (95% CI: 0.69-0.77). The model significantly outperforms ( P < .001) PSA density as a biomarker, which has an AUC of 0.69 (95% CI: 0.65-0.73). This model yields an individualized patient risk score with 90% negative predictive value and 50% positive predictive value., Conclusions: While further validation in an intended-use cohort is needed, the immunocyte transcriptomic model offers a promising tool for risk stratification of individual patients who are being considered for AS.- Published
- 2024
- Full Text
- View/download PDF
29. Initial Findings from a High Genetic Risk Prostate Cancer Clinic.
- Author
-
Sessine MS, Das S, Park B, Salami SS, Kaffenberger SD, Kasputis A, Solorzano M, Luke M, Vince RA, Kaye DR, Borza T, Stoffel EM, Cobain E, Merajver SD, Jacobs MF, Milliron KJ, Caba L, van Neste L, Mondul AM, and Morgan TM
- Subjects
- Adult, Aged, BRCA1 Protein genetics, BRCA2 Protein genetics, Biopsy, Checkpoint Kinase 2 genetics, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Digital Rectal Examination, Genetic Testing, Germ-Line Mutation, Humans, Life Style, Male, Medical History Taking, Middle Aged, Nutrition Surveys, Prostate pathology, Prostate-Specific Antigen blood, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Risk Factors, Urinalysis, Early Detection of Cancer, Genetic Predisposition to Disease, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics
- Abstract
Objective: To improve prostate cancer screening for high-risk men, we developed an early detection clinic for patients at high genetic risk of developing prostate cancer. Despite the rapidly growing understanding of germline variants in driving aggressive prostate cancer and the increased availability of genetic testing, there is little evidence surrounding how best to screen these men., Methods: We are reporting on the first 45 patients enrolled, men between the ages of 35-75, primarily with known pathogenic germline variants in prostate cancer susceptibility genes. Screening consists of an intake lifestyle survey, PSA, DRE, and SelectMDx urine assay. A biopsy was recommended for any of the following indications: 1) abnormal DRE, 2) PSA above threshold, or 3) SelectMDx above threshold. The primary outcomes were number needed to screen, and number needed to biopsy to diagnose a patient with prostate cancer., Results: Patients enrolled in the clinic included those with BRCA1 (n=7), BRCA2 (n=16), Lynch Syndrome (n=6), and CHEK2 (n = 4) known pathogenic germline variants. The median age and PSA were 58 (range 35-71) and 1.4 ng/ml (range 0.1-11.4 ng/ml), respectively. 12 patients underwent a prostate needle biopsy and there were 4positive biopsies for prostate cancer., Conclusion: These early data support the feasibility of opening a dedicated clinic for men at high genetic risk of prostate cancer. This early report on the initial enrollment of our long-term study will help optimize early detection protocols and provide evidence for personalized prostate cancer screening in men with key pathogenic germline variants., (Published by Elsevier Inc.)
- Published
- 2021
- Full Text
- View/download PDF
30. Evaluation of an RNAseq-Based Immunogenomic Liquid Biopsy Approach in Early-Stage Prostate Cancer.
- Author
-
Van Neste L, Wojno KJ, Henao R, Mane S, Korman H, Hafron J, Kernen K, Tinawi-Aljundi R, Putzi M, Kassis AI, and Kantoff PW
- Subjects
- Humans, Male, Middle Aged, Neoplasm Staging, Liquid Biopsy methods, Prostatic Neoplasms surgery, Sequence Analysis, RNA methods
- Abstract
The primary objective of this study is to detect biomarkers and develop models that enable the identification of clinically significant prostate cancer and to understand the biologic implications of the genes involved. Peripheral blood samples (1018 patients) were split chronologically into independent training ( n = 713) and validation ( n = 305) sets. Whole transcriptome RNA sequencing was performed on isolated phagocytic CD14+ and non-phagocytic CD2+ cells and their gene expression levels were used to develop predictive models that correlate to adverse pathologic features. The immune-transcriptomic model with the highest performance for predicting adverse pathology, based on a subtraction of the log-transformed expression signals of the two cell types, displayed an area under the curve (AUC) of the receiver operating characteristic of 0.70. The addition of biomarkers in combination with traditional clinical risk factors (age, serum prostate-specific antigen (PSA), PSA density, race, digital rectal examination (DRE), and family history) enhanced the AUC to 0.91 and 0.83 for the training and validation sets, respectively. The markers identified by this approach uncovered specific pathway associations relevant to (prostate) cancer biology. Increased phagocytic activity in conjunction with cancer-associated (mis-)regulation is also represented by these markers. Differential gene expression of circulating immune cells gives insight into the cellular immune response to early tumor development and immune surveillance.
- Published
- 2021
- Full Text
- View/download PDF
31. The trans-DATA study: aims and design of a translational breast cancer prognostic marker identification study.
- Author
-
de Ruijter TC, Smits KM, Aarts MJ, van Hellemond IEG, Van Neste L, de Vries B, Peer PGM, Veeck J, van Engeland M, and Tjan-Heijnen VCG
- Abstract
Background: The effect of extended adjuvant aromatase inhibition in hormone-positive breast cancer after sequential tamoxifen, aromatase inhibitor treatment of 5 years was recently investigated by the DATA study. This study found no statistically significant effect of prolonged aromatase therapy. However, subgroup analysis showed post hoc statistically significant benefits in certain sub-populations. The trans-DATA study is a translational sub-study aiming to identify DNA methylation markers prognostic of patient outcome., Methods: Patients from the DATA study are included in the trans-DATA study. Primary breast tumour tissue will be collected, subtyped and used for DNA isolation. A genome-wide DNA methylation discovery assay will be performed on 60 patients that had a distant recurrence and 60 patients that did not have a distant recurrence using the Infinium Methylation EPIC Bead Chip platform. Differentially methylated regions of interest will be selected based on Akaike's Information Criterion, Gene Ontology Analysis and correlation between methylation and expression levels. Selected candidate genes will subsequently be validated in the remaining patients using qMSP., Discussion: The trans-DATA study uses a cohort derived from a clinical randomised trial. This study was designed to avoid common pitfalls in marker discovery studies such as selection bias, confounding and lack of reproducibility. In addition to the usual clinical risk factors, the results of this study may identify predictors of high recurrence risk in hormone receptor-positive breast cancer patients treated with sequential tamoxifen and aromatase inhibitor therapy., Competing Interests: Competing interestsProf. dr. Tjan-Heijnen reports grants from AstraZeneca, during the conduct of the study; grants and non-financial support from Roche, grants and non-financial support from Pfizer, grants and non-financial support from Novartis, grants from Eisai, outside the submitted work. Dr. Peer reports grants from AstraZeneca, during the conduct of the study., (© The Author(s) 2019.)
