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Characterization of the c.190T > C missense mutation in BRCA1 codon 64 (Cys64Arg)

(2009) INTERNATIONAL JOURNAL OF ONCOLOGY. 34(4). p.1005-1015
Author
Organization
Abstract
In the Milan area (Northern Italy), we identified a family characterized by a high prevalence of ovarian and breast cancer cases (5 out of 6 subjects, over 3 generations), and a predominant prevalence of ovarian lesions (4 out of 5 patients). Analysis of BRCA1 and BRCA2 genes allowed the identification of the missense c.190T>C mutation in codon 64 (Cys64Arg) of BRCA1. The aims of the present investigation were to characterize the functional implications of the c.190T>C mutation at the molecular level, and to search whether additional polymorphisms might be linked to the peculiar phenotypic features observed in the Italian pedigree. Molecular modelling studies suggested that substitution of the cysteine 64 with an arginine likely disrupts the architecture of the BRCA1 RING finger domain, responsible for the interaction with BARD1, essential for the tumor-suppressor activity of the BRCA1-BARD1 complex. By splicing site information analysis, exonic splicing enhancer site characterization, and analysis of transcript fragment length and sequence, we showed that the c.190T>C mutation was able to modulate the splicing of exon 5 in a fashion opposite to the c.190T>G transversion, responsible for the functionally-related Cys64Gly amino acid substitution. Genotyping of BRCA1 and BRCA2 in the Italian family revealed the presence of two significant polymorphisms: the cancer-associated c.2612C>T SNP in BRCA1, and the c.-26G>A SNP in the BRCA2 gene, acting as an ovarian cancer risk modifier in carriers of deleterious BRCA1 mutations. Analysis of these SNPs in a genotypically-unrelated Polish family, characterized by prevalent breast neoplasms in carriers of the c.190T>C mutation, revealed a genetic profile consistent with the hypothetic role of both polymorphisms.
Keywords
BREAST-CANCER, OVARIAN-CANCER, GERMLINE MUTATIONS, SEQUENCE VARIANTS, UBIQUITIN LIGASE, FAMILIES, GENE, BRCA1-BARD1, RISK, PROTEINS

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MLA
Willems, Petra et al. “Characterization of the c.190T > C Missense Mutation in BRCA1 Codon 64 (Cys64Arg).” INTERNATIONAL JOURNAL OF ONCOLOGY 34.4 (2009): 1005–1015. Print.
APA
Willems, Petra, Magri, V., Cretnik, M., Fasano, M., Jakubowska, A., Levanat, S., Lubinski, J., et al. (2009). Characterization of the c.190T > C missense mutation in BRCA1 codon 64 (Cys64Arg). INTERNATIONAL JOURNAL OF ONCOLOGY, 34(4), 1005–1015.
Chicago author-date
Willems, Petra, V. Magri, M. Cretnik, M. Fasano, A. Jakubowska, S. Levanat, J. Lubinski, et al. 2009. “Characterization of the c.190T > C Missense Mutation in BRCA1 Codon 64 (Cys64Arg).” International Journal of Oncology 34 (4): 1005–1015.
Chicago author-date (all authors)
Willems, Petra, V. Magri, M. Cretnik, M. Fasano, A. Jakubowska, S. Levanat, J. Lubinski, E. Maras, V. Musani, Hubert Thierens, Veerle Vandersickel, Gianpaolo Perletti, and Anne Vral. 2009. “Characterization of the c.190T > C Missense Mutation in BRCA1 Codon 64 (Cys64Arg).” International Journal of Oncology 34 (4): 1005–1015.
Vancouver
1.
Willems P, Magri V, Cretnik M, Fasano M, Jakubowska A, Levanat S, et al. Characterization of the c.190T > C missense mutation in BRCA1 codon 64 (Cys64Arg). INTERNATIONAL JOURNAL OF ONCOLOGY. 2009;34(4):1005–15.
IEEE
[1]
P. Willems et al., “Characterization of the c.190T > C missense mutation in BRCA1 codon 64 (Cys64Arg),” INTERNATIONAL JOURNAL OF ONCOLOGY, vol. 34, no. 4, pp. 1005–1015, 2009.
@article{715111,
  abstract     = {{In the Milan area (Northern Italy), we identified a family characterized by a high prevalence of ovarian and breast cancer cases (5 out of 6 subjects, over 3 generations), and a predominant prevalence of ovarian lesions (4 out of 5 patients). Analysis of BRCA1 and BRCA2 genes allowed the identification of the missense c.190T>C mutation in codon 64 (Cys64Arg) of BRCA1. The aims of the present investigation were to characterize the functional implications of the c.190T>C mutation at the molecular level, and to search whether additional polymorphisms might be linked to the peculiar phenotypic features observed in the Italian pedigree. Molecular modelling studies suggested that substitution of the cysteine 64 with an arginine likely disrupts the architecture of the BRCA1 RING finger domain, responsible for the interaction with BARD1, essential for the tumor-suppressor activity of the BRCA1-BARD1 complex. By splicing site information analysis, exonic splicing enhancer site characterization, and analysis of transcript fragment length and sequence, we showed that the c.190T>C mutation was able to modulate the splicing of exon 5 in a fashion opposite to the c.190T>G transversion, responsible for the functionally-related Cys64Gly amino acid substitution. Genotyping of BRCA1 and BRCA2 in the Italian family revealed the presence of two significant polymorphisms: the cancer-associated c.2612C>T SNP in BRCA1, and the c.-26G>A SNP in the BRCA2 gene, acting as an ovarian cancer risk modifier in carriers of deleterious BRCA1 mutations. Analysis of these SNPs in a genotypically-unrelated Polish family, characterized by prevalent breast neoplasms in carriers of the c.190T>C mutation, revealed a genetic profile consistent with the hypothetic role of both polymorphisms.}},
  author       = {{Willems, Petra and Magri, V. and Cretnik, M. and Fasano, M. and Jakubowska, A. and Levanat, S. and Lubinski, J. and Maras, E. and Musani, V. and Thierens, Hubert and Vandersickel, Veerle and Perletti, Gianpaolo and Vral, Anne}},
  issn         = {{1019-6439}},
  journal      = {{INTERNATIONAL JOURNAL OF ONCOLOGY}},
  keywords     = {{BREAST-CANCER,OVARIAN-CANCER,GERMLINE MUTATIONS,SEQUENCE VARIANTS,UBIQUITIN LIGASE,FAMILIES,GENE,BRCA1-BARD1,RISK,PROTEINS}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{1005--1015}},
  title        = {{Characterization of the c.190T > C missense mutation in BRCA1 codon 64 (Cys64Arg)}},
  url          = {{http://dx.doi.org/10.3892/ijo_00000226}},
  volume       = {{34}},
  year         = {{2009}},
}

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