Genome-wide scan for prostate cancer susceptibility genes in the Johns Hopkins hereditary prostate cancer families
Genome-wide scan for prostate cancer susceptibility genes in the Johns Hopkins hereditary prostate cancer families
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DOI：
10.1002/pros.10306
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发表时间：
2003-12-01
期刊：
影响因子：
2.8
通讯作者：
Isaacs, WB
中科院分区：
文献类型：
--
作者：
Xu, JF;Gillanders, EM;Isaacs, WB
背景资料。虽然是深入研究的主题，但前列腺癌家族聚集性的遗传影响在很大程度上仍未确定。对前列腺癌家族中的连锁进行全基因组扫描可以用来系统地搜索能够影响疾病风险的基因。方法：188个家族的所有可用的家族成员，每个家庭至少有三个患有前列腺癌的一级亲属，在分布在基因组上的406个标记上进行了基因分型，平均间隔不到10 cM。主要使用非参数、多点方法分析基因数据，但也进行参数分析。结果：在D4S1615的4q21(LOD2.8LOD2.8，P=0.0002)有最强的连锁证据。另有两个区域的LOD值大于2：9q34(标记D9S1826，LOD=2.17，P=0.0008)和2q23(标记D2S151，LOD=2.03，P=0.001)。另有12个地区LOD得分超过1.0，其中1q24-25和7q22得分>；1.6。按诊断年龄分层的连锁结果表明，在诊断年龄较早和较晚的家庭中，与第2和4号染色体的联系分别最强。结论：我们的数据暗示了几个新的基因座含有前列腺癌易感基因，并提供了在其他全基因组扫描中发现的几个基因座上的联系的确证证据，包括三个证据最强的前列腺癌联系的区域(4q21、9q34和2q23)。这些数据还强调，需要结合来自大量前列腺癌家系的连锁数据，努力有效地解决这种疾病遗传方面的广泛异质性。
BACKGROUND. Although the subject of intensive study, the genetic influences responsible for familial clustering of prostate cancer remain largely unidentified. Genome-wide scans for linkage in prostate cancer families can be used to systematically search for genes capable of affecting risk for the disease.METHODS. All available family members from 188 families, each having at least three first-degree relatives affected with prostate cancer, were genotyped at 406 markers distributed across the genome at average intervals of less than 10 cM. Genotype data was analyzed using primarily a non-parametric, multipoint approach, although parametric analyses were performed as well.RESULTS. The strongest evidence for linkage was observed at D4S1615, at 4q21 (LOD of 2.8, P = 0.0002). Two other regions had LOD scores over 2.0: at 9q34 (marker D9S1826, LOD = 2.17, P = 0.0008) and at 2q23 (marker D2S151, LOD = 2.03, P = 0.001). An additional 12 regions had LOD scores over 1.0, including markers at 1q24-25 and 7q22 having scores >1.6. Stratifying the linkage results by age of diagnosis indicated that the linkages to chromosomes 2 and 4 were strongest in families with early and late ages of diagnosis, respectively.CONCLUSIONS. Our data implicate several new loci as harboring prostate cancer susceptibility genes, and provide confirmatory evidence of linkage at several loci identified previously in other genome-wide scans, including the three regions (4q21, 9q34, and 2q23) with strongest evidence for prostate cancer linkage. These data also emphasize the need to combine linkage data from large numbers of prostate cancer families in efforts to effectively address the extensive heterogeneity that characterizes genetic aspects of this disease.