Metabolite Predictors of Breast and Colorectal Cancer Risk in the Women’s Health Initiative
Abstract
:1. Introduction
2. Materials and Methods
2.1. Women’s Health Initiative
2.2. Case and Control Selection
2.3. Metabololite Profiling
2.3.1. Measurement of Serum Metabolites
2.3.2. Measurements of Urine Metabolites
2.4. Metabolite Quality Controls (QC)
2.5. Statistical Analysis
2.5.1. Participant Data
2.5.2. Imputing Missing Data
2.5.3. Algorithms Used for Selecting a Set of Metabolites
2.5.4. Assessing Prediction Performance
2.5.5. Final Selection of Metabolites
2.5.6. Post Hoc Sensitivity Analyses
3. Results
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristics | BC Cases (n = 577) | CRC Cases (n = 181) | Controls (n = 758) |
---|---|---|---|
Demographic factors | |||
Age (yrs) | 62; [56, 68] | 64; [58, 69] | 63; [57, 68] |
Body Mass Index (kg/m)2 | 27.73; [24.45, 32.45] * | 28.05; [24.9, 31.98] * | 27.16; [24.19, 31.18] |
Waist circumference (cm) | 86; [77, 96] * | 87; [78, 99] * | 84; [76, 93] * |
Self-reported race or ethnicity | |||
Alaska Native or American Indian | <10 * | <10 * | <10 * |
Asian or Pacific Islander | <10 * | <10 * | <10 * |
Hispanic or Latina | 25 (4%) | 10 (6%) | 35 (5%) |
Non-Hispanic Black or African American | 67 (12%) | 26 (14%) | 93 (12%) |
White | 477 (83) | 139 (77%) | 616 (81) |
Unknown | <10 | <10 | <10 |
Education | |||
Less than high school | 37 (6%) | 15 (8%) | 41 (5%) |
High school or GED | 120 (21%) | 43 (24%) | 166 (22%) |
School after high school | 209 (36%) | 74 (41%) | 284 (38%) |
College degree or higher | 207 (36%) | 48 (27%) | 267 (35%) |
Unknown | <10 | <10 | 0 |
Income | |||
<$20,000 | 104 (18%) | 56 (31%) | 165 (22%) |
$20,000–$35,000 | 171 (30%) | 47 (26%) | 232 (31%) |
$35,000–$50,000 | 100 (17%) | 37 (20%) | 132 (17%) |
$50,000–$75,000 | 85 (15%) | 21 (12%) | 134 (18%) |
>$75,000 | 81 (14%) | 13 (7%) | 95 (13%) |
Unknown | 36 (6%) | <10 | 0 |
Lifestyle factors | |||
Alcohol intake (svgs/wk) | 0.42; [0, 1.81] * | 0.21; [0, 2.73] * | 0.21; [0, 1.37] |
Total calcium (mg/d) | 1024.1; [647.5, 1557.2] * | 1029.3; [711.8, 1532.0] * | 973.8; [649.7, 1530.9] * |
Total folate (mcg/d) | 635.47; [420.94, 881.23] * | 619.21; [448.25, 861.41] * | 593.64; [419.06, 838.82] * |
Red or processed meat (svgs/d) | 1.87; [1.04, 2.95] * | 1.85; [1.1, 3.31] * | 1.83; [1.07, 3] * |
Energy expenditure (MET-hours/wk) | 7.08; [1.5, 16.75] * | 7.25; [1.38, 16.42] * | 7; [1.5, 15.5] * |
History of smoking (current yes/no) | 45 (7.84%) * | 16 (8.94%)* | 47 (6.2%) |
Any supplement use | 257 (44.54%) * | 71 (39.23%) | 328 (43.27%) |
Uses anti-diabetes medication | 24 (4.16%) | 16 (8.84%) | 35 (4.62%) |
Uses anti-hypertensive medication | 185 (32.06%) | 68 (37.57%) | 231 (30.47%) |
Uses anti-lipid medication | 42 (7.28%) | 16 (8.84%) | 50 (6.6%) |
Uses NSAIDs | 196 (33.97%) | 58 (32.04%) | 262 (34.56%) |
Clinical risk factors | |||
Gail 5-year risk score | 1.9; [1.16, 2.22] | 1.7; [1.1, 1.92] | 1.68; [1.15, 1.95] |
Family history of cancer | |||
