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

遗传因素参与前列腺癌的发展早已提出。西方国家已经报道了使用大规模遗传性前列腺癌家系的遗传分析。尽管这些国家努力鉴定与前列腺癌相关的高危易感基因，但均未成功。在日本，尚未发表关于家族性前列腺癌遗传分析的报告。在本研究中，我们提出了一个假说，即前列腺癌的家族聚集性是由于低风险基因的遗传多态性。许多基因参与这一类别：本研究采用PCR-RFLP、SSCP和直接测序等方法，分析了雄激素受体、雌激素受体、孕激素受体、维生素D受体、GST、CYP 1A 1、CYP 17、CYP 19、XRCC 1、p53、PSA、UGT 2B 15、SRD 5A、COMT、Cyclin D1、CDKNA 1、IGFBP 3等基因的遗传多态性，发现RNASEL Asp 541 Glu、HPC 2A 1a 541 Thr、p53密码子72 Arg/Pro、CYP 19 [TTTA]n、CyclinD 1 A870 G、CYP 1A 1 M1+M2、CDKNA 1 C/T、IGFBP 3 A/A、XRCC 1 Arg 399 G1 n、G S T p1、T1、M1、ER+ CYP 19 +COMT、UGT 2B 15 D/Y、UGT 2B 15 + CYP 19与前列腺癌风险相关。这些信息将有助于识别前列腺癌发展的高危人群。临床分期与RNASEL、p53、Cyclin D1和CYP 1A 1基因型相关，而病理分级与RNASEL、p53、IGFBP 3和CYP 1A 1基因型相关。这些信息将有助于识别前列腺癌发展的高危人群，并对前列腺癌的治疗方案进行分层。

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.