- Published
- 2019
- Full Text
- View/download PDF
32. Evaluation of an Epigenetic Assay for Predicting Repeat Prostate Biopsy Outcome in African American Men.
- Author
-
Waterhouse RL Jr, Van Neste L, Moses KA, Barnswell C, Silberstein JL, Jalkut M, Tutrone R, Sylora J, Anglade R, Murdock M, Shiffman Z, Vandenberg T, Shah N, Carter M, Krispin M, Groskopf J, and Van Criekinge W
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Neoplasm Grading, Prognosis, Prostatic Neoplasms ethnology, Prostatic Neoplasms genetics, Reproducibility of Results, Retrospective Studies, United States epidemiology, Black or African American, Biomarkers, Tumor genetics, Epigenesis, Genetic, Image-Guided Biopsy methods, Prostate pathology, Prostatic Neoplasms diagnosis
- Abstract
Objective: To evaluate an epigenetic assay performed on tissue from negative prostate biopsies in a group of African American (AA) men undergoing repeat biopsy, and to compare accuracy for predicting repeat biopsy outcome to prior studies conducted in predominantly Caucasian populations., Materials and Methods: The study population consisted of 211 AA men from 7 urology centers across the United States; all of whom were undergoing 12-core transrectal ultrasound-guided repeat biopsy within 30 months from a negative index biopsy. All biopsy cores from the negative index biopsy were profiled for the epigenetic biomarkers GSTP1, APC, and RASSF1 using ConfirmMDx for Prostate Cancer (MDxHealth, Irvine, CA)., Results: Upon repeat biopsy, 130 of 211 subjects (62%) had no prostate cancer (PCa) detected and 81 of 211 (38%) were diagnosed with PCa. Of the subjects with PCa, 54 (67%) were diagnosed with Gleason score (GS) ≤6 PCa and 27 (33%) with GS ≥7 disease. For detection of PCa at repeat biopsy, ConfirmMDx sensitivity was 74.1% and specificity was 60.0%, equivalent to prior studies (P = .235 and .697, respectively). For detection of GS ≥7 PCa, sensitivity was 78% and specificity was 53%. The negative predictive values for detection of all PCa and GS ≥7 PCa were 78.8% and 94.2%, respectively., Conclusion: In this group of AA men, we successfully validated an epigenetic assay to assess the need for repeat biopsy. Results were consistent with previous studies from predominantly Caucasian populations. Therefore, the ConfirmMDx assay is a useful tool for risk stratification of AA men who had an initial negative biopsy., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
33. Author Correction: Analysis of DNA methylation in cancer: location revisited.
- Author
-
Koch A, Joosten SC, Feng Z, de Ruijter TC, Draht MX, Melotte V, Smits KM, Veeck J, Herman JG, Van Neste L, Van Criekinge W, de Meyer T, and van Engeland M
- Abstract
The originally published article contained an error in the acknowledgements section in which the Universiteitsfonds Limburg/SWOL is incorrectly presented as awarding an SU2C- DCS International Translational Cancer Research Dream Team Grant (Stand Up To Cancer (SU2C)-AACR- DT1415, MEDOCC). This has been corrected in the HTML and PDF versions of the manuscript to reflect that Universiteitsfonds Limburg/SWOL is not the funding body that awarded this grant.
- Published
- 2018
- Full Text
- View/download PDF
34. Analysis of DNA methylation in cancer: location revisited.
- Author
-
Koch A, Joosten SC, Feng Z, de Ruijter TC, Draht MX, Melotte V, Smits KM, Veeck J, Herman JG, Van Neste L, Van Criekinge W, De Meyer T, and van Engeland M
- Subjects
- Genome, Human genetics, Humans, Neoplasms therapy, Biomarkers, Tumor genetics, DNA Methylation genetics, Epigenesis, Genetic, Neoplasms genetics
- Abstract
Changes in DNA methylation in cancer have been heralded as promising targets for the development of powerful diagnostic, prognostic, and predictive biomarkers. Despite the existence of more than 14,000 scientific publications describing DNA methylation-based biomarkers and their clinical associations in cancer, only 14 of these biomarkers have been translated into a commercially available clinical test. Methodological and experimental obstacles are both major causes of this disparity, but the genomic location of a DNA methylation-based biomarker is an intrinsic and essential property that also has an important and often overlooked role. Here, we examine the importance of the location of DNA methylation for the development of cancer biomarkers, and take a detailed look at the genomic location and other relevant characteristics of the various biomarkers with commercially available tests. We also emphasize the value of publicly available databases for the development of DNA methylation-based biomarkers and the importance of accurate reporting of the full methodological details of research findings.
- Published
- 2018
- Full Text
- View/download PDF
35. Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
- Author
-
Dijkstra S, Govers TM, Hendriks RJ, Schalken JA, Van Criekinge W, Van Neste L, Grutters JPC, Sedelaar JPM, and van Oort IM
- Subjects
- Aged, Biopsy, Cost-Benefit Analysis, Humans, Male, Middle Aged, Prostatic Neoplasms epidemiology, Prostatic Neoplasms pathology, Risk, Biomarkers, Tumor urine, Prostatic Neoplasms diagnosis, Prostatic Neoplasms economics
- Abstract
Objective: To assess the cost-effectiveness of a new urinary biomarker-based risk score (SelectMDx; MDxHealth, Inc., Irvine, CA, USA) to identify patients for transrectal ultrasonography (TRUS)-guided biopsy and to compare this with the current standard of care (SOC), using only prostate-specific antigen (PSA) to select for TRUS-guided biopsy., Materials and Methods: A decision tree and Markov model were developed to evaluate the cost-effectiveness of SelectMDx as a reflex test vs SOC in men with a PSA level of >3 ng/mL. Transition probabilities, utilities and costs were derived from the literature and expert opinion. Cost-effectiveness was expressed in quality-adjusted life years (QALYs) and healthcare costs of both diagnostic strategies, simulating the course of patients over a time horizon representing 18 years. Deterministic sensitivity analyses were performed to address uncertainty in assumptions., Results: A diagnostic strategy including SelectMDx with a cut-off chosen at a sensitivity of 95.7% for high-grade prostate cancer resulted in savings of €128 and a gain of 0.025 QALY per patient compared to the SOC strategy. The sensitivity analyses showed that the disutility assigned to active surveillance had a high impact on the QALYs gained and the disutility attributed to TRUS-guided biopsy only slightly influenced the outcome of the model., Conclusion: Based on the currently available evidence, the reduction of over diagnosis and overtreatment due to the use of the SelectMDx test in men with PSA levels of >3 ng/mL may lead to a reduction in total costs per patient and a gain in QALYs., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)
