Camp Nicola J, Farnham James M, Allen-Brady Kristina, Cannon-Albright Lisa A
Division of Genetic Epidemiology, Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA.
Prostate. 2007 Sep 15;67(13):1456-64. doi: 10.1002/pros.20631.
Chromosome 8q24 is a region of compelling interest for prostate cancer (PRCA). Linkage, association, and admixture analysis initially indicated the region. Subsequently, several variants at 8q24 have been found to independently associate with PRCA. One compelling hypothesis is allelic heterogeneity, whereby multiple variants affect the regulation of the same gene. In addition to potential allelic heterogeneity, 8q24 exhibits strong linkage disequilibrium over vast distances and is prone to chromosomal aberrations.
Allelic heterogeneity and complex chromosomal structure are factors that hinder progress towards gene identification using association. Linkage techniques, however, are robust to allelic heterogeneity and therefore can contribute important localization information. We have used a linkage-based localization technique to perform recombinant mapping in eight high-risk Utah pedigrees.
Using pedigree-based recombinant mapping we identify a 5.7 Mb region at 8q24.21-22, between markers D8S1774 and D8S557. Considering our region with the localization previously presented, we can delimit the 8q24 PRCA locus to a 2.0 Mb consensus interval from 127.5 to 129.5 Mb.
We have used a linkage-based, recombinant mapping technique in extended high-risk Utah pedigrees to successfully narrow the 8q24 PRCA locus. The region we present halves the 95% credible interval previously described using admixture analysis and contains only three annotated genes: FAM84B, MYC, and TMEM75. It should be noted that LD stretches far beyond the interval we describe, and hence this region adds important information about where to focus future efforts to isolate the causal variants and underlying gene, whether by linkage or association techniques.
8号染色体q24区域是前列腺癌（PRCA）研究中备受关注的区域。连锁分析、关联分析和混合分析最初都指向了该区域。随后，在8q24区域发现了多个与PRCA独立相关的变异。一个引人注目的假说是等位基因异质性，即多个变异影响同一基因的调控。除了潜在的等位基因异质性外，8q24在很长的距离上都表现出很强的连锁不平衡，并且容易发生染色体畸变。
等位基因异质性和复杂的染色体结构是阻碍通过关联分析鉴定基因的因素。然而，连锁技术对等位基因异质性具有较强的抗性，因此可以提供重要的定位信息。我们使用基于连锁的定位技术，在8个犹他州高危家系中进行重组定位。
通过基于家系的重组定位，我们在8q24.21 - 22区域，介于标记D8S1774和D8S557之间，确定了一个5.7 Mb的区域。结合我们的区域与之前报道的定位结果，我们可以将8q24 PRCA基因座限定在一个2.0 Mb的共识区间，即127.5至129.5 Mb之间。
我们在犹他州高危家系中使用基于连锁的重组定位技术，成功地缩小了8q24 PRCA基因座的范围。我们所确定的区域将之前使用混合分析描述的95%可信区间缩小了一半，并且只包含三个注释基因：FAM84B、MYC和TMEM75。需要注意的是，连锁不平衡延伸的范围远远超出我们所描述的区间，因此该区域为未来通过连锁或关联技术分离致病变异和潜在基因的研究重点提供了重要信息。
