Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA.
Eur J Hum Genet. 2013 Apr;21(4):437-43. doi: 10.1038/ejhg.2012.185. Epub 2012 Sep 5.
Prostate cancer (PrCa) is the most common male cancer in developed countries and the second most common cause of cancer death after lung cancer. We recently reported a genome-wide linkage scan in 69 Finnish hereditary PrCa (HPC) families, which replicated the HPC9 locus on 17q21-q22 and identified a locus on 2q37. The aim of this study was to identify and to detect other loci linked to HPC. Here we used ordered subset analysis (OSA), conditioned on nonparametric linkage to these loci to detect other loci linked to HPC in subsets of families, but not the overall sample. We analyzed the families based on their evidence for linkage to chromosome 2, chromosome 17 and a maximum score using the strongest evidence of linkage from either of the two loci. Significant linkage to a 5-cM linkage interval with a peak OSA nonparametric allele-sharing LOD score of 4.876 on Xq26.3-q27 (ΔLOD=3.193, empirical P=0.009) was observed in a subset of 41 families weakly linked to 2q37, overlapping the HPCX1 locus. Two peaks that were novel to the analysis combining linkage evidence from both primary loci were identified; 18q12.1-q12.2 (OSA LOD=2.541, ΔLOD=1.651, P=0.03) and 22q11.1-q11.21 (OSA LOD=2.395, ΔLOD=2.36, P=0.006), which is close to HPC6. Using OSA allows us to find additional loci linked to HPC in subsets of families, and underlines the complex genetic heterogeneity of HPC even in highly aggregated families.
前列腺癌（PrCa）是发达国家最常见的男性癌症，也是仅次于肺癌的第二大癌症死亡原因。我们最近报道了对 69 个芬兰遗传性前列腺癌（HPC）家族的全基因组连锁扫描，该扫描复制了 17q21-q22 上的 HPC9 基因座，并确定了 2q37 上的一个基因座。本研究的目的是鉴定和检测与 HPC 连锁的其他基因座。在这里，我们使用有序子集分析（OSA），在这些基因座的非参数连锁条件下，检测与 HPC 连锁的其他基因座在家族的亚组中，但不在整个样本中。我们根据家族与染色体 2、染色体 17 的连锁证据以及使用来自两个基因座中任何一个的最强连锁证据的最大得分进行分析。在与 2q37 弱连锁的 41 个家族亚组中观察到与 Xq26.3-q27 上的 5-cM 连锁区间显著连锁，其 OSA 非参数等位基因共享 LOD 分数峰值为 4.876（ΔLOD=3.193，经验 P=0.009），该区间与 HPCX1 基因座重叠。在分析结合来自两个主要基因座的连锁证据的过程中发现了两个新的峰；18q12.1-q12.2（OSA LOD=2.541，ΔLOD=1.651，P=0.03）和 22q11.1-q11.21（OSA LOD=2.395，ΔLOD=2.36，P=0.006），这两个峰接近 HPC6。使用 OSA 使我们能够在家族的亚组中找到与 HPC 连锁的其他基因座，并强调了 HPC 即使在高度聚集的家族中也存在复杂的遗传异质性。
