Identification of fifteen novel germline variants in the BRCA1 3′UTR reveals a variant in a breast cancer case that introduces a functional miR-103 target site

Brewster, Brooke L., Rossiello, Francesca, French, Juliet D., Edwards, Stacey L., Wong, Ming, Wronski, Ania, Whiley, Phillip, Waddell, Nic, Chen, Xiaowei, Bove, Betsy, kConFab, Hopper, John L., John, Esther M., Andrulis, Irene, Daly, Mary, Volorio, Sara, Bernard, Loris, Peissel, Bernard, Manoukian, Siranoush, Barile, Monica, Pizzamiglio, Sara, Verderio, Paolo, Spurdle, Amanda B., Radice, Paolo, Godwin, Andrew K., Southey, Melissa C., Brown, Melissa A. and Peterlongo, Paolo (2012) Identification of fifteen novel germline variants in the BRCA1 3′UTR reveals a variant in a breast cancer case that introduces a functional miR-103 target site. Human Mutation, 33 12: 1665-1675.

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Author Brewster, Brooke L.
Rossiello, Francesca
French, Juliet D.
Edwards, Stacey L.
Wong, Ming
Wronski, Ania
Whiley, Phillip
Waddell, Nic
Chen, Xiaowei
Bove, Betsy
kConFab
Hopper, John L.
John, Esther M.
Andrulis, Irene
Daly, Mary
Volorio, Sara
Bernard, Loris
Peissel, Bernard
Manoukian, Siranoush
Barile, Monica
Pizzamiglio, Sara
Verderio, Paolo
Spurdle, Amanda B.
Radice, Paolo
Godwin, Andrew K.
Southey, Melissa C.
Brown, Melissa A.
Peterlongo, Paolo
Total Author Count Override 182
Title Identification of fifteen novel germline variants in the BRCA1 3′UTR reveals a variant in a breast cancer case that introduces a functional miR-103 target site
Journal name Human Mutation  (ERA 2012 Listed)    (ERA 2010 Rank A)   Check publisher's open access policy
Publication date 2012-07-02
Sub-type Article
DOI 10.1002/humu.22159
Volume number 33
Issue number 12
ISSN 1059-7794; 1098-1004
Start page 1665
End page 1675
Total pages 11
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Collection year 2013
Language eng
Formatted abstract Mutations in the BRCA1 gene confer a substantial increase in breast cancer risk yet routine clinical genetic screening is limited to the coding regions and intron-exon boundaries, precluding the identification of mutations in non-coding and untranslated (UTR) regions. As 3′UTR mutations can influence cancer susceptibility by altering protein and microRNA (miRNA) binding regions, we screened the BRCA1 3′UTR for mutations in a large series of BRCA-mutation negative, population and clinic-based breast cancer cases and controls. Fifteen novel BRCA1 3′UTR variants were identified, the majority of which were unique to either cases or controls. Using luciferase reporter assays, three variants found in cases, c.*528G>C, c.*718A>G, and c.*1271T>C and four found in controls, c.*309T>C, c.*379G>A, c.*823C>T and c.*264C>T, reduced 3′UTR activity (p = <0.02), whereas two variants found in cases, c.*291C>T and c.*1139G>T, increased 3′UTR activity (p = < 0.01). Three case variants, c.*718A>G, c.*800T>C and c.*1340_1342delTGT, were predicted to create new miRNA binding sites and c.*1340_1342delTGT caused a reduction (25%, p = 0.0007) in 3′UTR reporter activity when co-expressed with the predicted targeting miRNA, miR-103. This is the most comprehensive identification and analysis of BRCA1 3′UTR variants published to date.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Thu, 05 Jul 2012, 10:31:39 EST by Lucy O'Brien on behalf of School of Chemistry & Molecular Biosciences