- Published
- 2017
- Full Text
- View/download PDF
36. Epigenetic risk score improves prostate cancer risk assessment.
- Author
-
Van Neste L, Groskopf J, Grizzle WE, Adams GW, DeGuenther MS, Kolettis PN, Bryant JE, Kearney GP, Kearney MC, Van Criekinge W, and Gaston SM
- Subjects
- Aged, Cohort Studies, DNA Methylation genetics, Humans, Male, Middle Aged, Prospective Studies, Risk Assessment methods, Biomarkers, Tumor genetics, Epigenesis, Genetic genetics, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics
- Abstract
Background: Early detection of aggressive prostate cancer (PCa) remains crucial for effective treatment of patients. However, PCa screening remains controversial due to a high rate of overdiagnosis and overtreatment. To better reconcile both objectives, more effective methods for assessing disease severity at the time of diagnosis are needed., Methods: The relationship between DNA-methylation and high-grade PCa was examined in a cohort of 102 prospectively enrolled men who received standard 12-core prostate biopsies. EpiScore, an algorithm that quantifies the relative DNA methylation intensities of GSTP1, RASSF1, and APC in prostate biopsy tissue, was evaluated as a method to compensate for biopsy under-sampling and improve risk stratification at the time of diagnosis., Results: DNA-methylation intensities of GSTP1, RASSF1, and APC were higher in biopsy cores from men diagnosed with GS ≥ 7 cancer compared to men with diagnosed GS 6 disease. This was confirmed by EpiScore, which was significantly higher for subjects with high-grade biopsies and higher NCCN risk categories (both P < 0.001). In patients diagnosed with GS ≥ 7, increased levels of DNA-methylation were present, not only in the high-grade biopsy cores, but also in other cores with no or low-grade disease (P < 0.001). By combining EpiScore with traditional clinical risk factors into a logistic regression model, the prediction of high GS reached an AUC of 0.82 (95%CI: 0.73-0.91) with EpiScore, DRE, and atypical histological findings as most important contributors., Conclusions: In men diagnosed with PCa, DNA-methylation profiling can detect under-sampled high-risk PCa in prostate biopsy specimens through a field effect. Predictive accuracy increased when EpiScore was combined with other clinical risk factors. These results suggest that EpiScore could aid in the detection of occult high-grade disease at the time of diagnosis, thereby improving the selection of candidates for Active Surveillance., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
37. A Four-Gene Promoter Methylation Marker Panel Consisting of GREM1, NEURL, LAD1, and NEFH Predicts Survival of Clear Cell Renal Cell Cancer Patients.
- Author
-
van Vlodrop IJH, Joosten SC, De Meyer T, Smits KM, Van Neste L, Melotte V, Baldewijns MMLL, Schouten LJ, van den Brandt PA, Jeschke J, Yi JM, Schuebel KE, Ahuja N, Herman JG, Aarts MJ, Bosman FT, Van Criekinge W, and van Engeland M
- Subjects
- Adult, Aged, Autoantigens genetics, Carcinoma, Renal Cell mortality, DNA Methylation genetics, Disease-Free Survival, Female, High-Throughput Nucleotide Sequencing, Humans, Intercellular Signaling Peptides and Proteins genetics, Kaplan-Meier Estimate, Kidney Neoplasms mortality, Male, Middle Aged, Neurofilament Proteins genetics, Non-Fibrillar Collagens genetics, Oligonucleotide Array Sequence Analysis, Prognosis, Promoter Regions, Genetic genetics, Proportional Hazards Models, Ubiquitin-Protein Ligases genetics, Collagen Type XVII, Biomarkers, Tumor genetics, Carcinoma, Renal Cell genetics, Kidney Neoplasms genetics
- Abstract
Purpose: The currently used prognostic models for patients with nonmetastatic clear cell renal cell carcinoma (ccRCC) are based on clinicopathologic features and might be improved by adding molecular markers. Epigenetic alterations occur frequently in ccRCC and are promising biomarkers. The aim of this study is to identify prognostic promoter methylation markers for ccRCC. Experimental Design: We integrated data generated by massive parallel sequencing of methyl-binding domain enriched DNA and microarray-based RNA expression profiling of 5-aza-2'-deoxycytidine-treated ccRCC cell lines to comprehensively characterize the ccRCC methylome. A selection of the identified methylation markers was evaluated in two independent series of primary ccRCC ( n = 150 and n = 185) by methylation-specific PCR. Kaplan-Meier curves and log-rank tests were used to estimate cause-specific survival. HRs and corresponding 95% confidence intervals (CI) were assessed using Cox proportional hazard models. To assess the predictive capacity and fit of models combining several methylation markers, Harrell C statistic and the Akaike Information Criterion were used. Results: We identified four methylation markers, that is, GREM1, NEURL, LAD1, and NEFH , that individually predicted prognosis of patients with ccRCC. The four markers combined were associated with poorer survival in two independent patient series (HR, 3.64; 95% CI, 1.02-13.00 and HR, 7.54; 95% CI, 2.68-21.19). These findings were confirmed in a third series of ccRCC cases from The Cancer Genome Atlas (HR, 3.60; 95% CI, 2.02-6.40). Conclusions: A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts outcome of patients with ccRCC and might be used to improve current prognostic models. Clin Cancer Res; 23(8); 2006-18. ©2016 AACR ., (©2016 American Association for Cancer Research.)
- Published
- 2017
- Full Text
- View/download PDF
38. Promoter CpG island methylation in ion transport mechanisms and associated dietary intakes jointly influence the risk of clear-cell renal cell cancer.