Yes | 80 (14%) | 30 (17%) | 124 (16%) |
No | 453 (79%) | 139 (77%) | 617 (8%) |
Unknown | 44 (8%) | 12 (7%) | 17 (2%) |
Personal history of cancer | |||
Yes | 27 (5%) | 13 (7%) | 39 (5.2%) |
No | 547 (95%) | 168 (93%) | 719 (95%) |
Unknown | <10 | 0 | 0 |
History of colonoscopy | |||
Yes | 253 (44%) | 71 (39%) | 355 (47%) |
No | 249 (43%) | 90 (50%) | 401 (53%) |
Unknown | 75 (13%) | 20 (11%) | <10 |
History of colon polyp removal | |||
Yes | 39 (7%) | 11 (6%) | 73 (10%) |
No | 454 (79%) | 145 (80%) | 677 (89%) |
Unknown | 84 (15%) | 25 (14%) | <10 |
History of treated diabetes | |||
Yes | 27 (5%) | 19 (11%) | 40 (5%) |
No | 549 (95%) | 162 (90%) | 717 (95%) |
Unknown | <10 | 0 | <10 |
History of treated hypertension | |||
Yes | 144 (25%) | 55 (30%) | 186 (25%) |
No | 356 (62%) | 104 (57%) | 568 (75%) |
Unknown | 77 (13%) | 22 (12%) | <10 |
Had at least one term pregnancy | 510 (88%) | 158 (87%) | 676 (89%) |
Post-menopausal hormone therapy use | |||
Never | 286 (50%) | 97 (54%) | 331 (44%) |
Past | 75 (13%) | 30 (17%) | 125 (16%) |
Current estrogen alone | 117 (20%) | 36 (20%) | 189 (25%) |
Current estrogen and progestin | 98 (17%) | 18 (10%) | 113 (15%) |
Study variables | |||
WHI enrollment date | |||
Baseline | 108 (19%) | 44 (24%) | 152 (20%) |
Year 1 | 220 (38%) | 65 (36%) | 285 (38%) |
Year 3 | 243 (42%) | 68 (38%) | 311 (41%) |
Year 6 | <10 | <10 | <10 |
Year 9 | 0 | <10 | <10 |
Calcium / Vitamin D (CaD) trial arm | |||
Not randomized to CaD | 462 (80%) | 147 (81%) | 560 (74%) |
Control arm | 54 (9%) | 19 (11%) | 104 (14%) |
Intervention arm | 61 (11%) | 15 (8%) | 94 (12%) |
Dietary Modification (DM) trial arm | |||
Not randomized to DM | 384 (67%) | 122 (67%) | 488 (64%) |
Control arm | 118 (20%) | 27 (15%) | 163 (22%) |
Intervention arm | 75 (13%) | 32 (18%) | 107 (14%) |
Hormone therapy (HT) trial arm | |||
Not randomized to HT | 495 (86%) | 144 (80%) | 641 (85%) |
Estrogen-only control arm | 19 (3%) | 13 (7%) | 27 (4%) |
Estrogen-only intervention arm | 15 (3%) | 11 (6%) | 34 (4%) |
Estrogen and progestin control arm | 16 (3%) | <10 | 30 (4%) |
Estrogen and progestin intervention arm | 32 (6%) | <10 | 26 (3%) |
Metabolites Selected | Proportion of Explained Variation 2 | Direction of Coefficient for Metabolites 3 |
---|---|---|
Breast Cancer | All covariates + metabolites: 0.27 | |
Serum: | ||
LC-MS | ||
Azelaic acid | 0.23 | − |
Choline | 0.23 | + |
Cysteinyl glycine | 0.23 | − |
Ethanolamine | 0.23 | + |
Gamma tocopherol | 0.23 | + |
Hippuric acid | 0.23 | − |
Isovaleryl carnitine | 0.23 | + |
N-isovaleryl glycine | 0.23 | − |
Sucrose | 0.23 | − |
Trimethylamine-N-oxide | 0.23 | + |
Valine | 0.23 | + |
Xylose | 0.23 | − |
Lipidyzer 4 | ||
Cholesteryl ester (CE 12:0) | 0.23 | − |
Cholesteryl ester (CE 20:0) | 0.23 | − |
Diacylglycerol (DAG 14:1) | 0.24 | + |
Free fatty Acid (FFA 18:4) | 0.23 | − |
Free fatty Acid (FFA 20:2) | 0.23 | + |
Hexosylceramide (HCER 22:0) | 0.23 | + |
Hexosylceramide (HCER 22:0) | 0.23 | − |
Phosphatidylcholine (PC 18:1) | 0.23 | + |
