Genetic analysis of prostate cancer : comprehensive assessment of genetic polymorphisms and application to genetic diagnosis

长期以来，人们一直认为前列腺癌的发生与遗传因素有关。西方国家已经报道了使用大规模遗传性前列腺癌家系进行遗传分析的报道。尽管努力确定与前列腺癌相关的高危易感基因，但这些国家的研究都失败了。在日本，还没有关于家族性前列腺癌的基因分析的报道。在这项研究中，我们提出了前列腺癌的家族聚集性是由于低危基因的遗传多态性所致的假说。该类别涉及多种基因：雄激素受体、雌激素受体、孕激素受体、维生素D受体、GSTs、CYP 1A1、CyP17、CyP19、XRCC1、P53、PSA、UGT2B15、SRD5A、COMT、Cyclin D1、CDKNA1、IGFBP3等。结果发现，RNASE基因Asp541Glu、HPC2A1a541Thr、P53密码子72Arg/Pro、Cyp19[TTTA]n、CyclinD1A870G、CyP1A1 M1+M2、CDKNA1C/T、IGFBP3 A/A、XRCC1Arg399G1n、G S T p1、T1、M1、ER+CyP19+COMT、UGT2B15 D/Y、UGT2B15+CyP19与前列腺癌的发生相关。这些信息将有助于识别前列腺癌的高危人群。临床分期与RNASEL、P53、Cyclin D1和CYP1A1等位基因有关，而病理分级与RNASE、P53、IGFBP3和CYP1A1等位基因有关。这些信息将有助于识别前列腺癌的高危人群，并对前列腺癌的治疗选择进行分层。

Involvement of genetic factors to prostate cancer development has long been proposed. Genetic analysis using large scale hereditary prostate cancer pedigrees has been reported from Western countries. Despite the effort to identify the high risk susceptibility gene associated with prostate cancer have been failed from those countries. In Japan, no reports have been published on genetic analysis of familial prostate cancer. In this study, we proposed the hypothesis that familial aggregation of prostate cancer was due to genetic polymorphisms of low risk genes. Many genes are involved in this category : androgen receptor, estrogen receptor, progesterone receptor, vitamin D receptor, GSTs,CYP 1A1,CYP17,CYP19,XRCC1,p53,PSA,UGT2B15,SRD5A,COMT,Cyclin D1,CDKNA1,IGFBP3,and so on. We analyzed genetic polymorphisms of these genes by PCR-RFLP,SSCP and direct sequencing methods.We found that RNASEL Asp541Glu,HPC2 A1a541Thr,p53codon 72 Arg/Pro、CYP19 [TTTA]n、CyclinD1 A870G、CYP1A1 M1+M2, CDKNA1 C/T,IGFBP3 A/A, XRCC1 Arg399G1n、G S T p1,T1,M1,ER+CYP19+COMT,UGT2B15 D/Y,UGT2B15+CYP19 are associated with prostate cancer risk. These information would be helpful to identify the high risk group for prostate cancer development. Clinical stage was associated with RNASEL,p53,Cyclin D1,and CYP1A1 genotypes, whereas, pathological grade was associated with RNASEL,p53,IGFBP3,and CYP1A1 genotypes. These information would be helpful to identify the high risk group for prostate cancer development and to stratify the treatment options to prostate cancer.