Ovarian carcinoma in situ with germline BRCA1 mutation and loss of heterozygosity at BRCA1 and TP53.
BACKGROUND
The two-hit hypothesis for the genesis of cancer predicts that cancer can develop when the wild-type allele of a tumor suppressor gene is lost in an individual with a germline mutation in that gene. Neither loss of heterozygosity (LOH) for BRCA1 nor mutations of the TP53 (also known as p53) gene have been documented prior to invasion in ovarian cancers arising in women with germline BRCA1 mutations. Such documentation is difficult because lesions are rarely identified in ovarian epithelium. We, therefore, looked for LOH at microsatellite polymorphisms linked to the BRCA1 and TP53 tumor suppressor loci in an incidental carcinoma in situ of the ovary removed prophylactically from a woman with a germline BRCA1 mutation.


METHODS
By use of laser-capture microdissection, we obtained pure populations of atypical ovarian epithelial cells and normal stromal cells. DNA was extracted, amplified with primers flanking polymorphic microsatellites linked to BRCA1 (D17S855 and D17S579) and TP53 (TP53 and D17S786), and analyzed for LOH at these microsatellites. We also tested for p53 expression in the abnormal epithelium by immunohistochemistry.


RESULTS
Both of the markers linked to TP53 showed LOH, as did an intragenic BRCA1-linked marker (D17S855). The other microsatellite marker for BRCA1 was uninformative. Immunohistochemical staining with an antibody to p53 showed strong immunoreactivity confined to the atypical epithelium.


CONCLUSIONS
BRCA1, as well as TP53, can undergo LOH prior to stromal invasion in BRCA1-associated ovarian cancer. Strong immunoreactivity for p53 suggests the presence of mutated p53 in these cells as well. These findings suggest that loss of function of these two tumor suppressor genes occurs early in ovarian carcinogenesis in BRCA1 mutation carriers.
Werness
B A
BA
Department of Pathology, University of Cincinnati Medical Center, OH 45267, USA. bruce.werness@uc.edu
Parvatiyar
P
P
Ramus
S J
SJ
Whittemore
A S
AS
Garlinghouse-Jones
K
K
Oakley-Girvan
I
I
DiCioccio
R A
RA
Wiest
J
J
Tsukada
Y
Y
Ponder
B A
BA
Piver
M S
MS
D000912:Antibodies, Neoplasm / Q000032:analysis; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1 / Q000235:genetics*; D008040:Genetic Linkage; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D011110:Polymorphism, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000276:immunology
D000912:Antibodies, Neoplasm; D017931:DNA Primers; D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53