The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine.
The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine.
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DOI：
10.1371/journal.pone.0013363
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发表时间：
2010-10-13
期刊：
影响因子：
3.7
通讯作者：
Neal DE
中科院分区：
文献类型：
--
作者：
Whitaker HC;Kote-Jarai Z;Ross-Adams H;Warren AY;Burge J;George A;Bancroft E;Jhavar S;Leongamornlert D;Tymrakiewicz M;Saunders E;Page E;Mitra A;Mitchell G;Lindeman GJ;Evans DG;Blanco I;Mercer C;Rubinstein WS;Clowes V;Douglas F;Hodgson S;Walker L;Donaldson A;Izatt L;Dorkins H;Male A;Tucker K;Stapleton A;Lam J;Kirk J;Lilja H;Easton D;IMPACT Study Steering Committee;IMPACT Study Collaborators;UK GPCS Collaborators;Cooper C;Eeles R;Neal DE
微生物蛋白-β（MSMB）调节细胞凋亡，并且使用全基因组关联研究，MSMB启动子中的rs 10993994单核苷酸多态性与前列腺癌风险增加有关。风险等位基因的启动子位置及其降低启动子活性的能力表明，rs 10993994风险等位基因可能导致良性组织中MSMB降低，从而导致前列腺癌风险增加。采用免疫组织化学方法检测前列腺组织中MSMB的表达，并与rs 10993994基因型进行比较。通过ELISA测定尿MSMB浓度，并与尿PSA、癌症的存在或不存在、rs 10993994基因型和发病年龄相关。前列腺组织和尿液中的MSMB水平随着肿瘤的发生而大大降低。在区分所有Gleason分级的前列腺癌患者时，尿MSMB优于尿PSA。高危等位基因与良性前列腺组织和尿液中MSMB染色的异质性和MSMB的丢失相关。这些数据表明，使用全基因组关联研究发现的一些高风险等位基因产生具有潜在临床实用性的表型效应。我们提供了前列腺癌的低等位基因多态性与人体组织和体液中潜在测试之间的第一个联系。有可能开发组织和尿MSMB作为前列腺癌风险、诊断和疾病监测的生物标志物。
Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.
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