The AA genotype of the regulatory BCL2 promoter polymorphism (-938C⟩A) is associated with a favorable outcome in lymph node-negative invasive breast cancer patients

Purpose: Expression of the antiapoptotic and antiproliferative protein Bcl-2 has been repeatedly shownto be associated with better clinical outcome in breastcancer.We recently showed a novel regulatory (-938C>A) single-nucleoticle polymorphism (SNP) in the inhibitory P2 BCL2 gene promoter generating significantly different BCL2 promoter activities. Experimental Design: Paraffin-embedded neoplastic and nonneoplastic tissues from 274 patients (161 still alive after a follow-up period of at least 80 months) with primary unilateral invasive breast carcinoma were investigated. BcI-2 expression of tumor cells was shown by immunohistochemistry; nonneoplastic tissues were used for genotyping. Both the BcI-2 expression and the (-938C>A) genotypes were correlated with the patients survival. Results: Kaplan-Meier curves revealed a significant association of the AA genotype with increased survival (P = 0.030) in lymph node -negative breast cancer patients, whereas no genotype effect could be observed in lymph node -positive cases. Ten-year survival rates were 88.6% for the AA genotype, 78.4% for the AC genotype, and 65.8%for the CC genotype. Multivariable Cox regression identified the BCL2 (-938CC) genotype as an independent prognostic factor for cancer-related death in lymph node - negative breast carcinoma patients (hazard ratio, 3.59; P = 0.032). Immunohistochemical BcI-2 expression was significantly associated with the clinical outcome of lymph node -positive but not of lymph node -negative breast cancer patients. In lymph node- negative cases, the (-938C>A) SNP was both significantly related with the immunohistochemically determined level of BcI-2 expression (P = 0.044) and the survival of patients with BcI-2 -expressing carcinomas (P = 0.006). Conclusions: These results suggest the (-938C>A) polymorphism as a survival prognosticator as well as indicator of a high-risk group within patients with lymph node - negative breast cancer.