Xu Jianfeng, Dimitrov Latchezar, Chang Bao-Li, Adams Tamara S, Turner Aubrey R, Meyers Deborah A, Eeles Rosalind A, Easton Douglas F, Foulkes William D, Simard Jacques, Giles Graham G, Hopper John L, Mahle Lovise, Moller Pal, Bishop Tim, Evans Chris, Edwards Steve, Meitz Julia, Bullock Sarah, Hope Questa, Hsieh Chih-Lin, Halpern Jerry, Balise Raymond N, Oakley-Girvan Ingrid, Whittemore Alice S, Ewing Charles M, Gielzak Marta, Isaacs Sarah D, Walsh Patrick C, Wiley Kathleen E, Isaacs William B, Thibodeau Stephen N, McDonnell Shannon K, Cunningham Julie M, Zarfas Katherine E, Hebbring Scott, Schaid Daniel J, Friedrichsen Danielle M, Deutsch Kerry, Kolb Suzanne, Badzioch Michael, Jarvik Gail P, Janer Marta, Hood Leroy, Ostrander Elaine A, Stanford Janet L, Lange Ethan M, Beebe-Dimmer Jennifer L, Mohai Caroline E, Cooney Kathleen A, Ikonen Tarja, Baffoe-Bonnie Agnes, Fredriksson Henna, Matikainen Mika P, Tammela Teuvo Lj, Bailey-Wilson Joan, Schleutker Johanna, Maier Christiane, Herkommer Kathleen, Hoegel Josef J, Vogel Walther, Paiss Thomas, Wiklund Fredrik, Emanuelsson Monica, Stenman Elisabeth, Jonsson Bjorn-Anders, Gronberg Henrik, Camp Nicola J, Farnham James, Cannon-Albright Lisa A, Seminara Daniela
Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Am J Hum Genet. 2005 Aug;77(2):219-29. doi: 10.1086/432377. Epub 2005 Jun 29.
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 < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.
多项分离分析已提供了存在主要前列腺癌（PC）易感基因的证据。尽管在十几项独立研究中进行了全基因组筛查，但很少有染色体区域被一致确定为感兴趣的区域。主要困难之一是遗传异质性，这可能是由于多个不完全显性的PC易感基因所致。在本研究中，我们在国际前列腺癌遗传学联盟（ICPCG）对大量PC家族的分析中探索了两种方法来克服这一困难。一种方法是合并总共1233个家族的连锁数据，以提高检测连锁的统计效力。使用参数分析（显性和隐性）和非参数分析，我们确定了五个具有“提示性”连锁的区域（LOD得分>1.86）：5q12、8p21、15q11、17q21和22q12。第二种方法是关注更可能分离高 penetrance 突变的家族子集，包括有大量受影响个体的家族或诊断时年龄较小的家族。在几个区域发现了更强的连锁证据，包括22q12处的“显著”连锁，LOD得分为3.57，以及在至少有五个受影响成员的269个家族中的五个提示性连锁（1q25、8q13、13q14、16p13和17q21）。此外，在诊断时平均年龄≤6岁的606个家族中发现了另外四个提示性连锁（3p24、5q35、11q22和Xq12）。尽管很难确定这些发现的真正统计显著性，但对这些结果的保守解释是，如果确实存在主要的PC易感基因，它们最有可能位于本大型研究中产生提示性或显著连锁信号的区域。
