title: Allelic transcripts dosage effect in morphologically normal ovarian cells from heterozygous carriers of a BRCA1/2 French Canadian founder mutation.
abstract: We hypothesized that the transcriptome of primary cultures of morphologically normal ovarian surface epithelial cells could be altered by the presence of a heterozygous BRCA1 or BRCA2 mutation. We aimed to discover early events associated with ovarian carcinogenesis, which could represent putative targets for preventive strategies of this silent killer tumor. We identified the first molecular signature associated with French Canadian BRCA1 or BRCA2 founder mutations in morphologically normal ovarian epithelial cells. We discovered that wild-type and mutated BRCA2 allelic transcripts were expressed not only in morphologically normal but also in tumor cells from BRCA2-8765delAG carriers. Further analysis of morphologically normal ovarian and tumor cells from BRCA1-4446C>T carriers lead to the same observation. Our data support the idea that one single hit in BRCA1 or BRCA2 is sufficient to alter the transcriptome of phenotypically normal ovarian epithelial cells. The highest level of BRCA2-mutated allele transcript expression was measured in cells originating from the most aggressive ovarian tumor. The penetrance of the mutation and the aggressiveness of the related tumor could depend on a dosage effect of the mutated allele transcript.
authors.affiliation: Institut du cancer de Montréal/Centre de recherche du Centre hospitalier de l'Université de Montréal, Québec, Canada.
authors.forename: Diala
authors.initials: D
authors.lastname: Abd-Rabbo
authors.forename: Christine
authors.initials: C
authors.lastname: Abaji
authors.forename: Guillaume B
authors.initials: GB
authors.lastname: Cardin
authors.forename: Abdelali
authors.initials: A
authors.lastname: Filali-Mouhim
authors.forename: Caroline
authors.initials: C
authors.lastname: Arous
authors.forename: Lise
authors.initials: L
authors.lastname: Portelance
authors.forename: Enrique
authors.initials: E
authors.lastname: Escobar
authors.forename: Sophie
authors.initials: S
authors.lastname: Cloutier
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Tonin
authors.forename: Diane M
authors.initials: DM
authors.lastname: Provencher
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: Christine M
authors.initials: CM
authors.lastname: Maugard
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D002170:Canada; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D018628:Gene Dosage / Q000502:physiology*; D019398:Genes, BRCA1 / Q000502:physiology; D024522:Genes, BRCA2 / Q000502:physiology; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010053:Ovary / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism*; D019683:Penetrance; D011792:Quebec; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D054928:Validation Studies as Topic
chemical_list: D012333:RNA, Messenger