A germline mutation in the BRCA1 3'UTR predicts Stage IV breast cancer.
A germline mutation in the BRCA1 3'UTR predicts Stage IV breast cancer.
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DOI：
10.1186/1471-2407-14-421
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发表时间：
2014-06-10
期刊：
影响因子：
3.8
通讯作者：
Weidhaas JB
中科院分区：
文献类型：
--
作者：
Dorairaj JJ;Salzman DW;Wall D;Rounds T;Preskill C;Sullivan CA;Lindner R;Curran C;Lezon-Geyda K;McVeigh T;Harris L;Newell J;Kerin MJ;Wood M;Miller N;Weidhaas JB
BRCA1 3’UTR (rs8176318) 中的种系变异此前已被证明可以预测高危家庭女性患乳腺癌和卵巢癌的风险，以及三阴性乳腺癌的风险增加。在这里，我们测试了这一假设，即该变异可以预测肿瘤生物学，就像癌症中的其他 3’UTR 突变一样。使用荧光素酶报告基因测定在体外测试了 BRCA1-3'UTR 变体对 BRCA1 基因表达的影响以及对外部刺激的反应改变。通过对乳腺肿瘤组织进行免疫荧光染色，将三阴性患者样本与变异体（TG 或 TT）或非变异体（GG）BRCA1 3’UTR 进行比较，进一步在体内测试基因表达。为了确定该变异对临床相关终点的重要性，对西爱尔兰乳腺癌患者的全面收集进行了该变异的测试。最后，利用来自佛蒙特大学高风险乳腺项目的一组女性，评估了该变异与乳腺筛查临床表型的关联。与乳腺癌细胞系中的非变体 3'UTR（G 等位基因）相比，具有 BRCA1-3'UTR 变体（T 等位基因）的荧光素酶报告基因显示出显着较低的基因表达，以及对外部激素刺激的反应改变。与非变异患者相比，携带纯合 TT 变异患者的三阴性样本中 BRCA1 基因表达降低，这在临床上得到了证实。 BRCA1-3’UTR 变异（TG 或 TT）还与西爱尔兰队列中患乳腺癌的风险适度增加相关（OR = 1.4，95% CI 1.1-1.8，p = 0.033）。更重要的是，携带 BRCA1-3’UTR 变异的患者出现 IV 期疾病的风险增加了 4 倍（p = 0.018，OR = 3.37，95% CI 1.3-11.0）。佛蒙特州队列中携带 BRCA1-3’UTR 变异的肥胖女性的乳房密度明显较低 (p = 0.0398)，这支持这一发现是由于肿瘤生物学而非筛查困难所致。 BRCA1 3’UTR 中的一个变异具有功能性，导致 BRCA1 表达减少、乳腺癌风险适度增加，最重要的是，可能由于侵袭性肿瘤生物学而导致 IV 期乳腺癌。
A germline, variant in the BRCA1 3’UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3’UTR mutations in cancer. The impact of the BRCA1-3’UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3’UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont. Luciferase reporters with the BRCA1-3’UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3’UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3’UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR = 1.4, 95% CI 1.1-1.8, p = 0.033). More importantly, patients with the BRCA1-3’UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p = 0.018, OR = 3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3’UTR-variant had significantly less dense breasts (p = 0.0398) in the Vermont cohort. A variant in the 3’UTR of BRCA1 is functional, leading to decreased BRCA1 expression, modest increased breast cancer risk, and most importantly, presentation with stage IV breast cancer, likely due to aggressive tumor biology.
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影响因子：
158.5
作者：
Kriege, M;Brekelmans, CTM;Klijn, JGM
通讯作者：
Klijn, JGM
DOI：
10.1073/pnas.0906947106
发表时间：
2009-09-15
影响因子：
11.1
作者：
Castellano, Leandro;Giamas, Georgios;Stebbing, Justin
通讯作者：
Stebbing, Justin
影响因子：
4.3
作者：
Pelletier, Cory;Speed, William C.;Weidhaas, Joanne B.
通讯作者：
Weidhaas, Joanne B.
DOI：
10.1038/nrm2831
发表时间：
2010-02
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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影响因子：
254.7
作者：
Parkin, DM;Bray, F;Pisani, P
通讯作者：
Pisani, P