Mapping the Human Exposome to Uncover the Causes of Breast Cancer

Vincent Bessonneau, Ruthann A Rudel, Vincent Bessonneau, Ruthann A Rudel

Abstract

Breast cancer is an important cause of morbidity and mortality for women, yet a significant proportion of variation in individual risk is unexplained. It is reasonable to infer that unexplained breast cancer risks are caused by a myriad of exposures and their interactions with genetic factors. Most epidemiological studies investigating environmental contribution to breast cancer risk have focused on a limited set of exposures and outcomes based on a priori knowledge. We hypothesize that by measuring a rich set of molecular information with omics (e.g., metabolomics and adductomics) and comparing these profiles using a case-control design we can pinpoint novel environmental risk factors. Specifically, exposome-wide association study approaches can be used to compare molecular profiles between controls and either breast cancer cases or participants with phenotypic measures associated with breast cancer (e.g., high breast density, chronic inflammation). Current challenges in annotating compound peaks from biological samples can be addressed by creating libraries of environmental chemicals that are breast cancer relevant using publicly available high throughput exposure and toxicity data, and by mass spectra fragmentation. This line of discovery and innovation will extend understanding of how environmental exposures interact with genetics to affect health, and provide evidence to support new breast cancer prevention strategies.

Keywords: adductomics; breast cancer; exposome; metabolomics.

Conflict of interest statement

R.A.R. and V.B. are employed at the Silent Spring Institute, a scientific research organization dedicated to studying environmental factors in women’s health. The Institute is a 501(c) 3 public charity funded by federal grants and contracts, foundation grants, and private donations, including from breast cancer organizations. The authors declare they have no actual or potential competing financial interests.

Figures

Figure 1
Figure 1
Conceptual diagram. Exposome-wide association studies using a prospective case-control design can discover novel environmental risk factors related to breast cancer. The exposome includes measurements of a rich set of molecular information in prediagnostic biospecimens. Cases can be breast cancer cases or cases with phenotypic measures related to breast cancer.

