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Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance

Highly penetrant variants of BRCA1/2 genes are involved in hereditary predisposition to breast and ovarian cancer. The detection of pathogenic BRCA variants has a considerable clinical impact, allowing appropriate cancer-risk management. However, a major drawback is represented by the identification...

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Autores principales: Gelli, Elisa, Colombo, Mara, Pinto, Anna Maria, De Vecchi, Giovanna, Foglia, Claudia, Amitrano, Sara, Morbidoni, Valeria, Imperatore, Valentina, Manoukian, Siranoush, Baldassarri, Margherita, Lo Rizzo, Caterina, Catania, Lorenza, Frullanti, Elisa, Tagliafico, Enrico, Cortesi, Laura, Spaggiari, Federica, Mencarelli, Maria Antonietta, Trevisson, Eva, Radice, Paolo, Renieri, Alessandra, Ariani, Francesca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468917/
https://www.ncbi.nlm.nih.gov/pubmed/30832263
http://dx.doi.org/10.3390/cancers11030295
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author Gelli, Elisa
Colombo, Mara
Pinto, Anna Maria
De Vecchi, Giovanna
Foglia, Claudia
Amitrano, Sara
Morbidoni, Valeria
Imperatore, Valentina
Manoukian, Siranoush
Baldassarri, Margherita
Lo Rizzo, Caterina
Catania, Lorenza
Frullanti, Elisa
Tagliafico, Enrico
Cortesi, Laura
Spaggiari, Federica
Mencarelli, Maria Antonietta
Trevisson, Eva
Radice, Paolo
Renieri, Alessandra
Ariani, Francesca
author_facet Gelli, Elisa
Colombo, Mara
Pinto, Anna Maria
De Vecchi, Giovanna
Foglia, Claudia
Amitrano, Sara
Morbidoni, Valeria
Imperatore, Valentina
Manoukian, Siranoush
Baldassarri, Margherita
Lo Rizzo, Caterina
Catania, Lorenza
Frullanti, Elisa
Tagliafico, Enrico
Cortesi, Laura
Spaggiari, Federica
Mencarelli, Maria Antonietta
Trevisson, Eva
Radice, Paolo
Renieri, Alessandra
Ariani, Francesca
author_sort Gelli, Elisa
collection PubMed
description Highly penetrant variants of BRCA1/2 genes are involved in hereditary predisposition to breast and ovarian cancer. The detection of pathogenic BRCA variants has a considerable clinical impact, allowing appropriate cancer-risk management. However, a major drawback is represented by the identification of variants of uncertain significance (VUS). Many VUS potentially affect mRNA splicing, making transcript analysis an essential step for the definition of their pathogenicity. Here, we characterize the impact on splicing of ten BRCA1/2 variants. Aberrant splicing patterns were demonstrated for eight variants whose alternative transcripts were fully characterized. Different events were observed, including exon skipping, intron retention, and usage of de novo and cryptic splice sites. Transcripts with premature stop codons or in-frame loss of functionally important residues were generated. Partial/complete splicing effect and quantitative contribution of different isoforms were assessed, leading to variant classification according to Evidence-based Network for the Interpretation of Mutant Alleles (ENIGMA) consortium guidelines. Two variants could be classified as pathogenic and two as likely benign, while due to a partial splicing effect, six variants remained of uncertain significance. The association with an undefined tumor risk justifies caution in recommending aggressive risk-reduction treatments, but prevents the possibility of receiving personalized therapies with potential beneficial effect. This indicates the need for applying additional approaches for the analysis of variants resistant to classification by gene transcript analyses.
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spelling pubmed-64689172019-04-23 Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance Gelli, Elisa Colombo, Mara Pinto, Anna Maria De Vecchi, Giovanna Foglia, Claudia Amitrano, Sara Morbidoni, Valeria Imperatore, Valentina Manoukian, Siranoush Baldassarri, Margherita Lo Rizzo, Caterina Catania, Lorenza Frullanti, Elisa Tagliafico, Enrico Cortesi, Laura Spaggiari, Federica Mencarelli, Maria Antonietta Trevisson, Eva Radice, Paolo Renieri, Alessandra Ariani, Francesca Cancers (Basel) Article Highly penetrant variants of BRCA1/2 genes are involved in hereditary predisposition to breast and ovarian cancer. The detection of pathogenic BRCA variants has a considerable clinical impact, allowing appropriate cancer-risk management. However, a major drawback is represented by the identification of variants of uncertain significance (VUS). Many VUS potentially affect mRNA splicing, making transcript analysis an essential step for the definition of their pathogenicity. Here, we characterize the impact on splicing of ten BRCA1/2 variants. Aberrant splicing patterns were demonstrated for eight variants whose alternative transcripts were fully characterized. Different events were observed, including exon skipping, intron retention, and usage of de novo and cryptic splice sites. Transcripts with premature stop codons or in-frame loss of functionally important residues were generated. Partial/complete splicing effect and quantitative contribution of different isoforms were assessed, leading to variant classification according to Evidence-based Network for the Interpretation of Mutant Alleles (ENIGMA) consortium guidelines. Two variants could be classified as pathogenic and two as likely benign, while due to a partial splicing effect, six variants remained of uncertain significance. The association with an undefined tumor risk justifies caution in recommending aggressive risk-reduction treatments, but prevents the possibility of receiving personalized therapies with potential beneficial effect. This indicates the need for applying additional approaches for the analysis of variants resistant to classification by gene transcript analyses. MDPI 2019-03-01 /pmc/articles/PMC6468917/ /pubmed/30832263 http://dx.doi.org/10.3390/cancers11030295 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gelli, Elisa
Colombo, Mara
Pinto, Anna Maria
De Vecchi, Giovanna
Foglia, Claudia
Amitrano, Sara
Morbidoni, Valeria
Imperatore, Valentina
Manoukian, Siranoush
Baldassarri, Margherita
Lo Rizzo, Caterina
Catania, Lorenza
Frullanti, Elisa
Tagliafico, Enrico
Cortesi, Laura
Spaggiari, Federica
Mencarelli, Maria Antonietta
Trevisson, Eva
Radice, Paolo
Renieri, Alessandra
Ariani, Francesca
Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance
title Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance
title_full Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance
title_fullStr Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance
title_full_unstemmed Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance
title_short Usefulness and Limitations of Comprehensive Characterization of mRNA Splicing Profiles in the Definition of the Clinical Relevance of BRCA1/2 Variants of Uncertain Significance
title_sort usefulness and limitations of comprehensive characterization of mrna splicing profiles in the definition of the clinical relevance of brca1/2 variants of uncertain significance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468917/
https://www.ncbi.nlm.nih.gov/pubmed/30832263
http://dx.doi.org/10.3390/cancers11030295
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