title: Identification of a preneoplastic gene expression profile in tubal epithelium of BRCA1 mutation carriers.
abstract: Microinvasive carcinomas and high-grade intraepithelial neoplasms are commonly discovered within the fallopian tube of BRCA1 mutation carriers at the time of risk-reducing salpingo-oophorectomy, suggesting that many BRCA1-mutated ovarian carcinomas originate in tubal epithelium. We hypothesized that changes in gene expression profiles within the histologically normal fallopian tube epithelium of BRCA1 mutation carriers would overlap with the expression profiles in BRCA1-mutated ovarian carcinomas and represent a BRCA1 preneoplastic signature. Laser capture microdissection of frozen sections was used to isolate neoplastic cells or histologically normal fallopian tube epithelium, and expression profiles were generated on Affymetrix U133 Plus 2.0 gene expression arrays. Normal-risk controls were 11 women wild type for BRCA1 and BRCA2 (WT-FT). WT-FT were compared with histologically normal fallopian tube epithelium from seven women with deleterious BRCA1 mutations who had foci of at least intraepithelial neoplasm within their fallopian tube (B1-FTocc). WT-FT samples were also compared with 12 BRCA1 ovarian carcinomas (B1-CA). The comparison of WT-FT versus B1-FTocc resulted in 152 differentially expressed probe sets, and the comparison of WT-FT versus B1-CA resulted in 4079 differentially expressed probe sets. The BRCA1 preneoplastic signature was composed of the overlap between these two lists, which included 41 concordant probe sets. Genes in the BRCA1 preneoplastic signature included several known tumor suppressor genes such as CDKN1C and EFEMP1 and several thought to be important in invasion and metastasis such as E2F3. The expression of a subset of genes was validated with quantitative reverse transcription-polymerase chain reaction and immunohistochemistry.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA. jzp@u.washington.edu
authors.forename: Joshua Z
authors.initials: JZ
authors.lastname: Press
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Wurz
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Norquist
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Christopher
authors.initials: C
authors.lastname: Pennil
authors.forename: Rochelle
authors.initials: R
authors.lastname: Garcia
authors.forename: Piri
authors.initials: P
authors.lastname: Welcsh
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Goff
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics; D050699:E2F3 Transcription Factor / Q000235:genetics; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005185:Fallopian Tube Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005187:Fallopian Tubes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D011230:Precancerous Conditions / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; D019394:Ki-67 Antigen