Phosphatidylcholine (PC 18:2) | 0.23 | + |
Phosphatidylcholine (PC 16:0/18:2) | 0.24 | − |
Phosphatidylethanolamine (PE 18:2) | 0.23 | + |
Triacylglycerol (TAG 12:0) | 0.23 | − |
Triacylglycerol (TAG 16:0) | 0.23 | − |
Triacylglycerol (TAG 18:0) | 0.23 | − |
Triacylglycerol (TAG 47:0/15:0) | 0.23 | − |
Triacylglycerol (TAG 48:4/18:2) | 0.23 | − |
Triacylglycerol (TAG 50:0/16:0) | 0.23 | + |
Triacylglycerol (TAG 50:2/18:2) | 0.23 | − |
Triacylglycerol (TAG 50:5/18:3) | 0.24 | − |
Triacylglycerol (TAG 52:2/18:2) | 0.24 | + |
Triacylglycerol (TAG 55:4/18:1) | 0.23 | − |
Urine | ||
NMR | ||
Dimethylamine | 0.23 | − |
Propanediol | 0.23 | − |
Formate | 0.23 | + |
Sucrose | 0.23 | − |
Taurine | 0.23 | + |
Uracil | 0.23 | − |
Trimethylamine-N-oxide | 0.23 | − |
2-Hydroxyisobutyrate | 0.23 | + |
2-Oxoglutarate | 0.23 | − |
GC-MS | ||
Unknown 73.012.10 5 | 0.23 | − |
Unknown 73.014.49 5 | 0.23 | + |
Unknown 73.016.52 5 | 0.23 | + |
Colorectal Cancer | All covariates + metabolites: 0.31 | |
Serum | ||
LC-MS | ||
Adenosine | 0.23 | − |
Leucic Acid | 0.21 | + |
Glycerate | 0.25 | + |
Myo-inositol | 0.22 | + |
N-Acetyl-glutamate | 0.22 | − |
N-Acetyl-glycine | 0.23 | + |
N-Acetylneuraminate | 0.22 | + |
2-Hydroxyglutarate | 0.22 | + |
Hydroxyproline | 0.21 | + |
7-Methylguanine | 0.22 | + |
Lipidyzer4 | ||
Lysophosphatidylcholine (LPC 20:3) | 0.22 | − |
Urine | ||
NMR | ||
Acetate | 0.21 | + |
Allantoin | 0.21 | − |
Histidine | 0.22 | − |
Isoleucine | 0.21 | + |
Taurine | 0.22 | + |
Threonine | 0.21 | + |
Trimethylamine-N-oxide | 0.21 | + |
Uracil | 0.22 | − |
GC-MS | ||
Unknown 103 17.03 5 | 0.21 | − |
Unknown 285 22.41 5 | 0.22 | + |
Unknown 57 9.58 5 | 0.22 | + |
Unknown 73 10.76 5 | 0.21 | − |
Unknown 73 17.66 5 | 0.21 | + |
Metabolite | Class | Function/Relevance |
---|---|---|
2-Hydroxyglutarate | Hydroxy acid | TCA intermediate; inhibitor of alpha-keto dehydrogenases, including histone demethylases; considered an oncometabolite |
N-Acetyl-glycine | Alpha amino acid | Lipid signaling mediator |
Taurine | Sulfur-containing amino acid | Metabolism of fats, bile acids |
Threonine | Amino acid | Metabolism of fats |
TAG (53:2/FA18:1) | Triglyceride | Fat storage; energy |
LPC (FA20:3) | Lysophosphatidyl choline | Cholesterol metabolism |
CE (FA20) | Cholesteryl ester | Cholesterol metabolism |
Acetate | Short chain fatty acid | Microbial metabolite; acetylation reactions, energy metabolism |
Glycerate | Sugar acid | Generation of ATP |
Adenosine | Nucleoside | Energy transfer, component of RNA/DNA |
Hypoxanthine | Purine | Metabolism of adenosine |
Uracil | Nucleic acid | Component of RNA |
7-Methylguanine | Purine | Component of RNA/DNA; potential biomarker of chicken |
Histidine | Amino acid | Protein synthesis, histamine and carnosine biosynthesis, scavenger of ROS |
Leucic acid | Hydroxy fatty acid | Leucine (branched-chain amino acid) metabolite; accelerates lipid peroxidation, oxidative stress |
Isoleucine | Branched-chain amino acid | Protein metabolism, hemoglobin production, glucose control, immunity |
