Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics
Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics
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DOI：
10.1007/s00439-006-0219-9
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发表时间：
2006-11-01
期刊：
影响因子：
5.3
通讯作者：
Schaid, Daniel J.
中科院分区：
文献类型：
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作者：
Schaid, Daniel J.
虽然人们广泛认识到前列腺癌进展到危及生命阶段的倾向差异很大，但尚未确定导致这种进展的分子事件。了解这些分子机制可以提供重要的预后信息，更有效的临床管理这种异质性癌症。因此，通过遗传连锁分析，我们检验了发展侵袭性前列腺癌的倾向可能具有重要遗传成分的假设。从1,233个家族性前列腺癌家族开始，基因组扫描数据可从国际前列腺癌遗传学联盟获得，我们选择了那些至少有三个成员具有临床侵袭性前列腺癌表型的家族，根据高肿瘤分级和/或阶段的定义，导致166个家系（13%）。然后将全基因组连锁数据合并，对这些家庭进行联合连锁分析。在染色体6p22.3（LOD = 3.0）、11q14.1-14.3（LOD = 2.4）和20p11.21-q11.21（LOD = 2.5）上发现了达到提示显著性水平的连锁信号。对于11号染色体，在诊断时平均年龄为65岁或更年轻的家系中观察到更强的连锁证据（LOD = 3.3）。显示跨层连锁异质性证据的其他染色体是7号染色体，在没有男性间疾病传播的家系中具有最强的连锁信号（7q21.11，LOD = 4.1），以及21号染色体，在具有非洲裔美国人血统的家系中具有最强的连锁信号（21q22.13-22.3; LOD = 3.2）。我们的研究结果表明，几个区域可能含有基因，当突变时，使男性更容易发展为更具侵略性的前列腺癌表型。这为尝试识别这些基因提供了基础，对患有侵袭性前列腺癌的男性及其亲属具有潜在的临床实用性。
While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1-14.3 (LOD = 2.4), and 20p11.21-q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13-22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives.