Xu Jianfeng, Gillanders Elizabeth M, Isaacs Sarah D, Chang Bao-Li, Wiley Kathy E, Zheng S Lilly, Jones MaryPat, Gildea Derek, Riedesel Erica, Albertus Julie, Freas-Lutz Diana, Markey Carol, Meyers Deborah A, Walsh Patrick C, Trent Jeffrey M, Isaacs William B
Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Prostate. 2003 Dec 1;57(4):320-5. doi: 10.1002/pros.10306.
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.
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.
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.
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.
尽管前列腺癌家族聚集现象是深入研究的课题，但导致这种现象的遗传影响因素仍大多未明。对前列腺癌家族进行全基因组连锁扫描，可用于系统地寻找能够影响该病发病风险的基因。
来自188个家族的所有在世家庭成员（每个家族至少有三名患前列腺癌的一级亲属），在全基因组平均间距小于10厘摩分布的406个标记处进行基因分型。尽管也进行了参数分析，但主要使用非参数多点方法分析基因型数据。
在4q21的D4S1615处观察到最强的连锁证据（对数优势比为2.8，P = 0.0002）。另外两个区域的对数优势比得分超过2.0：9q34（标记D9S1826，对数优势比 = 2.17，P = 0.0008）和2q23（标记D2S151，对数优势比 = 2.03，P = 0.001）。另有12个区域的对数优势比得分超过1.0，包括1q24 - 25和7q22处的标记得分>1.6。按诊断年龄对连锁结果进行分层分析表明，与2号和4号染色体的连锁分别在诊断年龄早和晚的家族中最强。
我们的数据表明有几个新的基因座含有前列腺癌易感基因，并为先前在其他全基因组扫描中确定的几个基因座的连锁提供了确证证据，包括前列腺癌连锁证据最强的三个区域（4q21、9q34和2q23）。这些数据还强调了有必要整合来自大量前列腺癌家族的连锁数据，以有效应对该病遗传方面广泛存在的异质性。