- Author
-
Deckers IA, van Engeland M, van den Brandt PA, Van Neste L, Soetekouw PM, Aarts MJ, Baldewijns MM, Keszei AP, and Schouten LJ
- Subjects
- Aged, Carcinoma, Renal Cell pathology, CpG Islands, Female, Humans, Kidney Neoplasms pathology, Male, Middle Aged, Netherlands, Potassium, Dietary adverse effects, Promoter Regions, Genetic, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Carcinoma, Renal Cell genetics, DNA Methylation, Ion Transport, Kidney Neoplasms genetics, Sodium Chloride, Dietary adverse effects
- Abstract
Background: Sodium intake, but not potassium or fluid intake, has been associated with higher renal cell cancer (RCC) risk. However, risk factors may differ by molecular subtypes of the tumour. In renal physiology, electrolyte and water homeostasis is facilitated by ion transport mechanisms (ITM). Aberrant regulation of ITM genes, for example by promoter CpG island methylation, may modify associations between sodium, potassium and fluid intake and RCC risk., Methods: We identified ARHGDIG , ATP1A1 , SCNN1B and SLC8A3 as ITM genes exhibiting RCC-specific promoter methylation and down-regulation. Methylation-specific polymerase chain reaction (PCR) was used to analyse promoter CpG island methylation in tumour DNA of 453 RCC cases from the Netherlands Cohort Study ( n = 120 852) after 20.3 years of follow-up. Diet was measured at baseline using food-frequency questionnaires. Cox regression analyses were restricted to clear-cell (cc)RCC ( n = 306) and stratified by tumours with no, low (1 gene) and high (≥ 2 genes) methylation., Results: Sodium intake (high vs low) increased ccRCC risk particularly in tumours with a high methylation index: hazard ratio (HR) [95% confidence interval (CI)]: 2.04 (1.16-3.58), whereas heterogeneity across the methylation index was not significant ( P -heterogeneity = 0.26). Potassium intake was differentially associated with ccRCC risk ( P -heterogeneity = 0.008); the risk for high (vs low) potassium intake was low for unmethylated tumours [HR (95% CI): 0.60 (0.36-1.01)], but high for tumours with a high methylation index [HR (95% CI): 1.60 (0.96-2.65)]. Risks similarly differed for fluid intake, though not significantly ( P -heterogeneity = 0.54)., Conclusions: Our findings suggest for the first time that dietary intakes are differentially associated with ccRCC risk according to molecular subtypes defined by ITM gene-specific promoter methylation., (© The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association)
- Published
- 2017
- Full Text
- View/download PDF
39. Detection of High-grade Prostate Cancer Using a Urinary Molecular Biomarker-Based Risk Score.
- Author
-
Van Neste L, Hendriks RJ, Dijkstra S, Trooskens G, Cornel EB, Jannink SA, de Jong H, Hessels D, Smit FP, Melchers WJ, Leyten GH, de Reijke TM, Vergunst H, Kil P, Knipscheer BC, Hulsbergen-van de Kaa CA, Mulders PF, van Oort IM, Van Criekinge W, and Schalken JA
- Subjects
- Aged, Biomarkers, Tumor genetics, Clinical Decision-Making methods, Humans, Male, Middle Aged, Neoplasm Grading, Patient Selection, Prostate pathology, Prostate-Specific Antigen analysis, Reproducibility of Results, Research Design, Risk Assessment methods, Risk Factors, Homeodomain Proteins genetics, Medical Overuse prevention & control, Prostatic Neoplasms pathology, Prostatic Neoplasms therapy, Prostatic Neoplasms urine, RNA, Messenger analysis, RNA, Messenger urine, Transcription Factors genetics
- Abstract
Background: To reduce overdiagnosis and overtreatment, a test is urgently needed to detect clinically significant prostate cancer (PCa)., Objective: To develop a multimodal model, incorporating previously identified messenger RNA (mRNA) biomarkers and traditional risk factors that could be used to identify patients with high-grade PCa (Gleason score ≥7) on prostate biopsy., Design, Setting, and Participants: In two prospective multicenter studies, urine was collected for mRNA profiling after digital rectal examination (DRE) and prior to prostate biopsy. The multimodal risk score was developed on a first cohort (n=519) and subsequently validated clinically in an independent cohort (n=386)., Outcome Measurements and Statistical Analysis: The mRNA levels were measured using reverse transcription quantitative polymerase chain reaction. Logistic regression was used to model patient risk and combine risk factors. Models were compared using the area under the curve (AUC) of the receiver operating characteristic, and clinical utility was evaluated with a decision curve analysis (DCA)., Results and Limitations: HOXC6 and DLX1 mRNA levels were shown to be good predictors for the detection of high-grade PCa. The multimodal approach reached an overall AUC of 0.90 (95% confidence interval [CI], 0.85-0.95) in the validation cohort (AUC 0.86 in the training cohort), with the mRNA signature, prostate-specific antigen (PSA) density, and previous cancer-negative prostate biopsies as the strongest, most significant components, in addition to nonsignificant model contributions of PSA, age, and family history. For another model, which included DRE as an additional risk factor, an AUC of 0.86 (95% CI, 0.80-0.92) was obtained (AUC 0.90 in the training cohort). Both models were successfully validated, with no significant change in AUC in the validation cohort, and DCA indicated a strong net benefit and the best reduction in unnecessary biopsies compared with other clinical decision-making tools, such as the Prostate Cancer Prevention Trial risk calculator and the PCA3 assay., Conclusions: The risk score based on the mRNA liquid biopsy assay combined with traditional clinical risk factors identified men at risk of harboring high-grade PCa and resulted in a better patient risk stratification compared with current methods in clinical practice. Therefore, the risk score could reduce the number of unnecessary prostate biopsies., Patient Summary: This study evaluated a novel urine-based assay that could be used as a noninvasive diagnostic aid for high-grade prostate cancer (PCa). When results of this assay are combined with traditional clinical risk factors, risk stratification for high-grade PCa and biopsy decision making are improved., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
