Cancer predisposing BARD1 mutations affect exon skipping and are associated with overexpression of specific BARD1 isoforms.
BARD1 is the main binding partner of BRCA1 and is required for its stability and tumor-suppressor functions. In breast cancer and other epithelial cell carcinomas, alternatively spliced isoforms of BARD1 are highly upregulated and correlated with poor outcome. Recent data indicate that germline mutations of BARD1 may predispose to breast and/or ovarian cancer. To evaluate the role of BARD1 germline mutations in predisposition to ovarian cancer we scanned a cohort of 255 patients for the presence of previously reported mutations located in exons 5, 8 and 10 using high-resolution melting analysis. Within this group we identified single-patients carrying mutation in exon 8 (c.1690C>T, p.Gln564Ter), two different variants in exon 10 (c.1972C>T, p.Arg658Tyr; c.1977A>G, p.=) and a carrier of novel missense mutation located in exon 5 (c.1361C>T, p.Pro454Leu). Three out of four identified mutations alter exonic splicing enhancing motives and result in expression of incorrect splicing skipping of exons 5, 8, and 2-9, respectively. Our data indicate that BARD1 variants may predispose to ovarian cancer in limited number of patients although based on actual data it is difficult to estimate its actual penetrance.
Department of Biology and Genetics, Medical University of Gdansk, 80-211 Gdansk, Poland.
Magdalena
M
Ratajska
Department of Biology and Genetics, Medical University of Gdansk, 80-211 Gdansk, Poland.
Magdalena
M
Matusiak
Department of Biology and Genetics, Medical University of Gdansk, 80-211 Gdansk, Poland.
Alina
A
Kuzniacka
Department of Biology and Genetics, Medical University of Gdansk, 80-211 Gdansk, Poland.
Bartosz
B
Wasag
Department of Biology and Genetics, Medical University of Gdansk, 80-211 Gdansk, Poland.
Izabela
I
Brozek
Department of Pathology, Medical University of Gdansk, 80-214 Gdansk, Poland.
Wojciech
W
Biernat
Department of Biology and Genetics, Medical University of Gdansk, 80-211 Gdansk, Poland.
Magdalena
M
Koczkowska
Department of Gynecology, Medical University of Gdansk, 80-402 Gdansk, Poland.
Jaroslaw
J
Debniak
Department of Gynecology, Medical University of Gdansk, 80-402 Gdansk, Poland.
Marcin
M
Sniadecki
European Centre of Bioinformatics and Genomics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-138 Poznan, Poland.
Piotr
P
Kozlowski
European Centre of Bioinformatics and Genomics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-138 Poznan, Poland.
Katarzyna
K
Klonowska
Laboratory of Molecular Gynecology and Obstetrics, University Hospital Geneva-Belle-Idée, 2, Chemin du Petit Bel Air, Chêne Bourg CH-1225, Switzerland.
Maxim
M
Pilyugin
Department of Gynecology, Medical University of Gdansk, 80-402 Gdansk, Poland.
Dariusz
D
Wydra
Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute of Medical Research, M519, QEII Medical Centre, Nedlands WA 6009, Australia.
Geoff
G
Laurent
Department of Biology and Genetics, Medical University of Gdansk, 80-211 Gdansk, Poland.
Janusz
J
Limon
Laboratory of Molecular Gynecology and Obstetrics, University Hospital Geneva-Belle-Idée, 2, Chemin du Petit Bel Air, Chêne Bourg CH-1225, Switzerland.
Irmgard
I
Irminger-Finger
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D020033:Protein Isoforms / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D055815:Young Adult
D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases