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Wild-type genotypes of BRCA1 gene SNPs combined with micro-RNA over-expression in mammary tissue leading to familial breast cancer with an increased risk of distant metastases’ occurrence

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Abstract

Germ line deleterious mutations of BRCA1 gene are not the unique factor that could inactivate BRCA1 protein which leads to familial breast cancer onset with distant metastases’ occurrence. The present research explores the role that could be assigned to BRCA1 SNPs to inactivate BRCA1 protein and therefore to the occurrence of familial breast cancer with an increased risk of distant metastases’ occurrence. The presence or the absence of BRCA1 protein was first analyzed by applying the immunohistochemistry technique to the tumors with sporadic and familial breast cancer. Then, a case–control study was conducted including 40 patients with familial breast cancer, 46 ones with sporadic breast cancer and 34 healthy controls based on the genotyping of nine BRCA1 SNPs (c.442.58delT, c.2082C>T, c.2311T>C, c.2612C>T, c.3113A>G, c.3119G>A, c.3548A>G, c.4308T>C and 4837A>G) via direct sequencing. Finally, the functional role that could be assigned to these SNPs was focused upon. miRbase site was used as a bioinformatics tool to predict potential micro-RNAs (miRs) targeting SNPs that are associated with familial breast cancer according to the results of this research. These predicted miRs were confirmed by Q-PCR analysis and correlated with BRCA1 protein expression among patients along with potential distant metastases. Clinical outcome showed that distant metastasis concerned 45 % of familial breast cancer patients and 19.5 % with sporadic breast cancer. Analysis of BRCA1 protein expression revealed a negative staining among 46.6 % of familial breast cancer patients and only 16.6 % within sporadic breast cancer ones. The association of four variants was identified within BRCA1 gene (c.442.58 delT, c.2311T>C, c.2612C>T and c.4308T>C) to familial breast cancer across their wild genotypes. miR-1179 was selected as potential miR that targets the region of BRCA1 mRNA containing the c.2311T>C variant within the TT genotype. The expression of miR-1179 was significantly associated with familial breast cancer patients without BRCA1 deleterious mutations compared to those with sporadic breast cancer according to TT genotype along with BRCA1 negative staining and according to the occurrence of distant metastases. Combination between TT genotype of c.2311T>C and miR-1179 over-expression could generate a lack of BRCA1 protein leading to a high risk of familial breast cancer with distant metastases.

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Abbreviations

FBC:

Familial breast cancer

FFPE:

Formalin-fixed, paraffin-embedded

HC:

Healthy controls

IHC:

Immunohistochemistry

miR:

micro-RNA

Q-PCR:

Quantitative real-time polymerase chain reaction

SBC:

Sporadic breast cancer

SNP:

Simple nucleotide polymorphism

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Acknowledgments

The authors would like to thank all those who have contributed to the realization of this work in Salah Azaiz Institute of Tunis, Laboratory of Genetic Immunology and Human Pathology, Laboratory of Genetics and Molecular Diagnostic “LOM” in Clermont-Ferrand and in Laboratory of Molecular screening in breast cancer in Montreal for their technical assistance.

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Laboratory of Genetics, Immunology and Human Pathology, Department of Biology, Faculty of Sciences of Tunis, University of Tunis El Manar, Campus Universitaire, 2092, Tunis, Tunisia

    Imen Medimegh, Wafa Troudi, Nejla Stambouli, Houssein Khodjet-El-Khil, Olfa Baroudi, Hajer Ayari, Ines Omrane & Amel Benammar Elgaaied

  2. Salah Azaiez Institute of Carcinology of Tunis, Tunis, Tunisia

    Amel Mezlini, Farhat Ben Ayed & Khaled Ben Romdhane

  3. Laboratory of Genetics and Molecular Diagnostic, Centre Jean Perrin, Clermont-Ferrand, France

    Nancy Uhrhammer, Maud Privat & Yve Jean Bignon

  4. Laboratory of Molecular Screening in the Treatment of Breast Cancer in Immunology and Cancer Research Institute, Montreal University, Montreal, Canada

    Sylvie Mader

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  1. Imen Medimegh
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  2. Wafa Troudi
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  3. Nejla Stambouli
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  7. Ines Omrane
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  10. Amel Mezlini
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  11. Farhat Ben Ayed
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  12. Khaled Ben Romdhane
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  13. Sylvie Mader
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  14. Yve Jean Bignon
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  15. Amel Benammar Elgaaied
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Corresponding author

Correspondence to Imen Medimegh.

Additional information

Wafa Troudi and Nejla Stambouli have equally contributed this work.

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Medimegh, I., Troudi, W., Stambouli, N. et al. Wild-type genotypes of BRCA1 gene SNPs combined with micro-RNA over-expression in mammary tissue leading to familial breast cancer with an increased risk of distant metastases’ occurrence. Med Oncol 31, 255 (2014). https://doi.org/10.1007/s12032-014-0255-6

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  • DOI: https://doi.org/10.1007/s12032-014-0255-6

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