Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2 French Canadian families with high risk of breast cancer.
Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2 French Canadian families with high risk of breast cancer.
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DOI：
10.1186/1471-2407-9-181
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发表时间：
2009-06-12
期刊：
影响因子：
3.8
通讯作者：
INHERIT BRCAs
中科院分区：
文献类型：
--
作者：
Desjardins S;Beauparlant JC;Labrie Y;Ouellette G;Durocher F;INHERIT BRCAs
奈梅亨断裂综合征是一种染色体不稳定疾病，其特征是小头畸形、生长迟缓、免疫缺陷和癌症发病率增加。对这些患者亲属的家族研究表明，他们患癌症的风险似乎也增加。在一项旨在确定乳腺癌易感性遗传决定因素的候选基因研究中，我们对 97 个高风险非 BRCA1 和 -BRCA2 乳腺癌家族以及 74 个健康的无关对照（也来自法裔加拿大人群）的 NBN 基因进行了全面测序。使用计算机程序（ESEfinder、NNSplice、Splice Site Finder 和 MatInspector）来评估已识别变体的假定影响。通过荧光素酶基因报告测定在 MCF-7、HEK293、HeLa 和 LNCaP 细胞系中进一步研究了启动子变体的作用。我们的病例系列中发现了 24 种变异，并在健康对照中进一步评估了它们的频率。仅在一个案例中观察到潜在有害的 p.Ile171Val 变异。在一名乳腺癌病例和一名健康对照中观察到 p.Arg215Trp 变异，表明该变异会损害 NBN 与组蛋白 γ-H2AX 的结合。启动子变体 c.-242-110delAGTA 在两个样本组之间显示出显着的频率变化。对带有该变体的启动子构建体进行的荧光素酶报告基因分析并未表明 MCF-7 乳腺癌细胞系中的表达发生变化，但表明 HEK293 和 LNCaP 细胞系中的荧光素酶表达均减少。我们对 NBN 序列变异的分析表明，在我们的高风险乳腺癌病例队列中，存在潜在的 NBN 改变，尽管频率较低。需要进一步分析来充分确定这些变异对乳腺癌易感性的确切影响，特别是位于 NBN 启动子区域的变异。
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. 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. 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. 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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影响因子：
14.9
作者：
Cartegni, L;Wang, JH;Krainer, AR
通讯作者：
Krainer, AR
影响因子：
7
作者：
Cheung, Vivian G.;Ewens, Warren J.
通讯作者：
Ewens, Warren J.
影响因子：
2.6
作者：
Miura, Y;Kataoka, H;Okada, H
通讯作者：
Okada, H
影响因子：
4.7
作者：
Figueroa, Jonine D.;Malats, Nuria;Garcia-Closas, Montserrat
通讯作者：
Garcia-Closas, Montserrat
影响因子：
3.8
作者：
Bogdanova, Natalia;Schuermann, Peter;Doerk, Thilo
通讯作者：
Doerk, Thilo