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Promoter-CpG island hypermethylation is a common molecular defect in cancer cells. It has been proposed as an alternative mechanism to inactivate BRCA1in the breast where somatic mutations of BRCA1 are rare. To better understand breast cancer progression, we explored the association between BRCA1 promoter methylation status and prognostic factors as well as survival among women with breast cancer. We also examined whether dietary methyl content and functional polymorphisms of genes involved in one-carbon metabolism influenced the methylation pattern. Promoter methylation of BRCA1 was assessed from 851 archived tumor tissues collected from a population-based study with women diagnosed with invasive or in situ breast cancer in 1996-1997, and who were followed for vital status through the end of 2002. About 59% of the tumors were methylated at the promoter of BRCA1. The BRCA1 promoter methylation was more frequent in cancers (i) that were classified as invasive (p=0.02); (ii) among premenopausal women (p=0.05); (iii) with at least one nodule involvement (p=0.003); (iv) with tumor size greater than 2 cm (p=0.004). BRCA1 promoter methylation was also associated with increased risk breast cancer-specific mortality (age-adjusted HR 1.71; 95% CI: 1.05-2.78) and all-cause mortality (age-adjusted HR 1.49; 95% CI: 1.02-2.18). Neither dietary methyl content (folate, methionine, choline, betaine and B vitamins) nor functional polymorphisms in this pathway were correlated with BRCA1 methylation status. Our study is the largest as well as the only population-based investigation on the prognostic value of BRCA1 promoter methylation. Our results indicate that BRCA1 promoter methylation is an important factor to consider in predicting breast cancer survival.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA