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BRCA1 and BRCA2 5′ noncoding region variants identified in breast cancer patients alter promoter activity and protein binding

(2018) HUMAN MUTATION. 39(12). p.2025-2039
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Abstract
The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5 ' noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC.
Keywords
breast cancer, BRCA1, BRCA2, promoter, transcription, variants of unknown clinical significance (VUS), OVARIAN-CANCER, REGULATORY ELEMENTS, GERMLINE VARIANTS, GENE-EXPRESSION, RISK, SUSCEPTIBILITY, TRANSCRIPTION, ASSOCIATION, MUTATIONS, COMPLEX

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MLA
Burke, Leslie J, Jan Sevcik, Gaetana Gambino, et al. “BRCA1 and BRCA2 5′ Noncoding Region Variants Identified in Breast Cancer Patients Alter Promoter Activity and Protein Binding.” HUMAN MUTATION 39.12 (2018): 2025–2039. Print.
APA
Burke, L. J., Sevcik, J., Gambino, G., Tudini, E., Mucaki, E. J., Shirley, B. C., Whiley, P., et al. (2018). BRCA1 and BRCA2 5′ noncoding region variants identified in breast cancer patients alter promoter activity and protein binding. HUMAN MUTATION, 39(12), 2025–2039.
Chicago author-date
Burke, Leslie J, Jan Sevcik, Gaetana Gambino, Emma Tudini, Eliseos J Mucaki, Ben C Shirley, Phillip Whiley, et al. 2018. “BRCA1 and BRCA2 5′ Noncoding Region Variants Identified in Breast Cancer Patients Alter Promoter Activity and Protein Binding.” Human Mutation 39 (12): 2025–2039.
Chicago author-date (all authors)
Burke, Leslie J, Jan Sevcik, Gaetana Gambino, Emma Tudini, Eliseos J Mucaki, Ben C Shirley, Phillip Whiley, Michael T Parsons, Kim De Leeneer, Sara Gutiérrez-Enríquez, Marta Santamariña, Sandrine M Caputo, Elizabeth Santana dos Santos, Jana Soukupova, Marketa Janatova, Petra Zemankova, Klara Lhotova, Lenka Stolarova, Mariana Borecka, Alejandro Moles-Fernández, Siranoush Manoukian, Bernardo Bonanni, Stacey L Edwards, Marinus J Blok, Thomas van Overeem Hansen, Maria Rossing, Orland Diez, Ana Vega, Kathleen Claes, David E Goldgar, Etienne Rouleau, Paolo Radice, Paolo Peterlongo, Peter K Rogan, Maria Caligo, Amanda B Spurdle, and Melissa A Brown. 2018. “BRCA1 and BRCA2 5′ Noncoding Region Variants Identified in Breast Cancer Patients Alter Promoter Activity and Protein Binding.” Human Mutation 39 (12): 2025–2039.
Vancouver
1.
Burke LJ, Sevcik J, Gambino G, Tudini E, Mucaki EJ, Shirley BC, et al. BRCA1 and BRCA2 5′ noncoding region variants identified in breast cancer patients alter promoter activity and protein binding. HUMAN MUTATION. 2018;39(12):2025–39.
IEEE
[1]
L. J. Burke et al., “BRCA1 and BRCA2 5′ noncoding region variants identified in breast cancer patients alter promoter activity and protein binding,” HUMAN MUTATION, vol. 39, no. 12, pp. 2025–2039, 2018.
@article{8582476,
  abstract     = {The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5 ' noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC.},
  author       = {Burke, Leslie J and Sevcik, Jan and Gambino, Gaetana and Tudini, Emma and Mucaki, Eliseos J and Shirley, Ben C and Whiley, Phillip and Parsons, Michael T and De Leeneer, Kim and Gutiérrez-Enríquez, Sara and Santamariña, Marta and Caputo, Sandrine M and Santana dos Santos, Elizabeth and Soukupova, Jana and Janatova, Marketa and Zemankova, Petra and Lhotova, Klara and Stolarova, Lenka and Borecka, Mariana and Moles-Fernández, Alejandro and Manoukian, Siranoush and Bonanni, Bernardo and Edwards, Stacey L and Blok, Marinus J and van Overeem Hansen, Thomas and Rossing, Maria and Diez, Orland and Vega, Ana and Claes, Kathleen and Goldgar, David E and Rouleau, Etienne and Radice, Paolo and Peterlongo, Paolo and Rogan, Peter K and Caligo, Maria and Spurdle, Amanda B and Brown, Melissa A},
  issn         = {1059-7794},
  journal      = {HUMAN MUTATION},
  keywords     = {breast cancer,BRCA1,BRCA2,promoter,transcription,variants of unknown clinical significance (VUS),OVARIAN-CANCER,REGULATORY ELEMENTS,GERMLINE VARIANTS,GENE-EXPRESSION,RISK,SUSCEPTIBILITY,TRANSCRIPTION,ASSOCIATION,MUTATIONS,COMPLEX},
  language     = {eng},
  number       = {12},
  pages        = {2025--2039},
  title        = {BRCA1 and BRCA2 5′ noncoding region variants identified in breast cancer patients alter promoter activity and protein binding},
  url          = {http://dx.doi.org/10.1002/humu.23652},
  volume       = {39},
  year         = {2018},
}

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