BRCA1 promoter methylation predicts adverse ovarian cancer prognosis.
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).


CONCLUSIONS
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.
Chiang
Jing Wang
JW
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard., 160W, Los Angeles, CA 90048, USA.
Karlan
Beth Y
BY
Cass
Llana
L
Baldwin
Rae Lynn
RL
D018899:CpG Islands; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D020868:Gene Silencing; D019398:Genes, BRCA1; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D011401:Promoter Regions, Genetic; D016896:Treatment Outcome