The study population of our breast cancer case-control study consists of 293 cases and 317 controls. We have tumor specimens and survival information for 248 cases. Study subjects were recruited between 1993 and 2003. Cases had pathologically confirmed breast cancer, and had, by self-report, no previous history of the disease. The controls were frequency-matched to cases by race and age, and had by self-report, no history of breast cancer. They are either hospital-based (n = 230) or population-based (n = 87). Hospital-based controls were recruited from family/internal medicine, thoracic and breast reduction surgery, and pulmonary, asthma, allergy, and dental clinics. Population-based controls were selected from Motor Vehicle Administration records. Inclusion criteria included being self-identified African-American or Caucasian and born in the United States. Subjects were excluded if they were HIV, HCV, or HBV carriers, were IV-drug users, were institutionalized, or were physically or mentally unable to sign a consent form and complete the questionnaire. Of the eligible subjects, 83% of the cases, 87% of the hospital-based controls with breast-reduction surgery, 92% of the other hospital controls, and 90% of the population-based controls, participated in the study. Tumor and blood samples were collected from cases, and blood samples from controls. An interviewer-administered questionnaire evaluated the demographic, medical, reproductive, family, and occupational history of the subjects. Additional information to determine body mass index, disease stage, metastasis and survival was obtained from medical records and pathology reports, State of Maryland records, and the National Death Index. We recently described a significant interaction between a common genetic variant (SNP309) in the MDM2 gene and the tumor p53 status in breast cancer survival. The SNP309 was found to have a dominant effect over p53 in breast cancer survival. We also observed that a MnSOD gene polymorphism was associated with breast cancer outcome after doxorubicin cancer therapy. We established a collaboration with Anne-Lise Borresen-Dale in Norway to validate the finding in a second study. This SNP could become a marker of the response to doxorubicin therapy in breast cancer, and possibly other human cancers. We are also studying the functional impact of this polymorphism on MnSOD activity and intracellular localization with David Wink's group in the NCI Radiation Biology Branch. Complementary to this line of research, we have a collaboration with Kent Hunter at the NCI Laboratory of Population Genetics to investigate the significance of germline genetic variations in cancer metastasis. The two laboratories use different but complementary approaches to identify candidate genes. Currently, the collaboration is validating candidate metastasis modifiers that were discovered in a mouse model of breast cancer metastasis. Lastly, we study differences in tumor biology between African-American and Caucasian women. We observed differences in respect to tissue inflammation and global gene expression. We are further pursuing these observations with in-depth pathway analysis to elucidate possible relationships to the aggressiveness of breast cancer in African-American women.
| Boersma, Brenda J; Howe, Tiffany M; Goodman, Julie E et al. (2006) Association of breast cancer outcome with status of p53 and MDM2 SNP309. J Natl Cancer Inst 98:911-9 |
