Absence of premalignant histologic, molecular, or cell biologic alterations in prophylactic oophorectomy specimens from BRCA1 heterozygotes.
BACKGROUND
The high mortality associated with ovarian carcinoma is largely a reflection of the inability to diagnose the disease at an early stage; the identification of a histologic lesion or molecular marker associated early stages of transformation would represent an important advance in understanding the natural history of this cancer. The existence of individuals with germline mutations in the ovarian and breast carcinoma susceptibility gene BRCA1 represents a unique opportunity to search for such premalignant alterations in ovarian tissues that are at unusually high risk for tumorigenesis. In this study, the authors addressed the hypothesis that pathologically normal ovaries removed from BRCA1 heterozygotes are likely to display premalignant histologic, molecular, and/or cell biologic alterations that may provide insight into early stages of ovarian tumorigenesis.


METHODS
Ovarian tissues from 18 BRCA1 heterozygotes and from 20 age-matched controls were examined in a blinded fashion for histologic evidence of surface epithelial pseudostratification, epithelial inclusion cysts, deep cortical invaginations of surface epithelium, increased stromal cell activity, and surface papillomatosis. Immunohistochemical analyses for expression of BRCA1, p53, and ERBB-2 and quantitation of cell proliferation (Ki-67 expression) and apoptosis (TUNEL assay), were also performed on all specimens.


RESULTS
Although histologic alterations were observed, there was no difference in frequency between cases and controls. Analysis of BRCA1 expression revealed ubiquitous nuclear immunoreactivity in the surface epithelial cells of all ovaries. Similarly, no evidence was found of p53 overexpression in any ovarian tissue or of a difference in ERBB-2 expression between cases and controls. Finally, no differences were observed in epithelial cell proliferation or apoptosis.


CONCLUSIONS
Clinically, normal ovaries from BRCA1 heterozygotes do not show evidence of premalignant alterations in histology, molecular markers, cell proliferation, or apoptosis, indicating that such changes are likely rare.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
R R
RR
Barakat
M G
MG
Federici
P E
PE
Saigo
M E
ME
Robson
K
K
Offit
J
J
Boyd
D000328:Adult; D000368:Aged; D017209:Apoptosis; D019313:BRCA1 Protein / Q000096:biosynthesis; D016923:Cell Death; D002455:Cell Division; D005260:Female; D015870:Gene Expression; D019398:Genes, BRCA1 / Q000235:genetics*; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010052:Ovariectomy; D010053:Ovary / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology
D019313:BRCA1 Protein; D019394:Ki-67 Antigen