Objective: To compare the clinical outcome of ovarian cancer patients whose tumors contain BRCA1 genes silenced by promoter hypermethylation to patients with germline BRCA1 mutations and to patients with wild-type BRCA genes.
Methods: Ovarian cancers from a hospital-based tumor bank were characterized as having a BRCA1 mutation; or a methylated BRCA1, BRCA1 pseudogene or MLH1 promotor; or a wild-type BRCA gene. Survival of patients with methylated BRCA1 promoters (N = 11) was compared to that of patients with wild-type BRCA genes (N = 30) and BRCA1 mutations (N = 22). A methylator phenotype was defined to include tumors with hypermethylation of BRCA1, hMLH1 and/or dBRCA1 pseudogene promoters (N = 23).
Results: All cohorts had comparable clinical factors except for age at diagnosis. Median age of methylated BRCA1 and wild-type BRCA patients was older than BRCA1 mutation carriers (60 and 63 versus 48 years; P = 0.04). The median disease-free interval was significantly shorter for patients with a methylated BRCA1 promoter (9.8 months) than for BRCA1 mutation carriers (39.5 months; P = 0.04). Median overall survival was also significantly shorter for patients with a methylated BRCA1 promoter (35.6 months) than BRCA1 mutation carriers (78.6 months; P = 0.02). The combined methylator phenotype cohort had significantly shorter survival (36.1 months) compared to wild-type BRCA patients (63.3 months; P = 0.02).
Conclusion: These data suggest that methylation of the BRCA1 promoter is associated with poor patient outcome. BRCA1 may be part of a global panel of methylated genes associated with aggressive disease.