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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
Author(s) -
Brewster Brooke L.,
Rossiello Francesca,
French Juliet D.,
Edwards Stacey L.,
Wong Ming,
Wronski Ania,
Whiley Phillip,
Waddell Nic,
Chen Xiaowei,
Bove Betsy,
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
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22159
Subject(s) - biology , three prime untranslated region , untranslated region , genetics , exon , breast cancer , mutation , microrna , coding region , microbiology and biotechnology , gene , cancer , messenger rna
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 noncoding and untranslated regions (UTR). 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 coexpressed with the predicted targeting miRNA, miR‐103 . This is the most comprehensive identification and analysis of BRCA1 3′UTR variants published to date. Hum Mutat 33:1665–1675, 2012. © 2012 Wiley Periodicals, Inc.