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

Abstract

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.

Application of Metabolomics to Epidemiologic Studies of Breast Cancer: New Perspectives for Etiology and Prevention

“…Most analyses in the HUNT2 21,22 study were reported by age groups or menopausal status and are described in the menopausal status paragraph.…”

“…Studies are generally conducted in Europe, 14,16,18,[21][22][23][24] the United States, 17,19,25 and Korea 15 and had variable sample sizes, spanning from 84 to 1,624 incident breast cancer cases. Most studies used a case-control approach nested within prospective cohorts.…”

“…Within the same cohorts, different metabolomics methods were used to maximize the number of metabolites measured. [21][22][23][24]…”

“…In the HUNT2 study, 22 several metabolites could be detected in serum levels, which were different in breast cancer cases diagnosed earlier (<5 years) and later (>10 years) after sample collection, although these compounds also correlated with the age of the participants.…”

“…Only five studies, 16,18,[21][22][23][24][25] which included both pre-and postmenopausal women, reported associations by menopausal status (Table 1). In SU.VI.MAX, associations differed by menopausal status, 23,24 with glutamine, glycerol-derived compounds, lipoproteins, lipids, and acetone being associated with breast cancer in premenopausal women and valine, lysine, creatine, creatinine, glycerol-derived compounds, lipids, and acetone being associated with cancer in postmenopausal women.…”