Rat Mcs1b is concordant to the genome-wide association-identified breast cancer risk locus at human 5q11.2 and MIER3 is a candidate cancer susceptibility gene.
Rat Mcs1b is concordant to the genome-wide association-identified breast cancer risk locus at human 5q11.2 and MIER3 is a candidate cancer susceptibility gene.
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DOI：
10.1158/0008-5472.can-12-0748
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发表时间：
2012-11-15
期刊：
影响因子：
11.2
通讯作者：
Samuelson DJ
中科院分区：
文献类型：
--
作者：
denDekker AD;Xu X;Vaughn MD;Puckett AH;Gardner LL;Lambring CJ;Deschenes L;Samuelson DJ
与乳腺癌风险相关的低等位基因已在基于人群的研究中被确定。大多数风险位点不包含或包含多个潜在的候选基因。大鼠乳腺癌易感性1b（Mss 1b）是RN 02上的一个数量性状基因座（QTL），当Copenhagen（COP）抗性等位基因渗入Wistar Furth（WF）易感基因组时，该基因座赋予降低的易感性。比较了5个含有COP RN 02片段的WF.COP同源系。当雌性为Mcs 1b耐药纯合子和Mcs 1b杂合子时，一个品系每只大鼠平均发生3.4 ± 2.0和5.5 ± 3.6个乳腺癌± SD。这些表型与易感基因型同窝仔显著不同（每只大鼠平均乳腺癌7.8 ± 3.1 ± SD，分别为P = 0.0001和P = 0.0413）。所有其它供试的同源系均感病。因此，Mcslb在遗传标记ENSRNOSNP 2740854和g2 UL 2 -27之间被缩小到1.8Mb的RN 02。乳腺移植物癌易感性分析用于确定供体（P = 0.0019），而不是受体Mcs 1b基因型（P = 0.9381），与异位乳腺癌的结果。大鼠Mcs 1b含有与人类5q11.2（在多个全基因组关联研究中鉴定的乳腺癌易感性位点）正交的序列。人/大鼠MAP 3 K1/Map 3 k1和MIER 3/Mier 3在这些正向节段内。我们确定Mier 3作为候选Mcs 1b基因的基础上，4.5倍高乳腺水平的Mier 3转录在易感相比，Mcs 1b耐药的女性。这些数据表明，rs 889312标记的人类5q11.2乳腺癌风险等位基因是乳腺自主的，MIER 3是候选的乳腺癌易感基因。
Low-penetrance alleles associated with breast cancer risk have been identified in population-based studies. Most risk loci contain either no or multiple potential candidate genes. Rat mammary carcinoma susceptibility 1b (Mcs1b) is a quantitative trait locus (QTL) on RN02 that confers decreased susceptibility when Copenhagen (COP) resistant alleles are introgressed into a Wistar Furth (WF) susceptible genome. Five WF.COP congenic lines containing COP RN02 segments were compared. One line developed an average of 3.4 ± 2.0 and 5.5 ± 3.6 mammary carcinomas per rat ± SD when females were Mcs1b resistant homozygous and Mcs1b heterozygous, respectively. These phenotypes were significantly different from susceptible genotype littermates (7.8 ± 3.1 mean mammary carcinomas per rat ± SD, P = 0.0001 and P = 0.0413, respectively). All other congenic lines tested were susceptible. Thus, Mcs1b was narrowed to 1.8 Mb of RN02 between genetic markers ENSRNOSNP2740854 and g2UL2-27. Mammary-gland-graft carcinoma-susceptibility assays were used to determine that donor (P = 0.0019), but not recipient Mcs1b genotype (P = 0.9381), was associated with ectopic mammary carcinoma outcome. Rat Mcs1b contains sequence orthologous to human 5q11.2, a breast cancer susceptibility locus identified in multiple genome-wide association studies. Human/rat MAP3K1/Map3k1 and MIER3/Mier3 are within these orthologous segments. We identified Mier3 as a candidate Mcs1b gene based on 4.5-fold higher mammary gland levels of Mier3 transcripts in susceptible compared to Mcs1b resistant females. These data suggest that the human 5q11.2 breast cancer risk allele marked by rs889312 is mammary-gland autonomous, and MIER3 is a candidate breast cancer susceptibility gene.
影响因子：
2.5
作者：
Blackburn AC;Jerry DJ
通讯作者：
Jerry DJ