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Calibration of pathogenicity due to variant-induced leaky splicing defects by using BRCA2 exon 3 as a model system

  1. Author:
    Tubeuf, Hélène [ORCID]
    Caputo, Sandrine M [ORCID]
    Sullivan,Teresa
    Rondeaux, Julie
    Krieger, Sophie
    Caux-Moncoutier, Virginie
    Hauchard, Julie
    Castelain, Gaia
    Fiévet, Alice [ORCID]
    Meulemans, Laëtitia
    Révillion, Françoise
    Léone, Mélanie
    Boutry-Kryza, Nadia
    Delnatte, Capucine
    Guillaud-Bataille, Marine
    Cleveland, Linda
    Reid,Susan
    Southon,Eileen
    Soukarieh, Omar [ORCID]
    Drouet, Aurélie
    Di Giacomo, Daniela [ORCID]
    Vezain, Myriam
    Bonnet-Dorion, Françoise
    Bourdon, Violaine
    Larbre, Hélène
    Muller, Danièle
    Pujol, Pascal
    Vaz, Fátima
    Audebert-Bellanger, Séverine
    Colas, Chrystelle
    Venat-Bouvet, Laurence [ORCID]
    Solano, Angela R
    Stoppa-Lyonnet, Dominique [ORCID]
    Houdayer, Claude
    Frebourg, Thierry
    Gaildrat, Pascaline
    Sharan, Shyam K [ORCID]
    Martins, Alexandra [ORCID]

  2. Author Address

    Inserm U1245, Universit 233; de Rouen., Department of Genetics, Institut Curie, PSL Research University., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA., Inserm U1245, Normandie Univ, UNIROUEN, Inserm U1245, Normandy Centre for Genomic and Personalized Medicine., Laboratoire de Biologie et G 233;n 233;tique du Cancer, Centre Fran 231;ois Baclesse., Service G 233;n 233;tique des Tumeurs, Institut Gustave Roussy., Laboratoire d 39;Oncologie Mol 233;culaire Humaine, Centre Oscar Lambret., Hospices Civils de Lyon., Department of Genetics, Nantes University Hospital., Department of Genetics, Institut Gustave Roussy., Mouse Cancer Genetics Program, Center for Cancer Research,, National Cancer Institute., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, US., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702., Department of Experimental Medicine, University of L 39;Aquila., IRIB Genomics Facility, Institute for Research and Innovation in Biomedicine-University of Rouen., Inserm U916, Department of Genetics, Institut Bergoni 233;., Department of Genetics, Institut Paoli-Calmettes., Biopoatholgy, Laboratoire d 39;Oncog 233;n 233;tique Mol 233;culaire, Institut Godinot., Laboratoire d 39;oncog 233;n 233;tique, Centre Paul Strauss., Service de G 233;n 233;tique m 233;dicale et Oncog 233;n 233;tique, CHU Arnaud de Villeneuve Montpellier., Breast Cancer Risk Evaluation Clinic, Portuguese Institute of Oncology of Lisbon, 1099-023., H 244;pital Morvan, CHU Brest., CdR Saint-Antoine, INSERM-UPMC, UMRS_938., Department of Medical Oncology, Centre Hospitalier Universitaire Dupuytren., INBIOMED, Fac of Medicine, University of Buenos Aires., Genetics department, Institute Curie., Normandie Univ, UNIROUEN, Inserm U1245, Normandy Centre for Genomic and Personalized Medicine, Department of Genetics, Institut Curie,Department of Genetics, Rouen University Hospital., Inserm U1245 and Department of Genetics, Inserm and University Hospital., Mouse Cancer Genetics Program, National Cancer Institute., Inserm U1245, Normandie Univ, UNIROUEN, Inserm U1245, Normandy Centre for Genomic and Personalized Medicine alexandra.martins@univ-rouen.fr.,
    1. Year: 2020
    2. Date: SEP 1
    3. Epub Date: 2020 07 08
  2. Journal: Cancer research
    1. 80
    2. 17
    3. Pages: 3593-3605
  4. Type of Article: Article
  5. ISSN: 0008-5472
  1. Abstract:

    BRCA2 is a clinically actionable gene implicated in breast and ovarian cancer predisposition that has become a high priority target for improving the classification of variants of unknown significance (VUS). Amongst all BRCA2 VUS, those causing partial/leaky splicing defects are the most challenging to classify because the minimal level of full-length transcripts (FL) required for normal function remains to be established. Here, we explored BRCA2 exon 3 (BRCA2e3) as a model for calibrating variant-induced spliceogenicity and estimating thresholds for BRCA2 haploinsufficiency. In silico predictions, minigene splicing assays, patients' RNA analyses, a mouse embryonic stem cell (mESC) complementation assay and retrieval of patient-related information were combined to determine the minimal requirement of FL BRCA2 transcripts. Of 100 BRCA2e3 variants tested in the minigene assay, 64 were found to be spliceogenic causing mild to severe RNA defects. Splicing defects were also confirmed in patients' RNA when available. Analysis of a neutral leaky variant (c.231T>G) showed that a reduction to ~60% of FL BRCA2 transcripts from a mutant allele does not cause any increase in cancer risk. Moreover, data obtained from mESCs suggest that variants causing a decline in FL BRCA2 to ~30% of wild-type are not pathogenic given that mESCs are fully viable and resistant to DNA-damaging agents in those conditions. In contrast, mESCs producing lower relative amounts of FL BRCA2 exhibited either null or hypomorphic phenotypes. Overall, our findings are likely to have broader implications on the interpretation of BRCA2 variants affecting the splicing pattern of other essential exons. Copyright ©2020, American Association for Cancer Research.

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External Sources

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  2. DOI: 10.1158/0008-5472.CAN-20-0895
  3. PMID: 32641407
  4. View record in Web of Science®
  5. WOS: 000567796800016
  6. PII : 0008-5472.CAN-20-0895

Library Notes

  1. Fiscal Year: FY2019-2020
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