Identification of a novel disease-associated variant in the BRCA1 3’UTR that introduces a functional miR-103 target site

Brewster, B.; Rossiello, Francesca; French, J. D.; Sl, Edwards; Em, Wong; Whiley, Phillip J.; Waddell, Nicola; Chen, X; Bove, Betsy; Spurdle, A.B.; Radice, Paolo; Godwin, AK; Southey, MC; Brown, Matthew A.; Peterlongo, Paolo

doi:10.1186/1897-4287-10-s2-a88

Cited by 13 publications

(18 citation statements)

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“…In addition, Brewster et al, (2012) found two common heterozygous polymorphisms, rs8176318 (c.*421G>T) and rs12516 (c.*1287C>T), in the 3'UTR of BRCA1. To determine whether any of the combinations of common BRCA1 3'UTR SNPs identified in the Fox Chase Cancer Center breast cancer cases displaying differential allelic expression of BRCA1 were likely to affect gene expression, each of the alternate BRCA1 3'UTR alleles were assayed for regulatory activity.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Genetic Variations in miRNA-Binding Sites of BRCA1 and BRCA2 Genes as Risk Factors for the Development of Early-Onset and/or Familial Breast Cancer

Ertürk¹,

Çeçener²,

Polatkan³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Although genetic markers identifying women at an increased risk of developing breast cancer exist, the majority of inherited risk factors remain elusive. Mutations in the BRCA1/BRCA2 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intronexon boundaries, precluding the identification of mutations in noncoding and untranslated regions. Because 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we aimed to determine genetic variation in the 3'UTR of BRCA1/BRCA2 in familial and early-onset breast cancer patients with and without mutations in the coding regions of BRCA1/ BRCA2 and to identify specific 3'UTR variants that may be risk factors for cancer development. The 3'UTRs of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis and DNA sequencing in 100 patients from 46 BRCA1/2 families, 54 non-BRCA1/2 families, and 47 geographically matched controls. Two polymorphisms were identified. SNPs c.*1287C>T (rs12516) (BRCA1) and c.*105A>C (rs15869) (BRCA2) were identified in 27% and 24% of patients, respectively. These 2 variants were also identified in controls with no family history of cancer (23.4% and 23.4%, respectively). In comparison to variations in the 3'UTR region of the BRCA1/2 genes and the BRCA1/2 mutational status in patients, there was a statistically significant relationship between the BRCA1 gene polymorphism c.*1287C>T (rs12516) and BRCA1 mutations (p=0.035) by Fisher's Exact Test. SNP c.*1287C>T (rs12516) of the BRCA1 gene may have potential use as a genetic marker of an increased risk of developing breast cancer and likely represents a non-coding sequence variation in BRCA1 that impacts BRCA1 function and leads to increased early-onset and/or familial breast cancer risk in the Turkish population.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Genetic Variations in miRNA-Binding Sites of BRCA1 and BRCA2 Genes as Risk Factors for the Development of Early-Onset and/or Familial Breast Cancer

Ertürk¹,

Çeçener²,

Polatkan³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…16,[21][22][23][24][25] The first published studies reported two variants: c.*36C4G, identified while screening 211 breast cancer cases, 22 and c.*372_387del16 while screening 78 breast cancer cases belonging to high-risk breast and ovarian cancer families. 25 Pietschmann et al screened BRCA1/BRCA2 coding sequences and 5ʹ-and 3ʹ-UTRs in 10 Iranian high-risk breast cancer families.…”

Section: Discussionmentioning

confidence: 99%

“…16 Brewster et al reported the largest study to date, with the screening of 1612 breast cancer cases and 1554 controls, sourced from five collections, and identified 23 rare variants, of which 15 were novel. 21 Using luciferase reporter assays and bioinformatics predictions, they were able to show that c.*1340_1342delTGT introduces a functional miR-103 target site and might be therefore pathogenic. 21 Data are much scarcer concerning the 3ʹ-UTR of BRCA2, as we are aware of only one small study published so far in 10 Iranian high-risk breast cancer families, 23 and 1 study performed on 100 Turkish earlyonset or familial breast cancer, 26 which both did not lead to the identification of any rare variant.…”

Section: Discussionmentioning

confidence: 99%

“…21 Using luciferase reporter assays and bioinformatics predictions, they were able to show that c.*1340_1342delTGT introduces a functional miR-103 target site and might be therefore pathogenic. 21 Data are much scarcer concerning the 3ʹ-UTR of BRCA2, as we are aware of only one small study published so far in 10 Iranian high-risk breast cancer families, 23 and 1 study performed on 100 Turkish earlyonset or familial breast cancer, 26 which both did not lead to the identification of any rare variant. Our study is thus the first to report the screening of this region in a large series, which showed that 3ʹ-UTR variants are extremely rare in BRCA2 (only one variant found, c. *172G4A).…”

Section: Discussionmentioning

confidence: 99%

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Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

et al. 2016

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Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3ʹ-untranslated regions (3ʹ-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1-and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3ʹ-UTR and one in BRCA2 3ʹ-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3ʹ-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3ʹ-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.

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“…MCF7 breast cancer-derived cells seeded in 24-well plates were transfected with both the reporter plasmid and a transfection control plasmid containing a Renilla reporter sequence (pRL-TK; Promega) using Lipofectamine 3000 (Life Technologies, CA, USA). Luciferase activity was measured after 48 h [3] and relative activities of the variant BRCA1 promoters were compared to the activity of the WT BRCA1 promoter. Biological replicates were generated using independent batches of cells cultured and transfected at separate times with independently prepared sets of plasmids.…”

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confidence: 99%

Caution: Plasmid DNA topology affects luciferase assay reproducibility and outcomes

et al. 2019

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Identification of a novel disease-associated variant in the BRCA1 3’UTR that introduces a functional miR-103 target site

Cited by 13 publications

References 0 publications

Evaluation of Genetic Variations in miRNA-Binding Sites of BRCA1 and BRCA2 Genes as Risk Factors for the Development of Early-Onset and/or Familial Breast Cancer

Evaluation of Genetic Variations in miRNA-Binding Sites of BRCA1 and BRCA2 Genes as Risk Factors for the Development of Early-Onset and/or Familial Breast Cancer

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

Caution: Plasmid DNA topology affects luciferase assay reproducibility and outcomes

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