Plasma Metabolomics and Breast Cancer Risk over 20 Years of Follow-up among Postmenopausal Women in the Nurses' Health Study

Abstract

Background: Metabolite profiles provide insight into biologic mechanisms contributing to breast cancer development. We explored the association between prediagnostic plasma metabolites (N = 307) and invasive breast cancer among postmenopausal women in a nested case–control study within the Nurses' Health Study (N = 1,531 matched pairs). Methods: Plasma metabolites were profiled via LC/MS-MS using samples taken ≥10 years (distant, N = 939 cases) and <10 years (proximate, N = 592 cases) before diagnosis. Multivariable conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI) comparing the 90th to 10th percentile of individual metabolite level, using the number of effective tests (NEF) to account for testing multiple correlated hypotheses. Associations of metabolite groups with breast cancer were evaluated using metabolite set enrichment analysis (MSEA) and weighted gene coexpression network analysis (WGCNA), with adjustment for the FDR. Results: No individual metabolites were significantly associated with breast cancer risk. MSEA showed negative enrichment of cholesteryl esters at the distant timepoint [normalized enrichment score (NES) = −2.26; Padj = 0.02]. Positive enrichment of triacylglycerols (TAG) with <3 double bonds was observed at both timepoints. TAGs with ≥3 double bonds were inversely associated with breast cancer at the proximate timepoint (NES = −2.91, Padj = 0.03). Conclusions: Cholesteryl esters measured earlier in disease etiology were inversely associated with breast cancer. TAGs with many double bonds measured closer to diagnosis were inversely associated with breast cancer risk. Impact: The discovered associations between metabolite subclasses and breast cancer risk can expand our understanding of biochemical processes involved in cancer etiology.

Association of serum metabolome profile with the risk of breast cancer in participants of the HUNT2 study

“…This general observation was coherent with the results of previously published reports. Brantley and coworkers reported that poly-unsaturated triglycerides and cholesteryl esters were inversely associated with breast cancer in the American Nurses’ Health Study ( 12 ). His and coworkers, using an earlier version of the analytical platform applied in the current study, showed the inverse correlation of several phosphatidylcholines and sphingomyelins with breast cancer risk in the European Prospective Investigation into Cancer (EPIC) cohort ( 15 ).…”

“…A few nested case-control studies compared pre-diagnostic samples collected from women who were cancer-free at the baseline, then developed breast cancer during a few years of follow-up, and matched women who remained healthy. These studies indicate that an increased risk of breast cancer was associated with an increased level of certain amino acids ( 10 – 12 ) or sex steroid metabolites (especially for postmenopausal women) ( 13 , 14 ). On the other hand, an inverse association between the risk of BC and serum/plasma level of phosphatidylcholines ( 15 ), lysophosphatidylcholines ( 11 , 16 ), cholesterol esters ( 12 ), and other lipid compounds ( 10 , 12 , 14 ) was observed.…”

“…These studies indicate that an increased risk of breast cancer was associated with an increased level of certain amino acids ( 10 – 12 ) or sex steroid metabolites (especially for postmenopausal women) ( 13 , 14 ). On the other hand, an inverse association between the risk of BC and serum/plasma level of phosphatidylcholines ( 15 ), lysophosphatidylcholines ( 11 , 16 ), cholesterol esters ( 12 ), and other lipid compounds ( 10 , 12 , 14 ) was observed. However, the importance of individual metabolites differed between studies and a common metabolic signature of the risk of breast cancer is yet to be proposed.…”

Serum amino acids quantification by plasmonic colloidosome-coupled MALDI-TOF MS for triple-negative breast cancer diagnosis

“…Brantley et al. has used liquid chromatography tandem mass spectrometry (LC-MS/MS) for the identification of 307 metabolites including phenylalanine, tyrosine and tryptophan in plasma, wherein the correlation of amino acid regulation with breast cancer development including TNBC was demonstrated [ 11 ]. The LC-MS/MS based on triple quadrupole mass spectrometer is considered as the gold standard for amino acids quantification, which however needs time-consuming sample pretreatment, complicated operations, long analysis time per sample and is at high cost, limiting its wide application in clinical diagnosis.…”

Plasma metabolomics analyses highlight the multifaceted effects of noise exposure and the diagnostic power of dysregulated metabolites for noise-induced hearing loss in steel workers

“…As abnormalities in gene and protein levels would eventually be reflected in metabolism, metabolomics analysis was proposed (Huang et al, 2018). In fact, differential metabolomics analysis was found to be effective in the studies of various kinds of diseases and disorders including obesity, depressive disorder (Du et al, 2021), and cancerous disease (Brantley et al, 2022), indicating the variety of effects of noise exposure. In a recent study, plasma metabolomics analysis was performed on noiseexposed workers in a factory, and 20 metabolites were identified to be potential markers associated with NIHL (Miao et al, 2021b).…”