40. Risk score predicts high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies.
- Author
-
Van Neste L, Partin AW, Stewart GD, Epstein JI, Harrison DJ, and Van Criekinge W
- Subjects
- Adenomatous Polyposis Coli genetics, Aged, Epigenesis, Genetic, False Negative Reactions, Glutathione S-Transferase pi genetics, Humans, Male, Middle Aged, Neoplasm Grading, Prostate pathology, Prostate-Specific Antigen blood, Prostatic Neoplasms diagnosis, Risk Factors, Tumor Suppressor Proteins genetics, Biopsy, Needle, DNA Methylation, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
Background: Prostate cancer (PCa) diagnosis is challenging because efforts for effective, timely treatment of men with significant cancer typically result in over-diagnosis and repeat biopsies. The presence or absence of epigenetic aberrations, more specifically DNA-methylation of GSTP1, RASSF1, and APC in histopathologically negative prostate core biopsies has resulted in an increased negative predictive value (NPV) of ∼90% and thus could lead to a reduction of unnecessary repeat biopsies. Here, it is investigated whether, in methylation-positive men, DNA-methylation intensities could help to identify those men harboring high-grade (Gleason score ≥7) PCa, resulting in an improved positive predictive value., Methods: Two cohorts, consisting of men with histopathologically negative index biopsies, followed by a positive or negative repeat biopsy, were combined. EpiScore, a methylation intensity algorithm was developed in methylation-positive men, using area under the curve of the receiver operating characteristic as metric for performance. Next, a risk score was developed combining EpiScore with traditional clinical risk factors to further improve the identification of high-grade (Gleason Score ≥7) cancer., Results: Compared to other risk factors, detection of DNA-methylation in histopathologically negative biopsies was the most significant and important predictor of high-grade cancer, resulting in a NPV of 96%. In methylation-positive men, EpiScore was significantly higher for those with high-grade cancer detected upon repeat biopsy, compared to those with either no or low-grade cancer. The risk score resulted in further improvement of patient risk stratification and was a significantly better predictor compared to currently used metrics as PSA and the prostate cancer prevention trial (PCPT) risk calculator (RC). A decision curve analysis indicated strong clinical utility for the risk score as decision-making tool for repeat biopsy., Conclusions: Low DNA-methylation levels in PCa-negative biopsies led to a NPV of 96% for high-grade cancer. The risk score, comprising DNA-methylation intensity and traditional clinical risk factors, improved the identification of men with high-grade cancer, with a maximum avoidance of unnecessary repeat biopsies. This risk score resulted in better patient risk stratification and significantly outperformed current risk prediction models such as PCPTRC and PSA. The risk score could help to identify patients with histopathologically negative biopsies harboring high-grade PCa. Prostate 76:1078-1087, 2016. © 2016 The Authors. The Prostate Published by Wiley Periodicals, Inc., (© 2016 The Authors. The Prostate Published by Wiley Periodicals, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
41. Evaluation of an Epigenetic Profile for the Detection of Bladder Cancer in Patients with Hematuria.
- Author
-
van Kessel KE, Van Neste L, Lurkin I, Zwarthoff EC, and Van Criekinge W
- Subjects
- Adult, Aged, Aged, 80 and over, Epigenomics, Female, Gene Expression Profiling, Hematuria etiology, Humans, Male, Middle Aged, Multivariate Analysis, Mutation, Sensitivity and Specificity, Urinary Bladder Neoplasms complications, Urinary Bladder Neoplasms urine, Young Adult, Urinary Bladder Neoplasms diagnosis, Urinary Bladder Neoplasms genetics
- Abstract
Purpose: Many patients enter the care cycle with gross or microscopic hematuria and undergo cystoscopy to rule out bladder cancer. Sensitivity of this invasive examination is limited, leaving many patients at risk for undetected cancer. To improve current clinical practice more sensitive and noninvasive screening methods should be applied., Materials and Methods: A total of 154 urine samples were collected from patients with hematuria, including 80 without and 74 with bladder cancer. DNA from cells in the urine was epigenetically profiled using 2 independent assays. Methylation specific polymerase chain reaction was performed on TWIST1. SNaPshot™ methylation analysis was done for different loci of OTX1 and ONECUT2. Additionally all samples were analyzed for mutation status of TERT (telomerase reverse transcriptase), PIK3CA, FGFR3 (fibroblast growth factor receptor 3), HRAS, KRAS and NRAS., Results: The combination of TWIST1, ONECUT2 (2 loci) and OTX1 resulted in the best overall performing panel. Logistic regression analysis on these methylation markers, mutation status of FGFR3, TERT and HRAS, and patient age resulted in an accurate model with 97% sensitivity, 83% specificity and an AUC of 0.93 (95% CI 0.88-0.98). Internal validation led to an optimism corrected AUC of 0.92. With an estimated bladder cancer prevalence of 5% to 10% in a hematuria cohort the assay resulted in a 99.6% to 99.9% negative predictive value., Conclusions: Epigenetic profiling using TWIST1, ONECUT2 and OTX1 results in a high sensitivity and specificity. Accurate risk prediction might result in less extensive and invasive examination of patients at low risk, thereby reducing unnecessary patient burden and health care costs., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
42. CLINICAL EVALUATION OF AN EPIGENETIC ASSAY TO PREDICT MISSED CANCER IN PROSTATE BIOPSY SPECIMENS.
- Author
-
Partin AW, VAN Criekinge W, Trock BJ, Epstein JI, and VAN Neste L
- Subjects
- Biopsy, Humans, Male, Predictive Value of Tests, Prostatic Neoplasms genetics, Risk Factors, Validation Studies as Topic, DNA Methylation, Early Detection of Cancer methods, Epigenesis, Genetic, Prostatic Neoplasms diagnosis
- Abstract
Approximately 1 million prostate biopsies are performed yearly in the United States, with only ~25% resulting in prostate cancer diagnosis. However, ~40% of men receive multiple biopsies for fear of cancer being missed. DNA hypermethylation is ideally suited for early disease detection and could be used to prevent unnecessary biopsies. Men with low-risk epigenetic signatures may forego subsequent biopsy and potential complications. A meta-analysis of two validation studies was conducted to gain additional insight into the benefits for patient risk stratification. In the Methylation Analysis to Locate Occult Cancer (MATLOC) study a negative predictive value of 90% was obtained, which represents a significant improvement over standard of care. This was confirmed in the Detection of Cancer Using Methylated Events in Negative Tissue (DOCUMENT) study (88% negative predictive value), which was designed to validate the performance in an independent cohort. The epigenetic assay, in combination with other known risk factors, may help reduce unnecessary repeat prostate biopsies and identify men at highest risk of harboring occult high-grade prostate cancer., Competing Interests: Potential Conflicts of Interest: Leander Van Neste and Wim Van Criekinge are employees of or consultants for MDxHealth and may have stock or stock options.
