Cytokine genotype polymorphisms in breast carcinoma: associations of TGF-beta1 with relapse

Markers of angiogenesis, cell proliferation, and cytokine regulation are associated with the development and course of autoimmune and malignant diseases. We investigated associations between cytokine production genotypes in breast cancer patients compared with controls and explored associations with known prognostic indices and relapse status. Eighty-eight females with breast carcinoma (BC) were studied in this case-control study comparing the cytokine genotypes of TNF-alpha TGF-beta1, IL-10, IL-6, and IFN-gamma with controls. Cytokine polymorphisms were identified by sequence-specific primers for codons, introns, or promoters regulating cytokine production. Patient characteristics, such as estrogen and progesterone receptor status, DNA ploidy, Her-2 neu expression, lymph node involvement, tumor size, and relapse status were evaluated. Cytokine genotypes were not associated with breast cancer compared with controls. Correlations between TGF-beta1 high-production genotypes and greater than four positive lymph nodes (OR=2.3; p=ns) and TNF-alpha high-production genotype and the mean level of estrogen receptor expression (66 +/- 24 vs. 34 +/- 36, p=0.016) were identified. The median patient follow-up interval from diagnosis to evaluation was 50.1 months (range 13-387 months). Relapse status was known for 84 of the patients. The odds of relapse in TGF-beta1 codon 10 CC genotypes was 2.81 times that in TGF-beta1 high-production genotypes (OR=2.81; 95% CI for OR: 1.0, 7.8; p=0.04). Mean progesterone receptor expression was decreased in relapsed patients (40.9 +/- 29.9% vs. 23.1 +/- 24.5, p=0.05). The other cytokine genotypes studied (IL-10, IL-6, IFN-gamma, and TNF-alpha production were not associated with breast cancer overall or relapse status. In this study, TGF-beta1 low-production genotypes (TGF-beta1 10 CC) were associated with an increased odds of disease relapse. This finding should be confirmed in a longitudinal study to further investigate the regulatory function of cytokine production as a prognostic indicator of relapse.