Genome-wide scan for prostate cancer susceptibility genes in the Johns Hopkins hereditary prostate cancer families

BACKGROUND: Although the subject of intensive study, the genetic influences responsible for familial clustering of prostate cancer remain largely unidentified. Genome-wide scans for linkage in prostate cancer families can be used to systematically search for genes capable of affecting risk for the disease. METHODS: All available family members from 188 families, each having at least three first-degree relatives affected with prostate cancer, were genotyped at 406 markers distributed across the genome at average intervals of less than 10 cM. Genotype data was analyzed using primarily a non-parametric, multipoint approach, although parametric analyses were performed as well. RESULTS: The strongest evidence for linkage was observed at D4S1615, at 4q21 (LOD of 2.8, P = 0.0002). Two other regions had LOD scores over 2.0: at 9q34 (marker D9S1826, LOD = 2.17, P = 0.0008) and at 2q23 (marker D2S151, LOD = 2.03, P = 0.001). An additional 12 regions had LOD scores over 1.0, including markers at 1q24-25 and 7q22 having scores >1.6. Stratifying the linkage results by age of diagnosis indicated that the linkages to chromosomes 2 and 4 were strongest in families with early and late ages of diagnosis, respectively. CONCLUSIONS: Our data implicate several new loci as harboring prostate cancer susceptibility genes, and provide confirmatory evidence of linkage at several loci identified previously in other genome-wide scans, including the three regions (4q21, 9q34, and 2q23) with strongest evidence for prostate cancer linkage. These data also emphasize the need to combine linkage data from large numbers of prostate cancer families in efforts to effectively address the extensive heterogeneity that characterizes genetic aspects of this disease.     

Genome-wide scan for prostate cancer susceptibility genes using families from the University of Michigan prostate cancer genetics project finds evidence for linkage on chromosome 17 near BRCA1

BACKGROUND: Previous linkage studies have suggested prostate cancer susceptibility genes located on chromosomes 1, 20, and X. Several putative prostate cancer candidate genes have also been identified including RNASEL, MSR1, and ELAC2. Presently, these linkage regions and candidate genes appear to explain only a small proportion of hereditary prostate cancer cases suggesting the need for additional whole genome analyses. METHODS: A genome-wide mode-of-inheritance-free linkage scan, using 405 genetic markers, was conducted on 175 pedigrees, the majority containing three or more affected individuals diagnosed with prostate cancer. Stratified linkage analyses were performed based on previously established criteria. RESULTS: Results based on the entire set of 175 pedigrees showed strong suggestive evidence for linkage on chromosome 17q (LOD = 2.36), with strongest evidence coming from the subset of pedigrees with four or more affected individuals (LOD = 3.27). Race specific analyses revealed strong suggestive evidence for linkage in our African-American pedigrees on chromosome 22q (LOD = 2.35). CONCLUSIONS: Genome-wide analysis of a large set of prostate cancer families indicates new areas of the genome that may harbor prostate cancer susceptibility genes. Specifically, our linkage results suggest that there is a prostate cancer susceptibility gene on chromosome 17 that is independent of ELAC2. Further research including combined analyses of independent genome-wide scan data may clarify the most important regions for future investigation.     

Genome-wide screen for prostate cancer susceptibility genes in men with clinically significant disease

BACKGROUND: One of the difficulties confronting genetic studies of prostate cancer is the complex and heterogeneous etiology. Given the high population frequency of lesions meeting the histological definition of prostate cancer, a significant portion of men with a positive family history may be diagnosed due to increased surveillance and associated higher likelihood of biopsy. Over diagnosis decreases power to detect genes that increase susceptibility to a clinically significant prostate cancer. METHODS: We re-evaluated all 623 men with prostate cancer in our 188 hereditary prostate cancer families and identified a subset of 244 men with more aggressive disease based upon meeting at least one of the following clinical and/or pathologic criteria: tumor grade Gleason score > or = 7, tumor stage T2c or higher, pretreatment PSA > or = 20 ng/ml, rising PSA after treatment, evidence of metastasis, or death from prostate cancer. RESULTS: Genome-wide screens were re-performed by defining men as affected only if they met the criteria for clinically significant disease. The new analyses identified stronger evidence for linkage in Xq27-28 and 22q, as well as several novel loci, including 3p and 9p. CONCLUSIONS: Although, these results need to be confirmed in independent studies, our approach represents an important step to overcome the impact of over diagnosis in genetic studies of prostate cancer. Larger studies that incorporate this approach are needed.     

Inherited susceptibility for aggressive prostate cancer

Whether or not there is inherited basis for prostate cancer aggressiveness is not clear, but advances in DNA analysis should provide an answer to this question in the very near future.     