- Published
- 2016
43. Promoter Methylation of CDO1 Identifies Clear-Cell Renal Cell Cancer Patients with Poor Survival Outcome.
- Author
-
Deckers IA, Schouten LJ, Van Neste L, van Vlodrop IJ, Soetekouw PM, Baldewijns MM, Jeschke J, Ahuja N, Herman JG, van den Brandt PA, and van Engeland M
- Subjects
- Aged, Carcinoma, Renal Cell pathology, CpG Islands genetics, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Netherlands, Prognosis, Promoter Regions, Genetic, Risk Factors, Biomarkers, Tumor genetics, Carcinoma, Renal Cell genetics, Cysteine Dioxygenase genetics, DNA Methylation genetics
- Abstract
Purpose: In this era of molecular diagnostics, prediction of clear-cell renal cell cancer (ccRCC) survival requires optimization, as current prognostic markers fail to determine individual patient outcome. Epigenetic events are promising molecular markers. Promoter CpG island methylation of cysteine dioxygenase type 1 (CDO1), which was identified as prognostic marker for breast cancer, is studied as a potential marker for ccRCC survival., Experimental Design: We collected primary tissues of 365 ccRCC cases identified within the prospective Netherlands Cohort Study (NLCS). In this population-based series, CDO1 promoter methylation was observed in 124 of 324 (38.3%) patients with successful methylation-specific PCR analysis. Kaplan-Meier curves and Wilcoxon tests were used to evaluate 10-year ccRCC-specific survival. Cox regression analysis was used to obtain crude and multivariate HRs and 95% confidence intervals (CI). The relative prognostic value of multivariate models with and without CDO1 promoter methylation was compared using likelihood-ratio tests., Results: Patients with CDO1 promoter methylation have a significantly poorer survival than those without (Wilcoxon P = 0.006). Differences in survival were independent of other prognostic factors, including age and sex (HR, 1.66; 95% CI, 1.12-2.45) and TNM stage, tumor size, and Fuhrman grade (HR, 1.89; 95% CI, 1.25-2.85). Multivariate models performed better with than without CDO1 promoter methylation status (likelihood-ratio P = 0.003). Survival curves were validated in an independent series of 280 ccRCC cases from The Cancer Genome Atlas (TCGA; Wilcoxon P < 0.001)., Conclusions: CDO1 promoter methylation may not substitute common prognostic makers to predict ccRCC survival, but offers additional, relevant prognostic information, indicating that it might be a novel molecular marker to determine ccRCC prognosis., (©2015 American Association for Cancer Research.)
- Published
- 2015
- Full Text
- View/download PDF
44. Formalin-fixed, paraffin-embedded (FFPE) tissue epigenomics using Infinium HumanMethylation450 BeadChip assays.
- Author
-
de Ruijter TC, de Hoon JP, Slaats J, de Vries B, Janssen MJ, van Wezel T, Aarts MJ, van Engeland M, Tjan-Heijnen VC, Van Neste L, and Veeck J
- Subjects
- Cluster Analysis, Fluorescence, Formaldehyde, Humans, Reproducibility of Results, DNA Methylation, Epigenomics methods, Oligonucleotide Array Sequence Analysis, Paraffin Embedding, Tissue Fixation
- Abstract
Current genome-wide methods to detect DNA-methylation in healthy and diseased tissue require high-quality DNA from fresh-frozen (FF) samples. However, well-annotated clinical samples are mostly available as formalin-fixed, paraffin-embedded (FFPE) tissues containing poor-quality DNA. To overcome this limitation, we here aimed to evaluate a DNA restoration protocol for usage with the genome-wide Infinium HumanMethylation450 BeadChip assay (HM-450K). Sixty-six DNA samples from normal colon (n=9) and breast cancer (n=11) were interrogated separately using HM-450K. Analyses included matched FF/FFPE samples and technical duplicates. FFPE DNA was processed with (FFPEr) or without a DNA restoration protocol (Illumina). Differentially methylated genes were finally validated in 24 additional FFPE tissues using nested methylation-specific PCR (MSP). In summary, β-values correlation between FFPEr duplicates was high (ρ=0.9927 (s.d. ±0.0015)). Matched FF/FFPEr correlation was also high (ρ=0.9590 (s.d. ±0.0184)) compared with matched FF/FFPE (ρ=0.8051 (s.d. ±0.1028). Probe detection rate in FFPEr samples (98.37%, s.d. ±0.66) was comparable to FF samples (99.98%, s.d. ±0.019) and substantially lower in FFPE samples (82.31%, s.d. ±18.65). Assay robustness was not decreased by sample archival age up to 10 years. We could also demonstrate no decrease in assay robustness when using 100 ng of DNA input only. Four out of the five selected differentially methylated genes could be validated by MSP. The gene failing validation by PCR showed high variation of CpG β-values in primer-binding sites. In conclusion, by using the FFPE DNA restoration protocol, HM-450K assays provide robust, accurate and reproducible results with FFPE tissue-derived DNA, which are comparable to those obtained with FF tissue. Most importantly, differentially methylated genes can be validated using more sensitive techniques, such as nested MSP, altogether providing an epigenomics platform for molecular pathological epidemiology research on archived samples with limited tissue amount.
- Published
- 2015
- Full Text
- View/download PDF
45. Spectrin repeat containing nuclear envelope 1 and forkhead box protein E1 are promising markers for the detection of colorectal cancer in blood.
- Author
-
Melotte V, Yi JM, Lentjes MH, Smits KM, Van Neste L, Niessen HE, Wouters KA, Louwagie J, Schuebel KE, Herman JG, Baylin SB, van Criekinge W, Meijer GA, Ahuja N, and van Engeland M
- Subjects
- Aged, Area Under Curve, Biomarkers, Tumor genetics, Cell Line, Tumor, Colorectal Neoplasms genetics, Cytoskeletal Proteins, DNA Methylation genetics, Female, Forkhead Transcription Factors genetics, Humans, Male, Middle Aged, Nerve Tissue Proteins genetics, Nuclear Proteins genetics, Promoter Regions, Genetic genetics, ROC Curve, Real-Time Polymerase Chain Reaction, Sensitivity and Specificity, Transfection, Biomarkers, Tumor blood, Colorectal Neoplasms blood, Forkhead Transcription Factors blood, Nerve Tissue Proteins blood, Nuclear Proteins blood
- Abstract
Identifying biomarkers in body fluids may improve the noninvasive detection of colorectal cancer. Previously, we identified N-Myc downstream-regulated gene 4 (NDRG4) and GATA binding protein 5 (GATA5) methylation as promising biomarkers for colorectal cancer in stool DNA. Here, we examined the utility of NDRG4, GATA5, and two additional markers [Forkhead box protein E1 (FOXE1) and spectrin repeat containing nuclear envelope 1 (SYNE1)] promoter methylation as biomarkers in plasma DNA. Quantitative methylation-specific PCR was performed on plasma DNA from 220 patients with colorectal cancer and 684 noncancer controls, divided in a training set and a test set. Receiver operating characteristic analysis was performed to measure the area under the curve of GATA5, NDRG4, SYNE1, and FOXE1 methylation. Functional assays were performed in SYNE1 and FOXE1 stably transfected cell lines. The sensitivity of NDRG4, GATA5, FOXE1, and SYNE1 methylation in all stages of colorectal cancer (154 cases, 444 controls) was 27% [95% confidence interval (CI), 20%-34%), 18% (95% CI, 12%-24%), 46% (95% CI, 38%-54%), and 47% (95% CI, 39%-55%), with a specificity of 95% (95% CI, 93%-97%), 99% (95% CI, 98%-100%), 93% (95% CI, 91%-95%), and 96% (95% CI, 94%-98%), respectively. Combining SYNE1 and FOXE1, increased the sensitivity to 56% (95% CI, 48%-64%), while the specificity decreased to 90% (95% CI, 87%-93%) in the training set and to 58% sensitivity (95% CI, 46%-70%) and 91% specificity (95% CI, 80%-100%) in a test set (66 cases, 240 controls). SYNE1 overexpression showed no major differences in cell proliferation, migration, and invasion compared with controls. Overexpression of FOXE1 significantly decreased the number of colonies in SW480 and HCT116 cell lines. Overall, our data suggest that SYNE1 and FOXE1 are promising markers for colorectal cancer detection., (©2014 American Association for Cancer Research.)
