title: High frequency of allelic loss at the BRCA1 locus in ovarian cancers: clinicopathologic and molecular associations.
abstract: BRCA1 dysfunction may occur by different mechanisms that are rarely evaluated concomitantly. We aimed to analyze BRCA1 germline mutations, loss of heterozygosity (LOH) and promoter methylation in unselected ovarian carcinomas in the context of their clinicopathologic characteristics and other molecular changes. BRCA1 mutations were analyzed in 257 carcinomas using single-strand conformation polymorphism (SSCP), heteroduplex, and sequencing methods. LOH at the BRCA1 locus was screened for in 180 cancers. Methylation analysis was performed for 241 tumors using quantitative methylation specific PCR (qMSP). BRCA1 alterations, comprising germline mutations, allelic loss, and/or aberrant promoter methylation, were found in 77.6% (125/161) of ovarian carcinomas. Patients with germline mutations were younger than non-carriers (P < 0.0001). Germline mutations and LOH were associated with advanced stages (P=0.009, P < 0.0001), high tumor grade (P=0.005, P < 0.0001), and TP53 mutations (P=0.003, P < 0.0001, for mutations and LOH, respectively). LOH was also associated with the serous histological type (P=0.004) and PIK3CA amplification (P=0.003). Aberrant promoter methylation was associated with LOH (P=0.017) and absence of germline mutations (P=0.037). The high frequency of LOH at the BRCA1 locus suggests that LOH may be an important mechanism of BRCA1 deficiency in ovarian carcinomas. Tumors with various BRCA1 alterations have a similar phenotype of high-grade, high-stage carcinomas with frequent TP53 mutations.
authors.affiliation: Department of Molecular Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. iworzep@coi.waw.pl
authors.forename: Iwona K
authors.initials: IK
authors.lastname: Rzepecka
authors.forename: Lukasz
authors.initials: L
authors.lastname: Szafron
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Stys
authors.forename: Mateusz
authors.initials: M
authors.lastname: Bujko
authors.forename: Joanna
authors.initials: J
authors.lastname: Plisiecka-Halasa
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Madry
authors.forename: Beata
authors.initials: B
authors.lastname: Osuch
authors.forename: Janina
authors.initials: J
authors.lastname: Markowska
authors.forename: Mariusz
authors.initials: M
authors.lastname: Bidzinski
authors.forename: Jolanta
authors.initials: J
authors.lastname: Kupryjanczyk
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D058534:Class I Phosphatidylinositol 3-Kinases; D019175:DNA Methylation; D005260:Female; D005784:Gene Amplification; D019398:Genes, BRCA1; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human