Whole exome sequencing in 75 high-risk families with validation and replication in independent case-control studies identifies TANGO2, OR5H14, and CHAD as new prostate cancer susceptibility genes.
Whole exome sequencing in 75 high-risk families with validation and replication in independent case-control studies identifies TANGO2, OR5H14, and CHAD as new prostate cancer susceptibility genes.
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DOI：
10.18632/oncotarget.13646
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发表时间：
2017-01-03
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影响因子：
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通讯作者：
Ostrander EA
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作者：
Karyadi DM;Geybels MS;Karlins E;Decker B;McIntosh L;Hutchinson A;Kolb S;McDonnell SK;Hicks B;Middha S;FitzGerald LM;DeRycke MS;Yeager M;Schaid DJ;Chanock SJ;Thibodeau SN;Berndt SI;Stanford JL;Ostrander EA
前列腺癌（PCa）的易感性是由一个连续体定义的，从罕见的，高外显率到常见的，低外显率的等位基因。迄今为止的研究主要集中在识别这个连续体末端的变异。采用另一种方法，我们通过对75个遗传性PCa家族的全外显子组序列数据进行基于疾病模型的变异过滤，专注于重要但难以捉摸的一类低频、中等渗透变异。在一项基于人群的2495名男性病例对照研究中，对341个候选风险变异进行了分析，确定了9个与PCa风险增加显著相关的变异。在一项针对7121名男性的独立巢式病例对照研究中，有TANGO2 p.Ser17Ter和已建立的HOXB13 p.Gly84Glu变异的风险关联证据。结合病例对照研究的荟萃分析确定了另外两个与风险相关的变异，OR5H14 p.Met59Val和CHAD p.Ala342Asp。TANGO2和HOXB13变异在病例中同时出现的频率比预期的要高，而在对照组中从未出现过。最后，在两项病例对照研究中，TANGO2 p.Ser17Ter分别与侵袭性疾病相关。我们的分析在TANGO2、OR5H14和CHAD基因中发现了三个新的PCa易感等位基因，这些等位基因不仅在多个高危家族中分离，而且在改变普通人群中男性的疾病风险方面也很重要。这是第一个成功的研究，利用测序在高风险家庭中识别低频，中等渗透的PCa风险突变的明确目的。
Prostate cancer (PCa) susceptibility is defined by a continuum from rare, high-penetrance to common, low-penetrance alleles. Research to date has concentrated on identification of variants at the ends of that continuum. Taking an alternate approach, we focused on the important but elusive class of low-frequency, moderately penetrant variants by performing disease model-based variant filtering of whole exome sequence data from 75 hereditary PCa families. Analysis of 341 candidate risk variants identified nine variants significantly associated with increased PCa risk in a population-based, case-control study of 2,495 men. In an independent nested case-control study of 7,121 men, there was risk association evidence for TANGO2 p.Ser17Ter and the established HOXB13 p.Gly84Glu variant. Meta-analysis combining the case-control studies identified two additional variants suggestively associated with risk, OR5H14 p.Met59Val and CHAD p.Ala342Asp. The TANGO2 and HOXB13 variants co-occurred in cases more often than expected by chance and never in controls. Finally, TANGO2 p.Ser17Ter was associated with aggressive disease in both case-control studies separately. Our analyses identified three new PCa susceptibility alleles in the TANGO2, OR5H14 and CHAD genes that not only segregate in multiple high-risk families but are also of importance in altering disease risk for men from the general population. This is the first successful study to utilize sequencing in high-risk families for the express purpose of identifying low-frequency, moderately penetrant PCa risk mutations.