Genome linkage screen for prostate cancer susceptibility loci: results from the Mayo Clinic Familial Prostate Cancer Study

Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a twofold to threefold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Several putative loci identified by genetic linkage have been reported to exist on chromosomes 1 (HPC1, PCAP, and CAPB), X (HPCX), 17 (HPC2), and 20 (HPC20), with genes RNASEL (HPC1) and ELAC2 (HPC2) tentatively defined. In this study, we report our genome linkage scan in 160 prostate cancer families, using the ABI Prism Linkage Mapping Set Version 2 with 402 microsatellite markers. The most significant linkage was found for chromosome 20, with a recessive model heterogeneity LOD score (HLOD) of 4.77, and a model-free LOD score (LOD - ZLR) of 3.46 for the entire group of pedigrees. Linkage for chromosome 20 was most prominent among families with a late age of diagnosis (average age at diagnosis >/= 66 years; maximum LOD - ZLR = 2.82), with <5 affected family members (LOD - ZLR = 3.02), with presence of hereditary prostate cancer (LOD - ZLR = 2.81), or with no male-to-male transmission of disease (LOD - ZLR = 3.84). No other chromosome showed significant evidence for linkage. However, chromosomes 6 and X showed suggestive results, with maximum LOD - ZLR values of 1.38 and 1.36, respectively. Subset analyses suggest additional chromosomal regions worth further follow-up.     

前列腺癌细胞凋亡通路基因表达与凋亡反应性的关系

目的　探讨凋亡通路基因表达改变与前列腺癌细胞凋亡反应性的关系。　方法　凋亡诱导剂鬼臼乙叉甙分别作用前列腺癌激素敏感与不敏感细胞LNCaP和PC 3,Hoechst 332 5 8染色检测凋亡发生率。收集LNCaP和PC 3细胞后提取总RNA ,合成cDNA探针并以生物素标记 ,在凋亡通路特异基因寡核苷酸片段cDNA膜上进行杂交反应 ,检测基因mRNA表达。　结果　鬼臼乙叉甙能诱导两种细胞凋亡 ,但PC 3细胞的凋亡反应性小于LNCaP细胞。与LNCaP细胞比较 ,PC 3细胞显著下调的基因为Bcl1 0、CIDE A、GADD4 5a和RIP2 ,以及Caspase 4、5和 6 ,显著上调的基因为TRAF4。两种细胞均强烈表达Caspase 1 4和TNFR2。　结论　凋亡通路基因表达改变与前列腺癌细胞凋亡反应性不同有关 ,在前列腺癌激素敏感性转化中可能有重要作用     

Mutation screening and association study of the candidate prostate cancer susceptibility genes MSR1, PTEN, and KLF6

BACKGROUND: MSR1, PTEN, and KLF6 have been implicated as candidate susceptibility genes for prostate tumorigenesis. METHODS: Three hundred Jewish prostate cancer patients were screened for alterations in these genes. RESULTS: MSR1 was conserved in all patients. PTEN screening revealed a novel missense mutation and a silent change. Five KLF6 alterations were detected in 17 patients, including Q160X, the only nonsense KLF6 germline mutation described to date in a cancer patient. The KLF6 IVS1-27G>A polymorphism, recently associated with prostate cancer risk, was detected in 11.9% of the patients and 17.3% of the controls (P = 0.043). IVS1-27A allele frequency was significantly lower in prostate cancer patients (P = 0.030), specifically in Ashkenazi patients (P = 0.047) compared to controls. CONCLUSIONS: We found no evidence that MSR1 and PTEN germline mutations are associated with prostate cancer risk in Jews. The negative association between KLF6 IVS1-27A and prostate cancer risk supports a population-specific effect of susceptibility alleles in prostate tumorigenesis.     

Genome-wide linkage analysis for aggressive prostate cancer in Utah high-risk pedigrees

BACKGROUND: It has been proposed that studying alternative phenotypes, such as tumor aggressiveness, may be a solution for overcoming the apparent heterogeneity that has hindered the identification of prostate cancer (PC) genes. We present the results of a genome-scan for predisposition to aggressive PC using the Utah high-risk pedigree resource. METHODS: We identified 259 subjects with aggressive PC in 57 extended and nuclear families. Parametric and non-parametric multipoint linkage statistics were calculated for a genome-wide set of 401 microsatellite markers using the MCLINK software package. Stratification analyses by the number of affected subjects per pedigree (<5, >or=5) and the average age at diagnosis of affected subjects (<70 years, >or=70 years) were also performed. RESULTS: No significant results were observed at the genome-wide level, but suggestive evidence for linkage was observed on chromosomes 9q (HLOD = 2.04) and 14q (HLOD = 2.08); several pedigrees showed individual evidence for linkage at each locus (LOD > 0.58). The subset of pedigrees with earlier age at onset demonstrated nominal linkage evidence on chromosomes 3q (HLOD = 1.79), 8q (HLOD = 1.67), and 20q (HLOD=1.82). The late-onset subset showed suggestive linkage on chromosome 6p (HLOD = 2.37) and the subset of pedigrees with fewer than five affected subjects showed suggestive linkage on chromosome 10p (HLOD = 1.99). CONCLUSIONS: Linkage evidence observed on chromosomes 6p, 8q, and 20q support previously reported PC aggressiveness loci. While these results are encouraging, further research is necessary to identify the gene or genes responsible for PC aggressiveness and surmount the overarching problem of PC heterogeneity.     