- Published
- 2015
- Full Text
- View/download PDF
46. We are all individuals... bioinformatics in the personalized medicine era.
- Author
-
Van Neste L and Van Criekinge W
- Subjects
- Humans, Computational Biology methods, Computational Biology trends, Precision Medicine methods, Precision Medicine trends
- Abstract
The medical landscape is evolving at a rapid pace, creating the opportunity for more personalized patient treatment and shifting the way healthcare is approached and thought about. With the availability of (epi)genome-wide, transcriptomic and proteogenomic profiling techniques detailed characterization of a disease at the level of the individual is now possible, offering the opportunity for truly tailored approaches for treatment and patient care. While improvements are still expected, the techniques and the basic analytical tools have reached a state that these can be efficiently deployed in both routine research and clinical practice. Still, some major challenges remain. Notably, holistic approaches, integrating data from several sources, e.g. genomic and epigenomic, will increase the understanding of the underlying biological concepts and provide insight into the causes, effects and effective solutions. However, creating and validating such a knowledge base, potentially for different levels of expertise, and integrating several data points into meaningful information is not trivial.
- Published
- 2015
- Full Text
- View/download PDF
47. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies.
- Author
-
Partin AW, Van Neste L, Klein EA, Marks LS, Gee JR, Troyer DA, Rieger-Christ K, Jones JS, Magi-Galluzzi C, Mangold LA, Trock BJ, Lance RS, Bigley JW, Van Criekinge W, and Epstein JI
- Subjects
- DNA Methylation, Epigenomics methods, Follow-Up Studies, Genes, APC, Glutathione S-Transferase pi biosynthesis, Humans, Male, Polymerase Chain Reaction, Predictive Value of Tests, Prognosis, Prostate metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Tumor Suppressor Proteins biosynthesis, Unnecessary Procedures statistics & numerical data, Biopsy methods, DNA, Neoplasm genetics, Epigenesis, Genetic, Glutathione S-Transferase pi genetics, Prostate pathology, Prostatic Neoplasms genetics, Tumor Suppressor Proteins genetics
- Abstract
Purpose: The DOCUMENT multicenter trial in the United States validated the performance of an epigenetic test as an independent predictor of prostate cancer risk to guide decision making for repeat biopsy. Confirming an increased negative predictive value could help avoid unnecessary repeat biopsies., Materials and Methods: We evaluated the archived, cancer negative prostate biopsy core tissue samples of 350 subjects from a total of 5 urological centers in the United States. All subjects underwent repeat biopsy within 24 months with a negative (controls) or positive (cases) histopathological result. Centralized blinded pathology evaluation of the 2 biopsy series was performed in all available subjects from each site. Biopsies were epigenetically profiled for GSTP1, APC and RASSF1 relative to the ACTB reference gene using quantitative methylation specific polymerase chain reaction. Predetermined analytical marker cutoffs were used to determine assay performance. Multivariate logistic regression was used to evaluate all risk factors., Results: The epigenetic assay resulted in a negative predictive value of 88% (95% CI 85-91). In multivariate models correcting for age, prostate specific antigen, digital rectal examination, first biopsy histopathological characteristics and race the test proved to be the most significant independent predictor of patient outcome (OR 2.69, 95% CI 1.60-4.51)., Conclusions: The DOCUMENT study validated that the epigenetic assay was a significant, independent predictor of prostate cancer detection in a repeat biopsy collected an average of 13 months after an initial negative result. Due to its 88% negative predictive value adding this epigenetic assay to other known risk factors may help decrease unnecessary repeat prostate biopsies., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
48. CHFR promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer.
- Author
-
Cleven AH, Derks S, Draht MX, Smits KM, Melotte V, Van Neste L, Tournier B, Jooste V, Chapusot C, Weijenberg MP, Herman JG, de Bruïne AP, and van Engeland M
- Subjects
- Aged, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Neoplasm Staging, Phenotype, Poly-ADP-Ribose Binding Proteins, Prognosis, Prospective Studies, Survival Rate, Ubiquitin-Protein Ligases, Cell Cycle Proteins genetics, Colorectal Neoplasms genetics, CpG Islands, DNA Methylation, Microsatellite Instability, Mutation genetics, Neoplasm Proteins genetics, Promoter Regions, Genetic genetics
- Abstract
Purpose: Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations between methylation and other factors affecting survival such as genetic alterations and use of adjuvant therapy. Here, we examine the prognostic impact of promoter methylation in patients with CRC treated with surgery alone in the context of microsatellite instability (MSI), BRAF and KRAS mutations., Experimental Methods: One hundred and seventy-three CRCs were analyzed for promoter methylation of 19 tumor suppressor and DNA repair genes, the CpG island methylator phenotype (CIMP), MSI, the exon 15 V600E BRAF mutation and KRAS codon 12 and 13 mutations., Results: Unsupervised hierarchical clustering based on methylation status of 19 genes revealed three subgroups: cluster 1 [CL1, 57% (98/173) of CRCs], cluster 2 [CL2, 25% (43/173) of CRCs], and cluster 3 [CL3, 18% (32/173) of CRCs]. CL3 had the highest methylation index (0.25, 0.49, and 0.69, respectively, P = <0.01) and was strongly associated with CIMP (P < 0.01). Subgroup analysis for tumor stage, MSI, and BRAF status showed no statistically significant differences in survival between CL1, CL2, and CL3 nor between CIMP and non-CIMP CRCs. Analyzing genes separately revealed that CHFR promoter methylation was associated with a poor prognosis in stage II, microsatellite stability (MSS), BRAF wild-type (WT) CRCs: multivariate Cox proportional HR = 3.89 [95% confidence interval (CI), 1.58-9.60, P < 0.01; n = 66] and HR = 2.11 (95% CI, 0.95-4.69, P = 0.068, n = 136) in a second independent population-based study., Conclusions: CHFR promoter CpG island methylation, which is associated with MSI, also occurs frequently in MSS CRCs and is a promising prognostic marker in stage II, MSS, BRAF WT CRCs., (©2014 American Association for Cancer Research.)
