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兄弟姐妹对进行了相似度分析，发现在1p36和8p23位点存在提示连锁。在本项目中，我们进一步研究了这些区域基因的关联和功能研究。已知的易感基因之一，巨相清除受体1 （MSR1）包含7个错义突变（Pro36Ala, Ser4lTyr, Val113Ala, Asp174Tyr, Pro275Ala, Gly369Ser, His441Arg）， 1个无义突变（Arg293X）和4个内含子序列变异（PRO3， INDELI, IVS-59, INDEL7）。在本研究中，我们没有发现Pro36Ala、Ser41Tyr、Val113Ala、asp194Tyr、Gly369Ser、His441Arg和IVS-59，但我们发现了Lys338X，启动子突变3个，内含子突变2个，外显子11突变6个。关联研究显示PRO3的G等位基因和INDEL1的存在与前列腺癌的发病有显著相关性。我们进一步观察到FDFT1（法尼二磷酸法尼基转移酶1）与rs26545629与前列腺癌风险的显著相关性。敲低FDFT1基因表达可显著抑制前列腺癌细胞的体外增殖。因此，我们观察到家族性前列腺癌的风险在8p23位点的一些基因。

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.