应用基因微矩阵芯片筛选前列腺癌的相关基因

目的　应用基因微矩阵芯片筛选前列腺癌的相关基因。　方法　按一步法提取前列腺癌及正常前列腺组织总RNA ,并纯化mRNA ,以包含 4 0 96个cDNA的基因微矩阵芯片对前列腺癌及正常前列腺基因表达谱进行分析。　结果　前列腺癌及正常前列腺组织中表达差别有显著性意义的基因共 3 4 1条 ,其中前列腺癌下调基因 12 8条 ,上调基因 2 13条 ;表达差别有极显著性意义的基因有15条 ,其中显著下调基因 6条 ,显著上调基因 9条。　结论　基因微矩阵芯片可有效筛查出前列腺癌的相关基因 ;前列腺癌发生发展由多种类型的基因参与调控 ,而非单一因素所致     

纳米金标芯片检测用于前列腺癌多基因诊断的实验研究

目的利用纳米金标基因芯片检测前列腺癌(prostatic cancer,PCa)特异性多基因,探讨其临床意义。方法应用纳米金标基因芯片对11个PCa特异性基因靶标(IGF1、P27、AR、PSMA、KLK3、PCNA、Ki-67、KLK1、KLK2、TMPRSS2、SREBF2)进行检测,对各基因表达进行研究。结果纳米金标基因芯片检测单链核酸的灵敏度达到80f mol/L,在优化条件下,目标上调基因呈阳性表达,下调及阴性对照无显色,可肉眼分辨。结论纳米金标基因芯片技术检测PCa特异性基因方法快速简单,灵敏度高,特异性好,可对选定的11个目标基因定性及半定量检测,不需要借助于特殊仪器,操作简单,样本保存时间长,在普通实验室即可完成。纳米金标基因芯片检测有望成为PCa早期诊断的新一代芯片检测系统。     

Mutation screen and association study of EZH2 as a susceptibility gene for aggressive prostate cancer

BACKGROUND: Several linkage studies have provided evidence for a prostate cancer aggressiveness gene on chromosome 7q. This report details the results of the first mutation screen and association study of EZH2 (located at 7q35) as a potential candidate gene for the development of aggressive prostate cancer. METHODS: In 10 families with linkage of chromosome 7q31-33 to aggressive prostate cancer, we sequenced the promoter region and all 20 exons of EZH2. We genotyped 11 variants in 287 prostate cancer probands and 96 controls. Association between the disease and the variants/haplotypes was evaluated taking into account clinical data and disease recurrence. RESULTS: The individual variation sites did not show significant differences in the allele frequencies between cases and controls. In contrast, one haplotype had a higher frequency in controls, and another haplotype was significantly more frequent in cases with low grade tumors (GI/II) and progression free survival (NED). CONCLUSION: We have possibly identified haplotypes which mark alleles that have a beneficial effect on the development of prostate cancer. Moreover, our results suggest that genetic variations of the EZH2 gene are not responsible for the linkage of 7q to aggressive prostate cancer.     

基于多组学整合的前列腺癌同源框基因NKX3.1调控相关基因研究

目的:同源框基因NKX3.1与前列腺癌发生和进展关系密切,本研究探索前列腺癌中NKX3.1调控的相关下游节点基因及可能的调控机制。方法:首先对前列腺癌相关的公开数据库进行生物信息多组学数据分析,筛选出与NKX3.1可能相关的5个下游信号通路节点基因;利用NKX3.1表达载体转染前列腺癌细胞系PC-3,实现NKX3.1在前列腺癌细胞过表达,通过Real-Time PCR验证上述节点基因转录水平表达改变。结果:经过生物信息多组学分析,筛选出在前列腺癌中与NKX3.1密切相关的信号通路节点基因MAZ、LPAR3、TUBB2A、CAMKK2和CPT1B。细胞水平验证实验表明,在NKX3.1过表达的前列腺癌细胞PC-3中表达显著变化(变化倍数3)的基因有CPT1B(上调4.641倍)、CAMKK2(上调3.439倍)、MAZ(下调5.236倍)。结论:NKX3.1可能通过下调MAZ、诱导CAMKK2和CPT1B表达抑制前列腺癌的发生或进展,其中可能通过CAMKK2下游调控通路及CPT1B参与调节前列腺癌代谢过程。