Inherited genetic variant predisposes to aggressive but not indolent prostate cancer
Inherited genetic variant predisposes to aggressive but not indolent prostate cancer
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DOI：
10.1073/pnas.0914061107
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发表时间：
2010-02-02
影响因子：
11.1
通讯作者：
Isaacs, William B.
中科院分区：
文献类型：
--
作者：
Xu, Jianfeng;Zheng, Siqun Lilly;Isaacs, William B.
尸检研究表明，大多数老年男性都会出现病变，如果在临床上检测到，将被诊断为前列腺癌 (PCa)。大多数这些癌症是惰性的并且仍然是局部的。然而，PCa 的一部分具有侵袭性，每年导致美国 27,000 多人死亡。迫切需要确定与侵袭性前列腺癌风险特别相关的因素，以减少这种常见疾病的过度诊断和过度治疗。为了寻找这些因素，我们比较了国家癌症研究所进行的易感性遗传标记 (CGEMS) 研究中检查的四个人群中被定义为患有更具侵袭性或侵袭性较低疾病的 PCa 患者的 SNP 频率。在来自美国和瑞典的另外三个独立研究人群中进一步评估了显示可能与疾病严重程度相关的 SNP。总共，我们分别研究了 4,829 名和 12,205 名患有侵袭性疾病的患者。我们发现，在所研究的七个人群中，与侵袭性较弱的患者相比，17p12处SNP rs4054823的TT基因型频率始终较高，在隐性模型下总体P值为2.1 x 10(-8)，超过了保守的全基因组显着性水平。与低度、非器官局限性疾病患者相比，重度、非器官局限性疾病患者的频率差异最大。这项研究表明，基因组中存在易患侵袭性而非惰性 PCa 的遗传变异，并表明应评估此类变异作为侵袭性 PCa 风险的潜在早期标志物的临床潜力。
Autopsy studies suggest that most aging men will develop lesions that, if detected clinically, would be diagnosed as prostate cancer (PCa). Most of these cancers are indolent and remain localized; however, a subset of PCa is aggressive and accounts for more than 27,000 deaths in the United States annually. Identification of factors specifically associated with risk for more aggressive PCa is urgently needed to reduce overdiagnosis and overtreatment of this common disease. To search for such factors, we compared the frequencies of SNPs among PCa patients who were defined as having either more aggressive or less aggressive disease in four populations examined in the Genetic Markers of Susceptibility (CGEMS) study performed by the National Cancer Institute. SNPs showing possible associations with disease severity were further evaluated in an additional three independent study populations from the United States and Sweden. In total, we studied 4,829 and 12,205 patients with more and less aggressive disease, respectively. We found that the frequency of the TT genotype of SNP rs4054823 at 17p12 was consistently higher among patients with more aggressive compared with less aggressive disease in each of the seven populations studied, with an overall P value of 2.1 x 10(-8) under a recessive model, exceeding the conservative genome-wide significance level. The difference in frequency was largest between patients with high-grade, non-organ-confined disease compared with those with low-grade, organ-confined disease. This study demonstrates that inherited variants predisposing to aggressive but not indolent PCa exist in the genome, and suggests that the clinical potential of such variants as potential early markers for risk of aggressive PCa should be evaluated.