Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, USA.
BMC Med Genet. 2012 Jun 19;13:46. doi: 10.1186/1471-2350-13-46.
Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive.
Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed.
Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded.
Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.
遗传变异可能导致前列腺癌风险的一部分。由于不完全外显率和遗传及表型异质性，前列腺癌遗传病因的全面阐明具有一定难度。目前的证据表明，已在包括 X 染色体在内的多个染色体上发现了与前列腺癌的遗传连锁，但尚未鉴定出致病基因。
使用来自国际前列腺癌遗传学合作组织（ICPCG）的 11 组多病例前列腺癌家系中的 26 个微卫星标记，对家系进行参数和非参数连锁分析。然后，对整个 1323 个家系和几个预定义亚组中的家系特异性连锁统计数据进行荟萃分析。
连锁统计数据的荟萃分析导致参数异质性最大 lod 得分（HLOD）为 1.28，等位基因共享 lod 得分（LOD）为 2.0，支持 Xq27-q28 与 138cM 处的连锁。在亚组分析中，发病年龄小于 65 岁的家系的最大 HLOD 为 1.8（在 138cM 处），而发病年龄为 65 岁或以上的家系的最大区域 HLOD 仅为 0.32。令人惊讶的是，只有 2-3 名受影响男性且有男性间前列腺癌传递证据的家系亚组，该区域的连锁证据最强（HLOD=3.24，134cM）。对于该亚组，当排除最初报道 Xq27-28 连锁的家系时，HLOD 略有增加（HLOD=134cM 处 3.47）。
尽管在完整的家系中，Xq27-28 区域的连锁证据并不强，但发病年龄较早的家系亚组的连锁证据强于发病较晚的家系。有 2-3 名受影响个体且有男性间疾病传递证据的家系亚组显示出更强的连锁信号。我们的研究结果表明，我们家系中的前列腺癌遗传基础比 X 染色体上的单个易感性位点要复杂得多，对 Xq27-28 区域的未来探索应集中于该区域最强的连锁证据的家系亚组。
