The molecular pathogenesis of hereditary ovarian carcinoma: alterations in the tubal epithelium of women with BRCA1 and BRCA2 mutations.
BACKGROUND
BRCA1 or BRCA2 (BRCA1/2)-mutated ovarian carcinomas may originate in the fallopian tube. The authors of this report investigated alterations in BRCA1/2 tubal epithelium to define the molecular pathogenesis of these carcinomas.


METHODS
Tubal epithelium was evaluated from 31 BRCA1/2 mutation carriers with gynecologic carcinomas (BRCA CA), 89 mutation carriers who underwent risk-reducing salpingo-oophorectomy (RRSO), and 87 controls. Ki-67 expression and p53 foci (≥10 of 12 consecutive staining cells) were scored by 2 investigators who were blinded to patient designations. Expression levels of p27 and p21 were evaluated within p53 foci. Loss of heterozygosity at the BRCA1/2 mutation site was evaluated in microdissected p53 foci and tubal neoplasms.


RESULTS
Background tubal proliferation as measured by Ki-67 staining was increased in the BRCA1 RRSO group (P = .005) compared with the control group. Women who had BRCA1/2 mutations had more p53 foci identified per tubal segment than women in the control group (P = .02). Levels of p27 were decreased in 12 of 28 p53 foci from women with BRCA1 mutations and in 0 of 16 p53 foci from controls (P = .002). There was no loss of the wild type BRCA1/2 allele in 5 tested p53 foci. Tubal neoplasia lost the wild type allele in 6 of 6 foci (P = .002).


CONCLUSIONS
The current results suggested a model of tubal carcinogenesis in women with BRCA1/2 mutations. Increased proliferation occurred globally in at-risk tubal epithelium. A mutation in the tumor protein p53 gene TP53 with clonal proliferation and loss of p27 occurred before neoplastic proliferation. Loss of the wild type BRCA1/2 allele occurred with neoplastic proliferation and before invasion.
Norquist
Barbara M
BM
Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA, USA. bnorquis@u.washington.edu
Garcia
Rochelle L
RL
Allison
Kimberly H
KH
Jokinen
Chris H
CH
Kernochan
Lauren E
LE
Pizzi
Catherine C
CC
Barrow
Bethany J
BJ
Goff
Barbara A
BA
Swisher
Elizabeth M
EM
D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D005185:Fallopian Tube Neoplasms / Q000235:genetics; D005187:Fallopian Tubes / Q000737:chemistry; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016158:Genes, p53; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*
D019394:Ki-67 Antigen