Witte John S, Suarez Brian K, Thiel Bonnie, Lin Jennifer, Yu Adong, Banerjee Tarit K, Burmester James K, Casey Graham, Catalona William J
Department of Epidemiology & Biostatistics, University of California, San Francisco, California 94143-0560, USA.
Prostate. 2003 Dec 1;57(4):298-308. doi: 10.1002/pros.10304.
Substantial evidence suggests that genetic factors play an important role in both the risk of prostate cancer and its biologic aggressiveness. Here we investigate prostate cancer susceptibility and aggressiveness with genome-wide linkage analyses of affected brothers.
We first undertook a new genome-wide linkage study of 259 brothers with prostate cancer. Our analyses tested whether the proportion of marker alleles shared by brothers was correlated with disease status or Gleason score. To further clarify 11 linkage regions observed here or previously, we genotyped and analyzed an additional 101 finely spaced markers in the 259 men, and in 594 previously studied brothers, allowing for a pooled genome-wide analysis of 853 affected brothers.
In the new study, we detected linkage to prostate cancer on chromosome 16q23 (P = 0.009), replicating previous results, and to chromosome 11q24 (P = 0.001). In the pooled analysis, the 16q23 linkage was strengthened (P = 0.0005), as was our previous linkage to chromosome 16p (P = 0.0001), and we detected linkage to chromosome 2q32 (P = 0.009). When evaluating Gleason score, our new study detected linkage to chromosome 7q32 (P = 0.0009), again replicating previous results, and to chromosomes 5p15 (P = 0.003), 9q34 (P = 0.009), 10q26 (P = 0.03), and 18p11 (P = 0.02). In the pooled analysis of Gleason score, we observed stronger linkage to chromosome 7q32 (P = 0.0002), but slightly weaker linkage to chromosomes 5q33 (P = 0.005) and 19q13 (P = 0.009) than previously reported. In addition, the new linkages to chromosomes 10q26 and 18p11 were strengthened (P = 0.0002 and P = 0.002, respectively).
Our results provide compelling evidence for loci harboring prostate cancer susceptibility and tumor aggressiveness genes, especially on chromosomes 16q23 and 7q32.
大量证据表明，遗传因素在前列腺癌的发病风险及其生物学侵袭性方面均发挥着重要作用。在此，我们通过对患前列腺癌的兄弟进行全基因组连锁分析，来研究前列腺癌的易感性和侵袭性。
我们首先对259对患前列腺癌的兄弟开展了一项新的全基因组连锁研究。我们的分析检测了兄弟间共享的标记等位基因比例是否与疾病状态或 Gleason 评分相关。为了进一步阐明在此处或之前观察到的11个连锁区域，我们对这259名男性以及594名之前研究过的兄弟中的另外101个精细定位的标记进行了基因分型和分析，从而能够对853名患前列腺癌的兄弟进行全基因组汇总分析。
在这项新研究中，我们在16号染色体q23区域检测到与前列腺癌的连锁关系（P = 0.009），重复了之前的结果，同时在11号染色体q24区域也检测到连锁关系（P = 0.001）。在汇总分析中，16号染色体q23区域的连锁关系得到加强（P = 0.0005），我们之前在16号染色体p区域的连锁关系同样如此（P = 0.0001），并且我们还检测到与2号染色体q32区域的连锁关系（P = 0.009）。在评估 Gleason 评分时，我们的新研究在7号染色体q32区域检测到连锁关系（P = 0.0009），再次重复了之前的结果，同时在5号染色体p15区域（P = 0.003）、9号染色体q34区域（P = 0.009）、10号染色体q26区域（P = 0.03）以及18号染色体p11区域（P = 0.02）也检测到连锁关系。在 Gleason 评分的汇总分析中，我们观察到与7号染色体q32区域的连锁关系更强（P = 0.0002），但与5号染色体q33区域（P = 0.005）和19号染色体q13区域（P = 0.009）的连锁关系比之前报道的略弱。此外，与10号染色体q26区域和18号染色体p11区域的新连锁关系得到加强（分别为P = 0.0002和P = 0.002）。
我们的研究结果为存在前列腺癌易感性和肿瘤侵袭性基因的位点提供了有力证据，尤其是在16号染色体q23区域和7号染色体q32区域。
