Genetic analysis of prostate cancer : identification of susceptibility gene in 1p36 and 8p23 loci

我们对家族性前列腺癌的同胞对进行了相似性分析，发现1 p36和8 p23位点存在连锁关系。在本项目中，我们进一步研究了这些区域中基因的关联和功能研究。巨噬细胞清道夫受体1（macrophase scavenger receptor 1，MSR 1）是已知的一个易感基因，它含有7个错义突变（Pro36 Ala，Ser 41 Tyr，Val 113 Ala，Asp 174 Tyr，Pro275 Ala，Gly 369 Ser，His 441 Arg），1个无义突变（Arg 293 X）和4个内含子序列变异（PRO3，INDELI，IVS-59，INDEL 7）。在本研究中，我们没有发现Pro36 Ala，Ser 41 Tyr，Val 113 Ala，asp 194 Tyr，Gly 369 Ser，His 441 Arg和IVS-59，但我们观察到Lys 338 X，3个启动子突变，2个内含子突变，6个外显子11突变。相关性研究显示，PRO3的G等位基因和INDEL 1的存在与前列腺癌的风险显著相关。我们进一步观察到FDFT 1（法尼基二磷酸法尼基转移酶1）的rs 26545629与前列腺癌风险的显著相关性。FDFT 1基因表达的敲低导致前列腺癌细胞在体外增殖的显着抑制。因此，我们观察到8 p23位点的一些基因的家族性前列腺癌的风险。

We have studied the likage analysis of sib-pair of familial prostate cancer, and have found suggestive linkage in 1p36 and 8p23 loci. In this project, we further studied the association and functional studies of genes in these regions. One of the know susceptibility gene, macrophase scavenger receptor 1 (MSR1) contains seven missense mutations (Pro36Ala, Ser4lTyr, Val113Ala, Asp174Tyr, Pro275Ala, Gly369Ser, His441Arg) , one nonsense mutation (Arg293X), and 4 sequence variants in introns (PRO3, INDELI, IVS-59, INDEL7). In this study, we did not identified Pro36Ala, Ser41Tyr, Val113Ala, asp194Tyr, Gly369Ser, His441Arg, and IVS-59, however, we observed Lys338X, 3 mutation in promoter, 2 mutation in introns, 6 mutations in Exon 11. Association studied showed that G allele of PRO3 and presence of INDEL1 were significantly associated with prostate cancer risk. We further observed the significant association with rs26545629 of FDFT1 (farnesydiphosphate farnesyltransferase 1) and prostate cancer risk. Knock-down of FDFT1 gene expression led to the significant inhibition of prostate cancer cell proliferation in vitro. Thus, we observed the familial prostate cancer risk in some genes in 8p23 locus.