References

    1. Brody J.G., Rudel R.A., Michels K.B., Moysich K.B., Bernstein L., Attfield K.R., Gray S. Environmental pollutants, diet, physical activity, body size, and breast cancer. Cancer. 2007;109:2627–2634. doi: 10.1002/cncr.22656.
    1. Ward E.M., Sherman R.L., Henley S.J., Jemal A., Siegel D.A., Feuer E.J., Firth A.U., Kohler B.A., Scott S., Ma J., et al. Annual Report to the Nation on the Status of Cancer, Featuring Cancer in Men and Women Age 20–49 Years. J. Natl. Cancer Inst. 2019;111:1279–1297. doi: 10.1093/jnci/djz106.
    1. Lichtenstein P., Holm N.V., Verkasalo P.K., Iliadou A., Kaprio J., Koskenvuo M., Pukkala E., Skytthe A., Hemminki K. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 2000;343:78–85. doi: 10.1056/NEJM200007133430201.
    1. Breast Cancer and the Environment: A Life Course Approach: Health and Medicine Division. [(accessed on 19 December 2019)]; Available online: .
    1. Rappaport S.M. Genetic Factors Are Not the Major Causes of Chronic Diseases. PLoS ONE. 2016;11:e0154387. doi: 10.1371/journal.pone.0154387.
    1. Mucci L.A., Hjelmborg J.B., Harris J.R., Czene K., Havelick D.J., Scheike T., Graff R.E., Holst K., Möller S., Unger R.H., et al. Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA. 2016;315:68–76. doi: 10.1001/jama.2015.17703.
    1. Yaghjyan L., Mahoney M.C., Succop P., Wones R., Buckholz J., Pinney S.M. Relationship between breast cancer risk factors and mammographic breast density in the Fernald Community Cohort. Br. J. Cancer. 2012;106:996–1003. doi: 10.1038/bjc.2012.1.
    1. Huo C.W., Chew G.L., Britt K.L., Ingman W.V., Henderson M.A., Hopper J.L., Thompson E.W. Mammographic density–A review on the current understanding of its association with breast cancer. Breast Cancer Res. Treat. 2014;144:479–502. doi: 10.1007/s10549-014-2901-2.
    1. Miller G.W., Jones D.P. The Nature of Nurture: Refining the Definition of the Exposome. Toxicol. Sci. 2014;137:1–2. doi: 10.1093/toxsci/kft251.
    1. Rodgers K.M., Udesky J.O., Rudel R.A., Brody J.G. Environmental chemicals and breast cancer: An updated review of epidemiological literature informed by biological mechanisms. Environ. Res. 2018;160:152–182. doi: 10.1016/j.envres.2017.08.045.
    1. Rappaport S.M. Biomarkers intersect with the exposome. Biomarkers. 2012;17:483–489. doi: 10.3109/1354750X.2012.691553.
    1. Wild C.P., Scalbert A., Herceg Z. Measuring the exposome: A powerful basis for evaluating environmental exposures and cancer risk. Environ. Mol. Mutagen. 2013;54:480–499. doi: 10.1002/em.21777.
    1. Rappaport S.M. Implications of the exposome for exposure science. J. Expo. Sci. Environ. Epidemiol. 2011;21:5–9. doi: 10.1038/jes.2010.50.
    1. Rappaport S.M., Barupal D.K., Wishart D., Vineis P., Scalbert A. The blood exposome and its role in discovering causes of disease. Environ. Health Perspect. 2014;122:769–774. doi: 10.1289/ehp.1308015.
    1. Bessonneau V., Pawliszyn J., Rappaport S.M. The Saliva Exposome for Monitoring of Individuals’ Health Trajectories. Environ. Health Perspect. 2017;125 doi: 10.1289/EHP1011.
    1. Patel C.J., Bhattacharya J., Butte A.J. An Environment-Wide Association Study (EWAS) on Type 2 Diabetes Mellitus. PLoS ONE. 2010;5:e10746. doi: 10.1371/journal.pone.0010746.
    1. Tzoulaki I., Patel C.J., Okamura T., Chan Q., Brown I.J., Miura K., Ueshima H., Zhao L., Van Horn L., Daviglus M.L., et al. A nutrient-wide association study on blood pressure. Circulation. 2012;126:2456–2464. doi: 10.1161/CIRCULATIONAHA.112.114058.
    1. Patel C.J., Rehkopf D.H., Leppert J.T., Bortz W.M., Cullen M.R., Chertow G.M., Ioannidis J.P. Systematic evaluation of environmental and behavioural factors associated with all-cause mortality in the United States national health and nutrition examination survey. Int. J. Epidemiol. 2013;42:1795–1810. doi: 10.1093/ije/dyt208.
    1. Nicholson J.K., Wilson I.D. Opinion: Understanding “global” systems biology: Metabonomics and the continuum of metabolism. Nat. Rev. Drug Discov. 2003;2:668–676. doi: 10.1038/nrd1157.
    1. German J.B., Hammock B.D., Watkins S.M. Metabolomics: Building on a century of biochemistry to guide human health. Metabolomics. 2005;1:3–9. doi: 10.1007/s11306-005-1102-8.
    1. Playdon M.C., Ziegler R.G., Sampson J.N., Stolzenberg-Solomon R., Thompson H.J., Irwin M.L., Mayne S.T., Hoover R.N., Moore S.C. Nutritional metabolomics and breast cancer risk in a prospective study. Am. J. Clin. Nutr. 2017;106:637–649. doi: 10.3945/ajcn.116.150912.
    1. Wishart D.S., Feunang Y.D., Marcu A., Guo A.C., Liang K., Vázquez-Fresno R., Sajed T., Johnson D., Li C., Karu N., et al. HMDB 4.0: The human metabolome database for 2018. Nucleic Acids Res. 2018;46:D608–D617. doi: 10.1093/nar/gkx1089.
    1. METLIN: A Technology Platform for Identifying Knowns and Unknowns. [(accessed on 25 November 2019)]; Available online: .
    1. US EPA Organization Distributed Structure-Searchable Toxicity (DSSTox) Database. [(accessed on 6 September 2017)]; Available online: .
    1. Kim S., Thiessen P.A., Bolton E.E., Chen J., Fu G., Gindulyte A., Han L., He J., He S., Shoemaker B.A., et al. PubChem Substance and Compound databases. Nucleic Acids Res. 2016;44:D1202–D1213. doi: 10.1093/nar/gkv951.
    1. Grashow R., Bessonneau V., Gerona R.R., Wang A., Trowbridge J., Lin T., Buren H., Rudel R.A., Morello-Frosch R. Integrating exposure knowledge and serum suspect screening as a new approach to biomonitoring: An application in firefighters and office workers. bioRxiv. 2019 doi: 10.1101/630848.
    1. Ring C.L., Arnot J.A., Bennett D.H., Egeghy P.P., Fantke P., Huang L., Isaacs K.K., Jolliet O., Phillips K.A., Price P.S., et al. Consensus Modeling of Median Chemical Intake for the U.S. Population Based on Predictions of Exposure Pathways. Environ. Sci. Technol. 2019;53:719–732. doi: 10.1021/acs.est.8b04056.
    1. Grigoryan H., Edmands W., Lu S.S., Yano Y., Regazzoni L., Iavarone A.T., Williams E.R., Rappaport S.M. Adductomics Pipeline for Untargeted Analysis of Modifications to Cys34 of Human Serum Albumin. Anal. Chem. 2016;88:10504–10512. doi: 10.1021/acs.analchem.6b02553.
    1. Grigoryan H., Edmands W.M.B., Lan Q., Carlsson H., Vermeulen R., Zhang L., Yin S.-N., Li G.-L., Smith M.T., Rothman N., et al. Adductomic signatures of benzene exposure provide insights into cancer induction. Carcinogenesis. 2018;39:661–668. doi: 10.1093/carcin/bgy042.
    1. Grigoryan H., Schiffman C., Gunter M.J., Naccarati A., Polidoro S., Dagnino S., Dudoit S., Vineis P., Rappaport S.M. Cys34 Adductomics Links Colorectal Cancer with the Gut Microbiota and Redox Biology. Cancer Res. 2019;79:6024–6031. doi: 10.1158/0008-5472.CAN-19-1529.

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