Schaid Daniel J, Stanford Janet L, McDonnell Shannon K, Suuriniemi Miia, McIntosh Laura, Karyadi Danielle M, Carlson Erin E, Deutsch Kerry, Janer Marta, Hood Lee, Ostrander Elaine A
Division of Biostatistics, Mayo Clinic, Rochester, MN, USA.
Hum Genet. 2007 Jul;121(6):729-35. doi: 10.1007/s00439-007-0368-5. Epub 2007 May 8.
Despite evidence that prostate cancer has a genetic etiology, it has been extremely difficult to confirm genetic linkage results across studies, emphasizing the large extent of genetic heterogeneity associated with this disease. Because prostate cancer is common--approximately one in six men will be diagnosed with prostate cancer in their life--genetic linkage studies are likely plagued by phenocopies (i.e., men with prostate cancer due to environmental or lifestyle factors), weakly penetrant alleles, or a combination of both, making it difficult to replicate linkage findings. One way to account for heterogeneous causes is to use clinical information that is related to the aggressiveness of disease as an endpoint for linkage analyses. Gleason grade is a measure of prostate tumor differentiation, with higher grades associated with more aggressive disease. This semi-quantitative score has been used as a quantitative trait for linkage analysis in several prior studies. Our aim was to determine if prior linkage reports of Gleason grade to specific loci could be replicated, and to ascertain if new regions of linkage could be found. Gleason scores were available for 391 affected sib pairs from 183 hereditary prostate cancer pedigrees as part of the PROGRESS study. Analyzing Gleason score as a quantitative trait, and using microsatellite markers, suggestive evidence for linkage (P-value <or= 0.001) was found on chromosomes 19q and 5q, with P-values <or= 0.01 observed on chromosomes 3q, 7q, and 16q. Our results confirm reports of Gleason score linkage to chromosome 19q and suggest new loci for further investigation.
尽管有证据表明前列腺癌具有遗传病因，但在各项研究中很难证实遗传连锁结果，这凸显了与该疾病相关的遗传异质性程度之高。由于前列腺癌很常见——大约每六个男性中就有一个在其一生中会被诊断出患有前列腺癌——遗传连锁研究可能受到表型模拟（即由于环境或生活方式因素导致患前列腺癌的男性）、低外显率等位基因或两者兼有的影响，使得难以重复连锁研究结果。解释异质病因的一种方法是使用与疾病侵袭性相关的临床信息作为连锁分析的终点。 Gleason分级是衡量前列腺肿瘤分化程度的指标，分级越高表明疾病侵袭性越强。在之前的几项研究中，这个半定量评分已被用作连锁分析的数量性状。我们的目的是确定之前关于Gleason分级与特定基因座的连锁报道是否能够被重复，并确定是否能找到新的连锁区域。作为PROGRESS研究的一部分，有来自183个遗传性前列腺癌家系的391对患病同胞对的Gleason评分数据。将Gleason评分作为数量性状进行分析，并使用微卫星标记，在19号染色体长臂和5号染色体上发现了提示性的连锁证据（P值≤0.001），在3号染色体长臂、7号染色体长臂和16号染色体上观察到P值≤0.01。我们的结果证实了Gleason评分与19号染色体长臂连锁的报道，并提示了新的基因座以供进一步研究。
