Prostate Cancer Mortality Associated with Aggregate Polymorphisms in Androgen-Regulating Genes: The Atherosclerosis Risk in the Communities (ARIC) Study.
Prostate Cancer Mortality Associated with Aggregate Polymorphisms in Androgen-Regulating Genes: The Atherosclerosis Risk in the Communities (ARIC) Study.
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DOI：
10.3390/cancers13081958
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发表时间：
2021-04-19
期刊：
影响因子：
5.2
通讯作者：
Ryan CJ
中科院分区：
文献类型：
--
作者：
Prizment AE;McSweeney S;Pankratz N;Joshu CE;Hwang JH;Platz EA;Ryan CJ
前列腺癌的生长是由雄激素通过激活前列腺肿瘤组织中的雄激素受体及其靶基因来驱动的。涉及雄激素调节的几个基因的改变可能会影响前列腺癌的预后，但尚未在基于人群的研究中进行测试。在这项流行病学研究中，我们证实，在临床试验中影响前列腺癌进展的 HSD3B1 基因的改变与诊断患有转移性疾病的男性前列腺癌死亡风险增加相关。此外，我们检查了三个关键雄激素调节基因（包括 HSD3B1）中预先指定的改变的累积效应，发现它们的组合容易死于前列腺癌。我们的研究结果表明，雄激素调节基因之间的相互作用可能会影响前列腺癌的预后，应进一步检查以制定前列腺癌治疗方案。雄激素代谢的遗传变异可能会影响前列腺癌（PC）的预后。临床研究始终将 PC 预后与关键雄激素调节基因中的四个单核苷酸多态性 (SNP) 联系起来：3-β-羟基类固醇脱氢酶 (HSD3B1) rs1047303、5-α-还原酶 2 (SRD5A2) rs523349 和溶质载体有机离子 (SLCO2B1) rs1789693 和rs12422149。我们在基于 ARIC 人群的前瞻性队列中测试了四个雄激素调节 SNP（单独或组合）与 PC 特异性死亡率的关联。对诊断患有 PC 的男性（N = 622；79% 白人，21% 黑人）进行了死亡跟踪（N = 350），其中包括 PC 死亡（N = 74）。 Cox 比例风险回归用于估计风险比 (HR) 和 95% CI，使用不同种族的风险对诊断时的中心、年龄、阶段和等级进行调整。先验遗传风险评分 (GRS) 是四个预选 SNP 中风险等位基因的未加权总和。功能获得性 rs1047303C 等位基因与诊断时转移性 PC 男性的 PC 特异性死亡率相关（每个风险等位基因的 HR = 4.89，p = 0.01）。较高的 GRS 与 PC 特异性死亡率相关（每个风险等位基因：HR = 1.26，p = 0.03）。我们证实，HSD3B1 rs1047303 中的功能获得等位基因与患有转移性疾病的男性较高的 PC 死亡率相关。此外，我们的研究结果表明，雄激素调节基因对 PC 特异性死亡率具有累积效应；然而，还需要进一步验证。
The growth of prostate cancer is driven by androgens through activation of the androgen receptors and its target genes in the prostate tumor tissue. Alterations in several genes involved in androgen regulation may influence the prognosis of prostate cancer, but have not been tested in a population-based study. In this epidemiological study, we confirmed that the alteration in the HSD3B1 gene that affected the progression of prostate cancer in clinical trials, is associated with increased risk of prostate cancer death in men diagnosed with metastatic disease. Additionally, we examined the cumulative effect of pre-specified alterations in the three critical androgen-regulating genes (including HSD3B1) and found that their combination predisposes to death from prostate cancer. Our findings suggest that an interplay between the androgen-regulating genes may influence the prognosis of prostate cancer and should be further examined for tailoring prostate cancer treatment. Genetic variations in androgen metabolism may influence prostate cancer (PC) prognosis. Clinical studies consistently linked PC prognosis with four single nucleotide polymorphisms (SNPs) in the critical androgen-regulating genes: 3-beta-hydroxysteroid dehydrogenase (HSD3B1) rs1047303, 5-alpha-reductase 2 (SRD5A2) rs523349, and solute carrier organic ion (SLCO2B1) rs1789693 and rs12422149. We tested the association of four androgen-regulating SNPs, individually and combined, with PC-specific mortality in the ARIC population-based prospective cohort. Men diagnosed with PC (N = 622; 79% White, 21% Black) were followed for death (N = 350) including PC death (N = 74). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95%CI adjusting for center, age, stage, and grade at diagnosis using separate hazards for races. A priori genetic risk score (GRS) was created as the unweighted sum of risk alleles in the four pre-selected SNPs. The gain-of-function rs1047303C allele was associated PC-specific mortality among men with metastatic PC at diagnosis (HR = 4.89 per risk allele, p = 0.01). Higher GRS was associated with PC-specific mortality (per risk allele: HR = 1.26, p = 0.03). We confirmed that the gain-of-function allele in HSD3B1 rs1047303 is associated with greater PC mortality in men with metastatic disease. Additionally, our findings suggest a cumulative effect of androgen-regulating genes on PC-specific mortality; however, further validation is required.
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影响因子：
28.4
作者：
Almassi, Nima;Reichard, Chad;Sharifi, Nima
通讯作者：
Sharifi, Nima
DOI：
10.1158/1078-0432.ccr-16-2245
发表时间：
2017-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Mostaghel EA;Cho E;Zhang A;Alyamani M;Kaipainen A;Green S;Marck BT;Sharifi N;Wright JL;Gulati R;True LD;Loda M;Matsumoto AM;Tamae D;Penning TN;Balk SP;Kantoff PW;Nelson PS;Taplin ME;Montgomery RB
通讯作者：
Montgomery RB
影响因子：
28.4
作者：
Hearn, Jason W. D.;Sweeney, Christopher J.;Sharifi, Nima
通讯作者：
Sharifi, Nima
影响因子：
6.2
作者：
Tsodikov A;Gulati R;de Carvalho TM;Heijnsdijk EAM;Hunter-Merrill RA;Mariotto AB;de Koning HJ;Etzioni R
通讯作者：
Etzioni R
影响因子：
45.3
作者：
Ryan, Charles J.;Smith, Matthew R.;Small, Eric J.
通讯作者：
Small, Eric J.