In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci.
In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci.
复制标题
DOI：
10.1007/s00335-014-9551-x
复制
发表时间：
2015-02
期刊：
影响因子：
--
通讯作者：
Cox TC
中科院分区：
文献类型：
--
作者：
Hadsell DL;Hadsell LA;Olea W;Rijnkels M;Creighton CJ;Smyth I;Short KM;Cox LL;Cox TC
遗传背景在乳腺发育和乳腺癌（BrCa）中起主导作用。尽管如此，遗传多样性在乳腺发育中的作用只是部分了解。本研究使用品系依赖性变异的近交系小鼠作图面板，以确定数量性状基因座（QTL）的潜在结构变异的乳腺导管发育，并确定这些QTL是否与基因组间隔赋予乳腺癌易感性在人类。对于大约一半的性状，在本研究中观察到的整套菌株之间的变异大于（P <0.05）用先前研究的菌株或用目前乳腺生物学常用的菌株观察到的变异。相关性也检测到与以前报道的乳腺肿瘤潜伏期和转移的变化。计算机全基因组关联（GWAS）鉴定了20个乳腺发育QTL（Mdq）。其中，5个与先前报道的人类BrCa基因座同线。该研究中最显著（P = 1 × 10 − 11）的关联是在MMU 6上，包含基因Plxna 4，Plxna 4os 1和Chchd 3。在MMU 5上，检测到一个QTL（p = 8 × 10 − 7），该QTL与h12q24.5上的人类BrCa基因座同线，包含基因Tbx3和Tbx5。高关联SNP（r2> 0.8）与基因组和表观基因组特征的交叉，以及候选基因与来自人BrCa的基因表达和存活数据的交叉突出了几个用于进一步研究的。这些结果支持这样的结论，即乳腺导管发育的遗传变异大于以前的认识。他们还表明，乳腺肿瘤潜伏期和转移指数可能受到控制正常乳腺导管发育的相同因素的变化的影响，并且对遗传多样性小鼠的进一步研究可以通过识别新的易感基因来提高我们对人类乳腺发育和乳腺癌之间联系的理解。
Genetic background plays a dominant role in mammary gland development and breast cancer (BrCa). Despite this, the role of genetic diversity in mammary gland development is only partially understood. This study used strain-dependent variation in an inbred mouse mapping panel, to identify quantitative trait loci (QTL) underlying structural variation in mammary ductal development, and determined if these QTL correlated with genomic intervals conferring breast cancer susceptibility in humans. For about half of the traits, the observed variation among the complete set of strains in this study was greater (P<0.05) than that observed with previously studied strains or with strains that are in current common use for mammary gland biology. Correlations were also detected with previously reported variation in mammary tumor latency and metastasis. In silico genome-wide association (GWAS) identified 20 mammary development QTL (Mdq). Of these, 5 were syntenic with previously reported human BrCa loci. The most highly significant (P=1×10−11) association of the study was on MMU6 and contained the genes Plxna4, Plxna4os1, and Chchd3. On MMU5, a QTL was detected (p=8×10−7) that was syntenic to a human BrCa locus on h12q24.5 containing the genes Tbx3 and Tbx5. Intersection of high-association SNP (r2 >0.8) with genomic and epigenomic features, and intersection of candidate genes with gene expression and survival data from human BrCa highlighted several for further study. These results support the conclusion that genetic variation in mammary ductal development is greater than previously appreciated. They also suggest that mammary tumor latency and metastatic index may be influenced by variations in the same factors that control normal mammary ductal development and that further studies of genetically diverse mice can improve our understanding of the connection between breast development and breast cancer in humans by identifying novel susceptibility genes.