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BMC Cancer
Published in: BMC Cancer 1/2009

Open Access 01-12-2009 | Research article

Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2French Canadian families with high risk of breast cancer

Authors: Sylvie Desjardins, Joly Charles Beauparlant, Yvan Labrie, Geneviève Ouellette, Francine Durocher, INHERIT BRCAs

Published in: BMC Cancer | Issue 1/2009

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Abstract

Background

The Nijmegen Breakage Syndrome is a chromosomal instability disorder characterized by microcephaly, growth retardation, immunodeficiency, and increased frequency of cancers. Familial studies on relatives of these patients indicated that they also appear to be at increased risk of cancer.

Methods

In a candidate gene study aiming at identifying genetic determinants of breast cancer susceptibility, we undertook the full sequencing of the NBN gene in our cohort of 97 high-risk non-BRCA1 and -BRCA2 breast cancer families, along with 74 healthy unrelated controls, also from the French Canadian population. In silico programs (ESEfinder, NNSplice, Splice Site Finder and MatInspector) were used to assess the putative impact of the variants identified. The effect of the promoter variant was further studied by luciferase gene reporter assay in MCF-7, HEK293, HeLa and LNCaP cell lines.

Results

Twenty-four variants were identified in our case series and their frequency was further evaluated in healthy controls. The potentially deleterious p.Ile171Val variant was observed in one case only. The p.Arg215Trp variant, suggested to impair NBN binding to histone γ-H2AX, was observed in one breast cancer case and one healthy control. A promoter variant c.-242-110delAGTA displayed a significant variation in frequency between both sample sets. Luciferase reporter gene assay of the promoter construct bearing this variant did not suggest a variation of expression in the MCF-7 breast cancer cell line, but indicated a reduction of luciferase expression in both the HEK293 and LNCaP cell lines.

Conclusion

Our analysis of NBN sequence variations indicated that potential NBN alterations are present, albeit at a low frequency, in our cohort of high-risk breast cancer cases. Further analyses will be needed to fully ascertain the exact impact of those variants on breast cancer susceptibility, in particular for variants located in NBN promoter region.
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Metadata
Title
Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2French Canadian families with high risk of breast cancer
Authors
Sylvie Desjardins
Joly Charles Beauparlant
Yvan Labrie
Geneviève Ouellette
Francine Durocher
INHERIT BRCAs
Publication date
01-12-2009
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2009
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-9-181

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