Abstract
Not all segments of the U.S. population have equally benefited from the advances in our knowledge and treatment of cancer. As a result, some population groups experience a disproportionally high cancer burden, leading to excessively high cancer mortality rates in the African American community when compared with other communities. For example, African American patients have the highest prostate and breast cancer mortalities among all U.S. racial and ethnic groups. This survival disparity has been attributed to a number of factors including differences in insurance status and medical care. However, other observations suggest that disparities in prostate and breast cancer survival between African American and European American patients can persist in randomized clinical trials (1), indicating that intrinsic differences in tumor biology may contribute to this survival health disparity. Moreover, African American breast cancer patients represent more frequently than European American patients with a high grade and estrogen receptor-negative disease, and the aggressive basal-like and triple-negative breast cancer subtypes are more common among them than women from other population groups. This pattern is reminiscent of disease presentation in West Africa (2), indicating that women of African ancestry tend to develop a different tumor biology than women of European descent. In two studies, we examined the tumor biology of prostate and breast cancer comparing African American patients with European American patients using large scale gene expression profiling and found significant differences in gene expression that are consistent with race/ethnic differences in the tumor microenvironment and immunobiology (3, 4). Intriguingly, an interferon gene signature was detected in African American prostate and breast tumors that may relate to an unknown etiologic agent in disease pathology. We think that tumor-induced mechanisms, environmental stimuli, and ancestry-driven intrinsic factors are candidate exposures that induce the interferon-related gene signature and the observed differences in the tumor microenvironment between African American patients and European American patients. The interferon signature may also influence therapeutic outcome because it has great homology with a recently discovered interferon-related DNA damage resistance signature, which predicts resistance to chemotherapy and radiation in breast cancer and perhaps other epithelial cancers (5, 6). In my presentation, I will discuss this signature and candidate factors that may induce it, and thereby affect tumor biology.
Recently, metabolomics emerged as a new discovery tool with the promise of identifying druggable metabolic dependencies of cancer cells. This research discovered new essential metabolomic pathways for tumor growth in human cancer and showed that resistance to chemotherapy can be metabolite-based. In a project that received startup funds through a NCI Director Innovation Award, we and collaborators at the Baylor College of Medicine assessed the abundance of 352 known and 184 unknown metabolites in 67 human breast tumors and 65 adjacent non-cancerous tissues (65 pairs) using an untargeted approach for metabolite discovery by Metabolon, Inc., and validated key metabolites in 70 ER-negative tumors and 36 adjacent non-cancerous tissues with targeted assays at two other laboratories. This work revealed that metabolite profiles were greatly different between tumor and non-cancerous tissue and by ER status and grade, but were not obviously associated with disease stage, body mass and menopausal status, and were only modestly affected by neoadjuvant therapy and sociodemographic variables. Further analyses identified a poor survival tumor subtype with distinct DNA methylation, high tissue 2-hydroxyglutarate, and a heightened occurrence in African American breast cancer patients. Lastly, using unsupervised hierarchical clustering, both ER-negative tumors and triple-negative/basal-like tumors separated into metabolite-defined subclusters that did not randomly represent the two patient groups. Instead, distinct clusters emerged that were significantly enriched for either African American or European American patients. In my presentation, I will discuss these findings and their relationship with MYC activation and a stem cell-like gene expression signature in breast tumors.
References
1 Albain,K.S., Unger,J.M., Crowley,J.J., Coltman,C.A., Jr. and Hershman,D.L. Racial disparities in cancer survival among randomized clinical trials patients of the Southwest Oncology Group, J Natl Cancer Inst., 101: 984-992, 2009.
2 Huo,D., Ikpatt,F., Khramtsov,A., Dangou,J.M., Nanda,R., Dignam,J., Zhang,B., Grushko,T., Zhang,C., Oluwasola,O., Malaka,D., Malami,S., Odetunde,A., Adeoye,A.O., Iyare,F., Falusi,A., Perou,C.M. and Olopade,O.I. Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer, J.Clin Oncol., 27: 4515-4521, 2009.
3 Wallace,T.A., Prueitt,R.L., Yi,M., Howe,T.M., Gillespie,J.W., Yfantis,H.G., Stephens,R.M., Caporaso,N.E., Loffredo,C.A. and Ambs,S. Tumor immunobiological differences in prostate cancer between African-American and European-American men, Cancer Res., 68: 927-936, 2008.
4 Martin,D.N., Boersma,B.J., Yi,M., Reimers,M., Howe,T.M., Yfantis,H.G., Tsai,Y.C., Williams,E.H., Lee,D.H., Stephens,R.M., Weissman,A.M. and Ambs,S. Differences in the Tumor Microenvironment between African-American and European-American Breast Cancer Patients, PLoS.ONE., 4: e4531, 2009.
5 Khodarev,N.N., Beckett,M., Labay,E., Darga,T., Roizman,B. and Weichselbaum,R.R. STAT1 is overexpressed in tumors selected for radioresistance and confers protection from radiation in transduced sensitive cells, Proc Natl Acad Sci U.S.A, 101: 1714-1719, 2004.
6 Weichselbaum,R.R., Ishwaran,H., Yoon,T., Nuyten,D.S., Baker,S.W., Khodarev,N., Su,A.W., Shaikh,A.Y., Roach,P., Kreike,B., Roizman,B., Bergh,J., Pawitan,Y., Van de Vijver,M.J. and Minn,A.J. An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer, Proc.Natl.Acad.Sci.U.S.A, 105: 18490-18495, 2008.
Citation Format: Stefan Ambs. Distinct immune and metabolic signatures in prostate and breast tumors of African American patients. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr PL01-01. doi:10.1158/1538-7755.DISP13-PL01-01
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