Failure of BRCA1 dysfunction to alter ovarian cancer survival.
OBJECTIVE
Many factors modify ovarian cancer survival. There are conflicting reports regarding survival of individuals with hereditary BRCA1-related ovarian cancer. None have controlled for other mechanisms of BRCA1 silencing in the control cohort.


METHODS
Fifty-nine cancers with presumed BRCA1 dysfunction because of mutation (24 germ-line and 16 somatic) or absent BRCA1 mRNA because of promoter hypermethylation (n = 19) were identified among 250 consecutively screened ovarian cancers. Controls were matched from the same population based on p53 mutation type, age at diagnosis, Fédération Internationale des Gynaecologistes et Obstetristes surgical stage and histological grade, residual disease, preoperative CA125, disease site, and the presence of BRCA1 mRNA translatable in an in vitro protein expression assay. BRCA1 promoter hypermethylation was determined by the methylation-specific PCR technique. The significance of promoter hypermethylation was confirmed by the absence of detectable BRCA1 mRNA.


RESULTS
The median survival for individuals with ovarian cancer BRCA1 dysfunction was 4.1 years versus 3.5 years in the case matched controls (P = 0.98). Grouped on the basis of the mechanism of BRCA1 dysfunction, median survival was 4.5, 2.8, and 2.3 years for germ-line, somatic, and BRCA1 promoter-silenced ovarian cancers. However, for the corresponding matched controls with wild-type BRCA1 sequence, the median survival was virtually identical: 4.6, 2.8, and 3.3 years, respectively. In a Cox proportional hazards analysis, only residual disease (P = 0.0001), age (P = 0.01), and Fédération Internationale des Gynaecologistes et Obstetristes stage (P = 0.011) entered the survival model.


CONCLUSIONS
In contrast with other published reports, we are unable to detect large survival differences between matched case-control cohorts of ovarian cancers with BRCA1 inactivation by any of three independent mechanisms.
Buller
Richard E
RE
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Iowa Hospital and Clinic, Iowa City 52242-1009, USA. richard-buller@uiowa.edu
Shahin
Mark S
MS
Geisler
John P
JP
Zogg
Melanie
M
De Young
Barry R
BR
Davis
Charles S
CS
D019313:BRCA1 Protein / Q000235:genetics*; D016022:Case-Control Studies; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D018807:Polymorphism, Single-Stranded Conformational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D015996:Survival Rate
D019313:BRCA1 Protein; D004273:DNA, Neoplasm; D012333:RNA, Messenger