Pre-diagnostic metabolite concentrations and prostate cancer risk in 1077 cases and 1077 matched controls in the European Prospective Investigation into Cancer and Nutrition

Schmidt, Julie A.; Fensom, Georgina K.; Rinaldi, Sabina; Scalbert, Augustin; Appleby, Paul N.; Achaintre, David; Gicquiau, Audrey; Gunter, Marc J.; Ferrari, Pietro; Kaaks, Rudolf; Kühn, Tilman; Floegel, Anna; Boeing, Heiner; Trichopoulou, Antonia; Λάγιου, Παγώνα; E, Anifantis; Agnoli, Claudia; Palli, Domenico; Trevisan, Morena; Tumino, Rosario; Bueno-de-Mesquita, H. Bas; Agudo, Antonio; Larrañaga, Nerea; Redondo‐Sánchez, Daniel; Barricarte, Aurelio; Huerta, José María; Quiŕos, J. Ramón; Wareham, Nick; Khaw, Kay Tee; Pérez-Cornago, Aurora; Johansson, Mattias; Cross, Amanda J.; Tsilidis, Konstantinos K.; Riboli, Elio; Key, Timothy J.; Travis, Ruth C.

doi:10.1186/s12916-017-0885-6

Cited by 53 publications

(102 citation statements)

References 45 publications

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“…In line with our results, analyses in ATBC showed an inverse association between metabolites related to energy metabolism (α‐ketoglutarate and citrate) and risk of aggressive prostate cancer . Our previous study in EPIC also suggested inverse associations of acylcarnitines and taurine with advanced prostate cancer . There are also some published data on dietary and lifestyle correlates of the metabolites in treelet component 2 …”

Section: Discussionsupporting

confidence: 91%

“…The current results on phosphatidylcholines and sphingomyelins (treelet component 1) and risk are broadly consistent with those of other prospective studies investigating individual metabolites, including our previously published results, which were conducted in a subset (~35%) of the current study population. For example, we previously reported inverse associations of many individual phosphatidylcholines, all of which were included with positive loadings in treelet component 1 or 3, with risk of advanced stage prostate cancer, and some associations remained when restricting the analysis to aggressive prostate cancer.…”

Section: Discussionsupporting

confidence: 91%

“…Results of the associations between individual metabolite concentrations and prostate cancer risk in the full dataset ( n case = 3,057) and in the data not previously published ( n case = 2,018) are shown in Supporting Information Tables S10–S23. Results from the new dataset were in line with those of the full dataset, although slightly weaker, with two obvious exceptions; acyl‐alkyl phosphatidylcholines were more often associated with overall prostate cancer in the new dataset than in the full dataset (Supporting Information Tables S10 and S17), and the same was the case for diacyl phosphatidylcholines and risk of low‐intermediate grade prostate cancer (Supporting Information Tables S15 and S22).…”

Section: Resultsmentioning

confidence: 99%

“…As a secondary analysis, we repeated the analysis of treelet components and risk of overall prostate cancer in the subset of participants, who were not included in our previously published analysis ( n case = 2,018) …”

Section: Methodsmentioning

confidence: 99%

“…For the purpose of comparison with previous studies, we also computed the associations of each individual metabolite and risk of prostate cancer, while accounting for multiple testing. This analysis was done for the full data set ( n case = 3,057), and separately for the data not previously published ( n case = 2,018).…”

Section: Methodsmentioning

confidence: 99%

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Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Schmidt

Fensom

Rinaldi

et al. 2019

Intl Journal of Cancer

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Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow‐up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Schmidt

Fensom

Rinaldi

et al. 2019

Intl Journal of Cancer

Self Cite

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Metabolomic effects of androgen deprivation therapy treatment for prostate cancer

