Department of Genetics, UCL Institute of Ophthalmology, University College London, London, UK.
Cell Therapy and Regenerative Medicine, CABIMER, Seville, Spain.
Ann Oncol. 2018 May 1;29(5):1292-1303. doi: 10.1093/annonc/mdy082.
MSR1 repeats are a 36-38 bp minisatellite element that have recently been implicated in the regulation of gene expression, through copy number variation (CNV).
Bioinformatic and experimental methods were used to assess the distribution of MSR1 across the genome, evaluate the regulatory potential of such elements and explore the role of MSR1 elements in cancer, particularly non-familial breast cancer and prostate cancer.
MSR1s are predominately located at chromosome 19 and are functionally enriched in regulatory regions of the genome, particularly regions implicated in short-range regulatory activities (H3K27ac, H3K4me1 and H3K4me3). MSR1-regulated genes were found to have specific molecular roles, such as serine-protease activity (P = 4.80 × 10-7) and ion channel activity (P = 2.7 × 10-4). The kallikrein locus was found to contain a large number of MSR1 clusters, and at least six of these showed CNV. An MSR1 cluster was identified within KLK14, with 9 and 11 copies being normal variants. A significant association with the 9-copy allele and non-familial breast cancer was found in two independent populations (P = 0.004; P = 0.03). In the white British population, the minor allele conferred an increased risk of 1.21-3.51 times for all non-familial disease, or 1.7-5.3 times in early-onset disease. The 9-copy allele was also found to be associated with increased risk of prostate cancer in an independent population (odds ratio = 1.27-1.56; P =0.009).
MSR1 repeats act as molecular switches that modulate gene expression. It is likely that CNV of MSR1 will affect risk of development of various forms of cancer, including that of breast and prostate. The MSR1 cluster at KLK14 represents the strongest risk factor identified to date in non-familial breast cancer and a significant risk factor for prostate cancer. Analysis of MSR1 genotype will allow development of precise stratification of disease risk and provide a novel target for therapeutic agents.
MSR1 重复序列是一个 36-38bp 的微卫星元件，最近被认为通过拷贝数变异 (CNV) 调节基因表达。
采用生物信息学和实验方法评估 MSR1 在基因组中的分布，评估此类元件的调控潜力，并探讨 MSR1 元件在癌症中的作用，特别是非家族性乳腺癌和前列腺癌。
MSR1 主要位于 19 号染色体上，并且在基因组的调控区域中功能丰富，特别是在短程调控活性 (H3K27ac、H3K4me1 和 H3K4me3) 相关区域。发现 MSR1 调节的基因具有特定的分子作用，如丝氨酸蛋白酶活性 (P=4.80×10-7) 和离子通道活性 (P=2.7×10-4)。在激肽释放酶基因座中发现了大量的 MSR1 簇，其中至少有六个显示出 CNV。在 KLK14 中鉴定到一个 MSR1 簇，其 9 个和 11 个拷贝是正常变异。在两个独立的人群中发现了与 9 拷贝等位基因和非家族性乳腺癌的显著关联 (P=0.004；P=0.03)。在白种英国人中，次要等位基因使所有非家族性疾病的发病风险增加了 1.21-3.51 倍，早期发病的风险增加了 1.7-5.3 倍。在另一个独立的人群中，也发现 9 拷贝等位基因与前列腺癌的发病风险增加相关 (比值比=1.27-1.56；P=0.009)。
MSR1 重复序列作为分子开关，调节基因表达。MSR1 的 CNV 很可能会影响各种形式癌症的发病风险，包括乳腺癌和前列腺癌。KLK14 中的 MSR1 簇是迄今为止在非家族性乳腺癌中发现的最强风险因素，也是前列腺癌的重要风险因素。MSR1 基因型分析将允许对疾病风险进行精确分层，并为治疗剂提供新的靶标。
