Dataset Information

Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.

ABSTRACT: BACKGROUND:Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). METHODS:The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. RESULTS:Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. CONCLUSIONS:We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. IMPACT:The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

SUBMITTER: Adams CD

PROVIDER: S-EPMC6746173 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.

Adams Charleen D CD Richmond Rebecca R Ferreira Diana L Santos DLS Spiller Wes W Tan Vanessa V Zheng Jie J Würtz Peter P Donovan Jenny J Hamdy Freddie F Neal David D Lane J Athene JA Smith George Davey GD Relton Caroline C Eeles Rosalind A RA Haiman Christopher A CA Kote-Jarai ZSofia Z Schumacher Fredrick R FR Olama Ali Amin Al AAA Benlloch Sara S Muir Kenneth K Berndt Sonja I SI Conti David V DV Wiklund Fredrik F Chanock Stephen J SJ Gapstur Susan S Stevens Victoria L VL Tangen Catherine M CM Batra Jyotsna J Clements Judith A JA Gronberg Henrik H Pashayan Nora N Schleutker Johanna J Albanes Demetrius D Wolk Alicja A West Catharine M L CML Mucci Lorelei A LA Cancel-Tassin Géraldine G Koutros Stella S Sorensen Karina Dalsgaard KD Maehle Lovise L Travis Ruth C RC Hamilton Robert J RJ Ingles Sue Ann SA Rosenstein Barry S BS Lu Yong-Jie YJ Giles Graham G GG Kibel Adam S AS Vega Ana A Kogevinas Manolis M Penney Kathryn L KL Park Jong Y JY Stanford Janet L JL Cybulski Cezary C Nordestgaard Børge G BG Brenner Hermann H Maier Christiane C Kim Jeri J John Esther M EM Teixeira Manuel R MR Neuhausen Susan L SL De Ruyck Kim K Razack Azad A Newcomb Lisa F LF Lessel Davor D Kaneva Radka P RP Usmani Nawaid N Claessens Frank F Townsend Paul A PA Dominguez Manuela Gago MG Roobol Monique J MJ Menegaux Florence F Khaw Kay-Tee KT Cannon-Albright Lisa A LA Pandha Hardev H Thibodeau Stephen N SN Martin Richard M RM

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20181023 1

<h4>Background</h4>Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).<h4>Methods</h4>The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen scre ...[more]

PMID: 30352818

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Project description:ImportanceThe nationwide fecal immunochemical test-based screening program has influenced surgical care for patients with colorectal cancer (CRC) in the Netherlands, although these implications have not been studied in much detail so far.ObjectiveTo compare surgical outcomes of patients diagnosed as having CRC through the fecal immunochemical test-based screening program (screen detected) and patients with non-screen-detected CRC.Design, setting, and participantsThis was a population-based comparative cohort study using the Dutch ColoRectal Audit and analyzed all Dutch hospitals performing CRC resections. Patients who underwent elective resection for CRC between January 2011 to December 2016 were included.InterventionsColorectal cancer surgery.Main outcomes and measuresPostoperative nonsurgical complications, postoperative surgical complications, postoperative 30-day or in-hospital mortality, and complicated course (postoperative complication resulting in a hospital stay >14 days and/or a reintervention and/or mortality). A risk-stratified comparison was made for different postoperative outcomes based on screening status (screen detected vs not screen detected), cancer stage (I-IV), and for cancer stage I to III also on age (aged ≤70 years and >70 years) and American Society of Anesthesiologists score (I-II and III-IV). To determine any residual case-mix-corrected differences in outcomes between patients with screen-detected and non-screen-detected cancer, univariable and multivariable logistic regression analyses were performed.ResultsIn total, 36 242 patients with colon cancer and 17 416 patients with rectal cancer were included for analysis. Compared with patients with non-screen-detected CRC, screen-detected patients were younger (mean [SD] age, 68 [5] vs 70 [11] years), more often men (3777 [60%] vs 13 506 [57%]), and had lower American Society of Anesthesiologists score (American Society of Anesthesiologists score III+: 838 [13%] vs 5529 [23%]). Patients with stage I to III colon cancer who were screen detected had a significantly lower mortality and complicated course rate compared with non-screen-detected patients. For patients with rectal cancer, only a significant difference was found in mortality rate in patients with a cancer stage IV disease, which was higher in the screen-detected group. Compared with non-screen-detected colon cancer, an independent association was found for screen-detected colon cancer on nonsurgical complications (adjusted odds ratio, 0.81; 95% CI, 0.73-0.91), surgical complications (adjusted odds ratio, 0.80; 95% CI, 0.72-0.89), and complicated course (adjusted odds ratio, 0.80; 95% CI, 0.71-0.90). Screen-detected rectal cancer had significantly higher odds on mortality.Conclusions and relevancePostoperative outcomes were significantly better for patients with colon cancer referred through the fecal immunochemical test-based screening program compared with non-screen-detected patients. These differences were not found in patients with rectal cancer. The outcomes of patients with screen-detected colon cancer were still better after an extensive case-mix correction, implying additional underlying factors favoring patients referred for surgery through the screening program.

Project description:Circulating tumor cells (CTCs), an advantageous target of liquid biopsy, is an important biomarker for the prognosis and monitoring of cancer. Currently, detection techniques for CTCs are mainly based on the physical and/or epithelial characteristics of tumor cells. However, biofunctional activity markers that can indicate the high metastatic capacity of CTCs are lacking.Functional microarray, quantitative real-time polymerase chain reaction, and Western blot were used on five prostate cancer cell lines with different metastatic capacities to identify the metastasis-related metabolic genes. The identified genes were detected in the CTCs of 64 clinical samples using the RNA in situ hybridization. A multi-criteria weighted model was used to determine the optimal metabolic markers for the CTCs test. Based on five fluorescent signals targeting DAPI, CD45, metabolic, epithelial (EpCAM/CKs), and mesenchymal (Vimentin/Twist) markers, the filtration-enriched CTCs were classified as GM+CTCs/GM-CTCs (metabolic types) or E-CTCs/H-CTCs/M-CTCs (EMT types). Correlation analysis and ROC curve were conducted on 54 prostate cancer samples to evaluate the clinical significance of CTCs subtypes.Eight metastasis-related metabolic genes were identified, including HK2, PDP2, G6PD, PGK1, PHKA1, PYGL, PDK1, and PKM2. Among them, PGK1 and G6PD were determined as optimal glucose metabolic (GM) markers for CTCs. GM+CTCs (marked by PGK1/G6PD) were detectable in 64.8% (35/54) of prostate cancer patients, accounting for 46.5% (134/288) of total CTCs. An increased GM+CTCs level was associated with advanced tumor stage and metastasis (P?<? 0.05). In the discrimination of cancer metastasis from non-metastasis, GM+CTCs presented a higher AUC of the ROC curve (0.780) compared with the EMT CTCs subtypes (E-CTCs 0.729, H-CTCs 0.741, and M-CTCs 0.648). A triple tPSA-Gleason-GM+CTCs marker increased the AUC to 0.904, which was better than that of the tPSA-Gleason-H-CTCs marker (0.874).The metabolic marker (PGK1/G6PD) is determined as the indicator for the biofunctional activity analysis of CTCs, compared with the existing morphological (EMT) classification on CTCs. The metabolic characterization of CTCs demonstrates that hypermetabolic GM+CTCs are promising biomarkers for prostate cancer metastasis.

Dataset Information

Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.

Publications

Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.

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