Linkage and association studies of prostate cancer susceptibility: Evidence for linkage at 8p22-23
Linkage and association studies of prostate cancer susceptibility: Evidence for linkage at 8p22-23
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DOI：
10.1086/321967
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发表时间：
2001-08-01
影响因子：
9.8
通讯作者：
Isaacs, WB
中科院分区：
文献类型：
--
作者：
Xu, JF;Zheng, SQL;Isaacs, WB
多项证据表明，8号染色体的短臂中含有前列腺癌发生过程中重要的基因。尽管这些证据大多来自于前列腺癌细胞中8p位点的频繁体细胞改变（例如，杂合性的丧失），但研究也表明8p基因在前列腺癌遗传易感性的介导中起作用。为了进一步研究后一种可能性，我们使用8号染色体短臂上的24个标记，对159个遗传前列腺癌（HPC）谱系进行了连锁分析。在完整的家族中，在8p22-23处发现了前列腺癌连锁的证据，峰值HLOD为1.84 (P = 0.004)，家族连锁比例（alpha）的估计值为0.14，在D8S1130处。在79个平均诊断年龄为> ~ 65岁的家庭中，等位基因共享LOD评分为2.64 (P = 0.005)，跨越10 cM的6个标记的LOD评分为>2.0。有趣的是，在这项研究中分析的少数德系犹太人（n = 11）对这种联系的贡献不成比例。对假定的前列腺癌易感基因PG1（先前定位于8p22-23区域）进行HPC先证者突变筛查，并对病例受试者（包括HPC先证者和不相关病例受试者）和未受影响的对照组进行关联分析。PG1基因snp或其他序列变异的等位基因、基因型或单倍型频率在病例和对照组之间无统计学差异。然而，病例受试者在所有三个PG1 snp中表现出更高的低频率等位基因纯合率的趋势，并且观察到PG1变体向病例受试者的过度传播。总之，这些结果为前列腺癌易感基因8p22-23的存在提供了证据。评估PG1基因和其他候选基因在这一领域似乎是有必要的。
Multiple lines of evidence have implicated the short arm of chromosome 8 as harboring genes important in prostate carcinogenesis. Although most of this evidence comes from the identification of frequent somatic alterations of 8p loci in prostate cancer cells (e.g., loss of heterozygosity), studies have also suggested a role for 8p genes in mediation of inherited susceptibility to prostate cancer. To further examine this latter possibility, we performed linkage analyses, in 159 pedigrees affected by hereditary prostate cancer (HPC), using 24 markers on the short arm of chromosome 8. In the complete set of families, evidence for prostate cancer linkage was found at 8p22-23, with a peak HLOD of 1.84 (P = .004), and an estimate of the proportion of families linked (alpha) of 0.14, at D8S1130. In the 79 families with average age at diagnosis >65 years, an allele-sharing LOD score of 2.64 (P = .005) was observed, and six markers spanning a distance of 10 cM had LOD scores >2.0. Interestingly, the small number of Ashkenazi Jewish pedigrees (n = 11) analyzed in this study contributed disproportionately to this linkage. Mutation screening in HPC probands and association analyses in case subjects (a group that includes HPC probands and unrelated case subjects) and unaffected control subjects were carried out for the putative prostate cancer-susceptibility gene, PG1, previously localized to the 8p22-23 region. No statistical differences in the allele, genotype, or haplotype frequencies of the SNPs or other sequence variants in the PG1 gene were observed between case and control subjects. However, case subjects demonstrated a trend toward higher homozygous rates of less-frequent alleles in all three PG1 SNPs, and overtransmission of a PG1 variant to case subjects was observed. In summary, these results provide evidence for the existence of a prostate cancer-susceptibility gene at 8p22-23. Evaluation of the PG1 gene and other candidate genes in this area appears warranted.