Circulating amino acids and amino acid-related metabolites and risk of breast cancer among predominantly premenopausal women

Zeleznik, Oana A.; Balasubramanian, Raji; Zhao, Yibai; Frueh, Lisa; Jeanfavre, Sarah; Ávila-Pacheco, Julián; Clish, Clary B.; Tworoger, Shelley S.; Eliassen, A. Heather

doi:10.1038/s41523-021-00262-4

Cited by 19 publications

(20 citation statements)

References 95 publications

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“…However, because cases and controls were matched on date of blood collection and were processed together for aliquoting and metabolomic analyses, any biases would likely have been toward the null. Previously, using NHS and HPFS samples stored long term, metabolites have been identified that were significantly associated with multiple health outcomes (e.g., pancreatic cancer, 82 breast cancer, 83 , 84 prostate cancer, 85 rheumatoid arthritis, 86 and cardiovascular disease 87 ), and these findings have been replicated in other studies, 88 – 91 suggesting that storage time does not substantially impact biomarker-disease associations.…”

Section: Discussionmentioning

confidence: 91%

Prediagnostic Plasma Metabolomics and the Risk of Exfoliation Glaucoma

Kang

Zeleznik

Frueh

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose The etiology of exfoliation glaucoma (XFG) is poorly understood. We aimed to identify a prediagnostic plasma metabolomic signature associated with XFG. Methods We conducted a 1:1 matched case-control study nested within the Nurses’ Health Study and Health Professionals Follow-up Study. We collected blood samples in 1989–1990 (Nurses’ Health Study) and 1993–1995 (Health Professionals Follow-up Study). We identified 205 incident XFG cases through 2016 (average time to diagnosis from blood draw = 11.8 years) who self-reported glaucoma and were confirmed as XFG cases with medical records. We profiled plasma metabolites using liquid chromatography-mass spectrometry. We evaluated 379 known metabolites (transformed for normality using probit scores) using multiple conditional logistic models. Metabolite set enrichment analysis was used to identify metabolite classes associated with XFG. To adjust for multiple comparisons, we used number of effective tests (NEF) and the false discovery rate (FDR). Results Mean age of cases ( n = 205) at diagnosis was 71 years; 85% were women and more than 99% were Caucasian; controls ( n = 205) reported eye examinations as of the matched cases’ index date. Thirty-three metabolites were nominally significantly associated with XFG ( P < 0.05), and 4 metabolite classes were FDR-significantly associated. We observed positive associations for lysophosphatidylcholines (FDR = 0.02) and phosphatidylethanolamine plasmalogens (FDR = 0.004) and inverse associations for triacylglycerols (FDR < 0.0001) and steroids (FDR = 0.03). In particular, the multivariable-adjusted odds ratio with each 1 standard deviation higher plasma cortisone levels was 0.49 (95% confidence interval, 0.32–0.74; NEF = 0.05). Conclusions In plasma from a decade before diagnosis, lysophosphatidylcholines and phosphatidylethanolamine plasmalogens were positively associated and triacylglycerols and steroids (e.g., cortisone) were inversely associated with XFG risk.

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Section: Discussionmentioning

confidence: 91%

Prediagnostic Plasma Metabolomics and the Risk of Exfoliation Glaucoma

Kang

Zeleznik

Frueh

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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“…Regardless, disruption of BCAA biosynthesis and degradation was associated with breast cancer risk in the Korean Cancer Prevention Study-II [45], and higher plasma levels of valine were associated with increased breast cancer risk in the SU.VI.MAX prospective cohort [46]. Neither lysine nor valine were associated with breast cancer risk in 4 additional prospective cohorts [47][48][49][50].…”