N-Acetyl-glutamate | Alpha amino acid | Involved in the urea cycle |
Allantoin | Imidazoles | Microbial metabolite; uric acid metabolite; found in dairy |
N-Acetyl-neuraminate | Amino sugar | Component of glycoproteins and mucins involved in immunity |
Hydroxyproline | Amino acid | Component of collagen; biomarker of meat |
Myo-inositol | Sugar alcohol | Component of phosphatidylinositol; increases insulin sensitivity; biomarker of whole grains |
Trimethylamine-N-oxide | Amine oxide | Microbial metabolite formed from choline, betaine, and carnitine; associated with cardiovascular disease; biomarker of fish and red meat |
Metabolites Selected | Proportion of Explained Variation 2 | Direction of Coefficient for Metabolites 3 |
---|---|---|
Breast Cancer | All covariates + metabolites: 0.27 | |
Serum | ||
LC-MS | ||
Cystenyl-glycine | 0.22 | − |
Ethanolamine | 0.21 | + |
Sucrose | 0.22 | − |
Lipidyzer 4 | ||
Free fatty acid (FFA 20:2) | 0.22 | + |
Phosphatidylcholine (PC 16:0/18:2) | 0.23 | + |
Triacylglyceride (TAG 48:4/18:2) | 0.22 | − |
Triacylglyceride (TAG 50:5/18:3) | 0.22 | − |
Triacylglyceride (TAG 52:2/18:2) | 0.22 | + |
Urine | ||
NMR | ||
Uracil | 0.22 | − |
2-Hydroxyisobutyrate | 0.22 | + |
GC-MS | ||
Unknown 73.0 14.49 5 | 0.21 | + |
Unknown 73.0 12.10 5 | 0.22 | − |
Colorectal Cancer | All covariates + metabolites: 0.33 | |
Serum | ||
LC-MS | ||
Adenosine | 0.20 | − |
Leucic acid | 0.18 | + |
Glycerate | 0.23 | + |
Hypoxanthine | 0.18 | + |
Myoinositol | 0.19 | + |
N-Acetylneuraminate | 0.19 | − |
2-Hydroxyglutarate | 0.19 | + |
7-Methylguanine | 0.19 | + |
Lipidyzer | ||
CE (FA20) | 0.17 | − |
TAG (53:2/18:1) | 0.18 | + |
Urine | ||
NMR | ||
Histidine | 0.18 | − |
Taurine | 0.19 | + |
Threonine | 0.17 | + |
GC-MS | ||
Unknown 103 17.03 5 | 0.18 | − |
Unknown 285 22.41 5 | 0.18 | + |
Unknown 57 9.58 5 | 0.18 | + |
Unknown 73 10.76 5 | 0.18 | − |
Unknown 73 17.27 5 | 0.17 | + |
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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Navarro, S.L.; Williamson, B.D.; Huang, Y.; Nagana Gowda, G.A.; Raftery, D.; Tinker, L.F.; Zheng, C.; Beresford, S.A.A.; Purcell, H.; Djukovic, D.; et al. Metabolite Predictors of Breast and Colorectal Cancer Risk in the Women’s Health Initiative. Metabolites 2024, 14, 463. https://doi.org/10.3390/metabo14080463
Navarro SL, Williamson BD, Huang Y, Nagana Gowda GA, Raftery D, Tinker LF, Zheng C, Beresford SAA, Purcell H, Djukovic D, et al. Metabolite Predictors of Breast and Colorectal Cancer Risk in the Women’s Health Initiative. Metabolites. 2024; 14(8):463. https://doi.org/10.3390/metabo14080463
Chicago/Turabian StyleNavarro, Sandi L., Brian D. Williamson, Ying Huang, G. A. Nagana Gowda, Daniel Raftery, Lesley F. Tinker, Cheng Zheng, Shirley A. A. Beresford, Hayley Purcell, Danijel Djukovic, and et al. 2024. "Metabolite Predictors of Breast and Colorectal Cancer Risk in the Women’s Health Initiative" Metabolites 14, no. 8: 463. https://doi.org/10.3390/metabo14080463