A metabolome-wide case-control study of african american breast cancer patients

Abstract

Background: Breast cancer survivors face long-term sequelae compared to the general population, suggesting altered metabolic profiles after breast cancer. We used metabolomics approaches to investigate the metabolic differences between breast cancer patients and women in the general population, aiming to elaborate metabolic changes among breast cancer patients and identify potential targets for clinical interventions to mitigate long-term sequelae.

Methods: Serum samples were retrieved from 125 breast cancer cases recruited from the Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC), and 125 healthy controls selected from Chicago Multiethnic Prevention and Surveillance Study (COMPASS). We used liquid chromatography-high resolution mass spectrometry to obtain untargeted metabolic profiles and partial least squares discriminant analysis (PLS-DA) combined with fold change to select metabolic features associated with breast cancer. Pathway analyses were conducted using Mummichog to identify differentially enriched metabolic pathways among cancer patients. As potential confounders we included age, marital status, tobacco smoking, alcohol drinking, type 2 diabetes, and area deprivation index in our model. Random effects of residence for intercept was also included in the model. We further conducted subgroup analysis by treatment timing (chemotherapy/radiotherapy/surgery), lymph node status, and cancer stages.

Results: The entire study participants were African American. The average ages were 57.1 for cases and 58.0 for controls. We extracted 15,829 features in total, among which 507 features were eventually selected by our criteria. Pathway enrichment analysis of these 507 features identified three differentially enriched metabolic pathways related to prostaglandin, leukotriene, and glycerophospholipid. The three pathways demonstrated inconsistent patterns. Metabolic features in the prostaglandin and leukotriene pathways exhibited increased abundances among cancer patients. In contrast, metabolic intensity in the glycerolphospholipid pathway was deregulated among cancer patients. Subgroup analysis yielded consistent results. However, changes in these pathways were strengthened when only using cases with positive lymph nodes, and attenuated when only using cases with stage I disease.

Conclusion: Breast cancer in African American women is associated with increase in serum metabolites involved in prostaglandin and leukotriene pathways, but with decrease in serum metabolites in glycerolphospholipid pathway. Positive lymph nodes and advanced cancer stage may strengthen changes in these pathways.

Keywords: breast cancer; glycerophospholipid; leukotriene; metabolome; metabolomics; prostaglandin.

Fig. 1

Identification of metabolic features associated with breast cancer. The positive fold change (log2) indicates higher feature intensity among cases. (1) Scenario 1, all breast cancer cases (n = 125); (2) Scenario 2, cases without any treatments (chemotherapy, radiotherapy, and surgery) before serum collection (n = 68); (3) Scenario 3, cases with any treatments (chemotherapy, radiotherapy, and surgery) before serum collection (n = 57); (4) Scenario 4, cases with negative lymph nodes (n = 72); (5) Scenario 5, cases with positive lymph nodes (n = 52); (6) Scenario 6, cases with stage I cancer (n = 49); (7) Scenario 7, cases with stage II/III cancer (n = 76)