Section: Discussionmentioning

confidence: 93%

Childhood adiposity, serum metabolites and breast density in young women

et al. 2022

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Background Childhood adiposity is inversely associated with young adult percent dense breast volume (%DBV) and absolute dense breast volume (ADBV), which could contribute to its protective effect for breast cancer later in life. The objective of this study was to identify metabolites in childhood serum that may mediate the inverse association between childhood adiposity and young adult breast density. Methods Longitudinal data from 182 female participants in the Dietary Intervention Study in Children (DISC) and the DISC 2006 (DISC06) Follow-Up Study were analyzed. Childhood adiposity was assessed by anthropometry at the DISC visit with serum available that occurred closest to menarche and expressed as a body mass index (BMI) z-score. Serum metabolites were measured by untargeted metabolomics using ultra-high-performance liquid chromatography–tandem mass spectrometry. %DBV and ADBV were measured by magnetic resonance imaging at the DISC06 visit when participants were 25–29 years old. Robust mixed effects linear regression was used to identify serum metabolites associated with childhood BMI z-scores and breast density, and the R package mediation was used to quantify mediation. Results Of the 115 metabolites associated with BMI z-scores (FDR < 0.20), 4 were significantly associated with %DBV and 6 with ADBV before, though not after, adjustment for multiple comparisons. Mediation analysis identified 2 unnamed metabolites, X-16576 and X-24588, as potential mediators of the inverse association between childhood adiposity and dense breast volume. X-16576 mediated 14% (95% confidence interval (CI) = 0.002, 0.46; P = 0.04) of the association of childhood adiposity with %DBV and 11% (95% CI = 0.01, 0.26; P = 0.02) of its association with ADBV. X-24588 also mediated 7% (95% CI = 0.001, 0.18; P = 0.05) of the association of childhood adiposity with ADBV. None of the other metabolites examined contributed to mediation of the childhood adiposity–%DBV association, though there was some support for contributions of lysine, valine and 7-methylguanine to mediation of the inverse association of childhood adiposity with ADBV. Conclusions Additional large longitudinal studies are needed to identify metabolites and other biomarkers that mediate the inverse association of childhood adiposity with breast density and possibly breast cancer risk.

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“…This allowed us to search for components putatively associated with a risk of breast cancer. This work has a similar design to a few other studies performed recently using different analytical platforms and targeting different cohorts ( 10 – 17 , 23 , 24 ). A strong correlation between serum metabolite concentrations and participants’ age was observed in our study, which putatively reflected the adaptation of energy and lipid metabolism due to age-related changes in hormonal balance.…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2023

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BackgroundThe serum metabolome is a potential source of molecular biomarkers associated with the risk of breast cancer. Here we aimed to analyze metabolites present in pre-diagnostic serum samples collected from healthy women participating in the Norwegian Trøndelag Health Study (HUNT2 study) for whom long-term information about developing breast cancer was available.MethodsWomen participating in the HUNT2 study who developed breast cancer within a 15-year follow-up period (BC cases) and age-matched women who stayed breast cancer-free were selected (n=453 case-control pairs). Using a high-resolution mass spectrometry approach 284 compounds were quantitatively analyzed, including 30 amino acids and biogenic amines, hexoses, and 253 lipids (acylcarnitines, glycerides, phosphatidylcholines, sphingolipids, and cholesteryl esters).ResultsAge was a major confounding factor responsible for a large heterogeneity in the dataset, hence age-defined subgroups were analyzed separately. The largest number of metabolites whose serum levels differentiated BC cases and controls (82 compounds) were observed in the subgroup of younger women (<45 years old). Noteworthy, increased levels of glycerides, phosphatidylcholines, and sphingolipids were associated with reduced risk of cancer in younger and middle-aged women (≤64 years old). On the other hand, increased levels of serum lipids were associated with an enhanced risk of breast cancer in older women (>64 years old). Moreover, several metabolites could be detected whose serum levels were different between BC cases diagnosed earlier (<5 years) and later (>10 years) after sample collecting, yet these compounds were also correlated with the age of participants. Current results were coherent with the results of the NMR-based metabolomics study performed in the cohort of HUNT2 participants, where increased serum levels of VLDL subfractions were associated with reduced risk of breast cancer in premenopausal women.ConclusionsChanges in metabolite levels detected in pre-diagnostic serum samples, which reflected an impaired lipid and amino acid metabolism, were associated with long-term risk of breast cancer in an age-dependent manner.

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Circulating amino acids and amino acid-related metabolites and risk of breast cancer among predominantly premenopausal women

Cited by 19 publications

References 95 publications

Prediagnostic Plasma Metabolomics and the Risk of Exfoliation Glaucoma

Prediagnostic Plasma Metabolomics and the Risk of Exfoliation Glaucoma

Childhood adiposity, serum metabolites and breast density in young women

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

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