- Published
- 2014
- Full Text
- View/download PDF
49. Genome-wide unmasking of epigenetically silenced genes in lung adenocarcinoma from smokers and never smokers.
- Author
-
Tessema M, Yingling CM, Liu Y, Tellez CS, Van Neste L, Baylin SS, and Belinsky SA
- Subjects
- Adenocarcinoma mortality, Adenocarcinoma pathology, Azacitidine analogs & derivatives, Azacitidine pharmacology, Cell Line, Tumor, CpG Islands, DNA Methylation, Decitabine, Disease Progression, Genome-Wide Association Study, Humans, Lung Neoplasms mortality, Lung Neoplasms pathology, Promoter Regions, Genetic, Reproducibility of Results, Adenocarcinoma genetics, Epigenesis, Genetic drug effects, Gene Expression Regulation, Neoplastic drug effects, Gene Silencing, Lung Neoplasms genetics, Smoking
- Abstract
Lung cancer in never smokers (NS) shows striking demographic, clinicopathological and molecular distinctions from the disease in smokers (S). Studies on selected genetic and epigenetic alterations in lung cancer identified that the frequency and profile of some abnormalities significantly differ by smoking status. This study compared the transcriptome of lung adenocarcinoma cell lines derived from S (n = 3) and NS (n = 3) each treated with vehicle (control), histone deacetylation inhibitor (trichostatin A) or DNA methylation inhibitor (5-aza-2'-deoxycytidine). Among 122 genes reexpressed following 5-aza-2'-deoxycytidine but not trichostatin A treatment in two or more cell lines (including 32 genes in S-only and 12 NS-only), methylation was validated for 80% (98/122 genes). After methylation analysis of 20 normal tissue samples and 14 additional non-small cell lung cancer cell lines (total 20), 39 genes frequently methylated in normal (>20%, 4/20) and 21 genes rarely methylated in non-small cell lung cancer (≤10%, 2/20) were excluded. The prevalence for methylation of the remaining 38 genes in lung adenocarcinomas from S (n = 97) and NS (n = 75) ranged from 8-89% and significantly differs between S and NS for CPEB1, CST6, EMILIN2, LAYN and MARVELD3 (P < 0.05). Furthermore, methylation of EMILIN2, ROBO3 and IGDCC4 was more prevalent in advanced (Stage II-IV, n = 61) than early (Stage I, n = 110) tumors. Knockdown of MARVELD3, one of the novel epigenetically silenced genes, by small interfering RNA significantly reduced anchorage-independent growth of lung cancer cells (P < 0.001). Collectively, this study has identified multiple, novel, epigenetically silenced genes in lung cancer and provides invaluable resources for the development of diagnostic and prognostic biomarkers., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2014
- Full Text
- View/download PDF
50. Reduced Rate of Repeated Prostate Biopsies Observed in ConfirmMDx Clinical Utility Field Study.
- Author
-
Wojno KJ, Costa FJ, Cornell RJ, Small JD, Pasin E, Van Criekinge W, Bigley JW, and Van Neste L
- Abstract
Background: The diagnosis of prostate cancer is dependent on histologic confirmation in biopsy core tissues. The biopsy procedure is invasive, puts the patient at risk for complications, and is subject to significant sampling errors. An epigenetic test that uses methylation-specific polymerase chain reaction to determine the epigenetic status of the prostate cancer-associated genes GSTP1, APC, and RASSF1 has been clinically validated and is used in clinical practice to increase the negative predictive value in men with no history of prostate cancer compared with standard histopathology. Such information can help to avoid unnecessary repeat biopsies. The repeat biopsy rate may provide preliminary clinical utility evidence in relation to this assay's potential impact on the number of unnecessary repeat prostate biopsies performed in US urology practices., Objective: The purpose of this preliminary study was to quantify the number of repeat prostate biopsy procedures to demonstrate a low repeat biopsy rate for men with a history of negative histopathology who received a negative epigenetic assay result on testing of the residual prostate tissue., Methods: In this recently completed field observation study, practicing urologists used the epigenetic test called ConfirmMDx for Prostate Cancer (MDxHealth, Inc, Irvine, CA) to evaluate cancer-negative men considered at risk for prostate cancer. This test has been previously validated in 2 blinded multicenter studies that showed the superior negative predictive value of the epigenetic test over standard histopathology for cancer detection in prostate biopsies. A total of 5 clinical urology practices that had ordered a minimum of 40 commercial epigenetic test requisitions for patients with previous, cancer-negative biopsies over the course of the previous 18 months were contacted to assess their interest to participate in the study. Select demographic and prostate-screening parameter information, as well as the incidence of repeat biopsy, specifically for patients with a negative test result, was collected and merged into 1 collective database. All men from each of the 5 sites who had negative assay results were included in the analysis., Results: A total of 138 patients were identified in these urology practices and were included in the analysis. The median age of the men was 63 years, and the current median serum prostate-specific antigen level was 4.7 ng/mL. Repeat biopsies had been performed in 6 of the 138 (4.3%) men with a negative epigenetic assay result, in whom no evidence of cancer was found on histopathology., Conclusion: In this study, a low rate of repeat prostatic biopsies was observed in the group of men with previous histopathologically negative biopsies who were considered to be at risk for harboring cancer. The data suggest that patients managed using the ConfirmMDx for Prostate Cancer negative results had a low rate of repeat prostate biopsies. These results warrant a large, controlled, prospective study to further evaluate the clinical utility of the epigenetic test to lower the unnecessary repeat biopsy rate.
- Published
- 2014
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.