A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics
A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics
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DOI：
10.1086/432377
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发表时间：
2005-08-01
影响因子：
9.8
通讯作者：
Seminara, D
中科院分区：
文献类型：
--
作者：
Xu, JF;Dimitrov, L;Seminara, D
多种分离分析提供了前列腺癌主要易感基因存在的证据。尽管在十几项独立研究中进行了全基因组筛选，但很少有染色体区域被一致地确定为感兴趣的区域。主要的困难之一是遗传异质性，可能是由于多个不完全渗透的pc易感基因。在这项研究中，我们通过对国际前列腺癌遗传学协会（ICPCG）大量PC家族的分析，探索了两种方法来克服这一困难。一种方法是将来自1233个家庭的连锁数据结合起来，以增加检测连锁的统计能力。通过参数（显性和隐性）和非参数分析，我们确定了5个具有“暗示”连锁的区域（LOD评分bbbb1.86）： 5q12、8p21、15q11、17q21和22q12。第二种方法是关注那些更有可能分离出高渗透性突变的家庭亚群，包括有大量受影响个体或诊断年龄较早的家庭。在几个区域发现了更强的联系证据，包括22q12的“显著”联系，LOD评分为3.57，以及269个至少有5个受影响成员的家庭中的5个暗示联系（1q25、8q13、13q14、16p13和17q21）。此外，在606个平均诊断年龄的家庭中发现了另外四个提示关联（3p24、5q35、11q22和Xq12）
Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric ( dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score > 1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of