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Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11

(2018) HUMAN MUTATION. 39(4). p.515-526
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Abstract
For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programs was evaluated. Aberrant splicing was confirmed for 12 alterations. In silico prediction tools were helpful to determine for which variants cDNA analysis is warranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5 breakpoint in intron 4; 3 breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G>C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies.
Keywords
alternative splicing, BRCA1/2, cDNA analysis, in silico prediction tools, learning algorithms, UNCERTAIN SIGNIFICANCE, FUNCTIONAL-ANALYSIS, SEQUENCE VARIANTS, UNCLASSIFIED VARIANTS, INTEGRATED EVALUATION, MOLECULAR DIAGNOSIS, PREDICTION, MUTATIONS, ENHANCERS, NONSENSE

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Citation

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Chicago
Baert, Annelot, Eva Machackova, Ilse Coene, Carol Cremin, Kristin Turner, Cheryl Portigal-Todd, Marie Jill Asrat, et al. 2018. “Thorough in Silico and in Vitro cDNA Analysis of 21 Putative BRCA1 and BRCA2 Splice Variants and a Complex Tandem Duplication in BRCA2 Allowing the Identification of Activated Cryptic Splice Donor Sites in BRCA2 Exon 11.” Human Mutation 39 (4): 515–526.
APA
Baert, Annelot, Machackova, E., Coene, I., Cremin, C., Turner, K., Portigal-Todd, C., Asrat, M. J., et al. (2018). Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11. HUMAN MUTATION, 39(4), 515–526.
Vancouver
1.
Baert A, Machackova E, Coene I, Cremin C, Turner K, Portigal-Todd C, et al. Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11. HUMAN MUTATION. 2018;39(4):515–26.
MLA
Baert, Annelot, Eva Machackova, Ilse Coene, et al. “Thorough in Silico and in Vitro cDNA Analysis of 21 Putative BRCA1 and BRCA2 Splice Variants and a Complex Tandem Duplication in BRCA2 Allowing the Identification of Activated Cryptic Splice Donor Sites in BRCA2 Exon 11.” HUMAN MUTATION 39.4 (2018): 515–526. Print.
@article{8551696,
  abstract     = {For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programs was evaluated. Aberrant splicing was confirmed for 12 alterations. In silico prediction tools were helpful to determine for which variants cDNA analysis is warranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5 breakpoint in intron 4; 3 breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G{\textrangle}C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies.},
  author       = {Baert, Annelot and Machackova, Eva and Coene, Ilse and Cremin, Carol and Turner, Kristin and Portigal-Todd, Cheryl and Asrat, Marie Jill and Nuk, Jennifer and Mindlin, Allison and Young, Sean and MacMillan, Andree and Van Maerken, Tom and Trbusek, Martin and McKinnon, Wendy and Wood, Marie E and Foulkes, William D and Santamari{\~n}a, Marta and de la Hoya, Miguel and Foretova, Lenka and Poppe, Bruce and Vral, Anne and Rosseel, Toon and De Leeneer, Kim and Vega, Ana and Claes, Kathleen},
  issn         = {1059-7794},
  journal      = {HUMAN MUTATION},
  keyword      = {alternative splicing,BRCA1/2,cDNA analysis,in silico prediction tools,learning algorithms,UNCERTAIN SIGNIFICANCE,FUNCTIONAL-ANALYSIS,SEQUENCE VARIANTS,UNCLASSIFIED VARIANTS,INTEGRATED EVALUATION,MOLECULAR DIAGNOSIS,PREDICTION,MUTATIONS,ENHANCERS,NONSENSE},
  language     = {eng},
  number       = {4},
  pages        = {515--526},
  title        = {Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11},
  url          = {http://dx.doi.org/10.1002/humu.23390},
  volume       = {39},
  year         = {2018},
}

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