Chi

Lin

Tolstikov³

et al. 2020

Cancer Medicine

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Androgen deprivation therapy (ADT) is the main treatment strategy for men with metastatic prostate cancer (PC). However, ADT is associated with various metabolic disturbances, including impaired glucose tolerance, insulin resistance and weight gain, increasing risk of diabetes and cardiovascular death. Much remains unknown about the metabolic pathways and disturbances altered by ADT and the mechanisms. We assessed the metabolomic effects of ADT in the serum of 20 men receiving ADT. Sera collected before (baseline), 3 and 6 months after initiation of ADT was used for the metabolomics and lipidomics analyses. The ADT‐associated metabolic changes were identified by univariable and multivariable statistical analysis, ANOVA, and Pearson correlation. We found multiple key changes. First, ADT treatments reduced the steroid synthesis as reflected by the lower androgen sulfate and other steroid hormones. Greater androgen reduction was correlated with higher serum glucose levels, supporting the diabetogenic role of ADT. Second, ADT consistently decreased the 3‐hydroxybutyric acid and ketogenesis. Third, many acyl‐carnitines were reduced, indicating the effects on the fatty acid metabolism. Fourth, ADT was associated with a corresponding reduction in 3‐formyl indole (a.k.a. indole‐3‐carboxaldehyde), a microbiota‐derived metabolite from the dietary tryptophan. Indole‐3‐carboxaldehyde is an agonist for the aryl hydrocarbon receptor and regulates the mucosal reactivity and inflammation. Together, these ADT‐associated metabolomic analyses identified reduction in steroid synthesis and ketogenesis as prominent features, suggesting therapeutic potential of restricted ketogenic diets, though this requires formal testing. ADT may also impact the microbial production of indoles related to the immune pathways. Future research is needed to determine the functional impact and underlying mechanisms to prevent ADT‐linked comorbidities and diabetes risk.

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Prospective serum metabolomic profiling of lethal prostate cancer

Huang

Mondul

Weinstein

et al. 2019

Intl Journal of Cancer

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Impaired metabolism may play an important role in the pathogenesis of lethal prostate cancer, yet there is a paucity of evidence regarding the association. We conducted a large prospective serum metabolomic analysis of lethal prostate cancer in 523 cases and 523 matched controls nested within the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention (ATBC) Study. Median time from baseline fasting serum collection to prostate cancer death was 18 years (maximum 30 years). We identified 860 known biochemicals through an ultrahigh‐performance LC–MS/MS platform. Conditional logistic regression models estimated odds ratios (OR) and 95% confidence intervals of risk associated with 1‐standard deviation (s.d.) increases in log‐metabolite signals. We identified 34 metabolites associated with lethal prostate cancer with a false discovery rate (FDR) < 0.15. Notably, higher serum thioproline, and thioproline combined with two other cysteine‐related amino acids and redox metabolites, cystine and cysteine, were associated with reduced risk (1‐s.d. OR = 0.75 and 0.71, respectively; p ≤ 8.2 × 10−5). By contrast, the dipeptide leucylglycine (OR = 1.36, p = 8.2 × 10−5), and three gamma‐glutamyl amino acids (OR = 1.28–1.30, p ≤ 4.6 × 10−4) were associated with increased risk of lethal prostate cancer. Cases with metastatic disease at diagnosis (n = 179) showed elevated risk for several lipids, including especially the ketone body 3‐hydroxybutyrate (BHBA), acyl carnitines, and dicarboxylic fatty acids (1.37 ≤ OR ≤ 1.49, FDR < 0.15). These findings provide a prospective metabolomic profile of lethal prostate cancer characterized by altered biochemicals in the redox, dipeptide, pyrimidine, and gamma‐glutamyl amino acid pathways, whereas ketone bodies and fatty acids were associated specifically with metastatic disease.

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Pre-diagnostic metabolite concentrations and prostate cancer risk in 1077 cases and 1077 matched controls in the European Prospective Investigation into Cancer and Nutrition

Cited by 53 publications

References 45 publications

Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Metabolomic effects of androgen deprivation therapy treatment for prostate cancer

Prospective serum metabolomic profiling of lethal prostate cancer

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