前列腺癌进展和去势抵抗个体差异的遗传研究

Over-diagnosis and over-treatment of indolent prostate cancer and the development of castration-resistant prostate cancer (CRPC) after androgen deprivation therapy are two major problems in prostate cancer diagnosis and treatment. There is a large individual difference in prostate cancer progression and time to develop CRPC and it may be influenced by genetic factors. In the past few years, genome-wide association studies (GWAS) has made significant progress and discovered more than 40 prostate cancer susceptibility loci. However, no genetic variants that are associated with prostate cancer progression and development of CRPC have been identified. To address these scientific problems and take advantages of already completed GWAS of 400 prostate cancer patients, we propose to use two-stage case-case and follow-up study designs to 1) screen for genetic variants that are associated with prostate cancer progression and time to develop CRPC ; 2) confirm the associations in additional 800 case samples; 3) use functional assays to study the molecular mechanisms of these genetic variants and their target genes in prostate cancer progression and CRPC. Results from this study may help to reduce over-diagnosis and over-treatment of indolent prostate cancer, and provide new insights about therapeutic targets for the development of novel drugs, and promote individualized treatment of prostate cancer.

非进展性前列腺癌的过度诊断和治疗以及经去势治疗后的患者产生去势抵抗（CRPC）是临床前列腺癌诊疗中存在的两个重要问题。前列腺癌进展和去势抵抗过程中存在个体差异，遗传因素可能发挥关键作用。过去几年，全基因组关联研究（GWAS）在前列腺癌遗传研究中取得了重大进展，发现了40多个前列腺癌易感位点，但前列腺癌进展和CRPC转化的遗传机制尚不明确。为阐述这一科学问题，本课题拟应用两阶段病例-病例和病例随访研究设计，基于已完成的400例前列腺癌GWAS数据，1）通过收集补充临床病理和随访信息，筛选与前列腺癌进展和CRPC转化相关的遗传位点；2）在新的800例样本中对结果进行验证，找出真正遗传位点；3）采用分子生物学手段研究相关遗传变异及其靶基因参与前列腺癌进展及去势抵抗的分子机制。研究结果将有助于减少非进展性前列腺癌的过度诊疗，为研发新型药物治疗靶点提供新思路，促进前列腺癌个体化诊疗。

遗传因素影响着前列腺癌的发生发展，项目组前期已完成中国人群前列腺癌全基因组关联研究以及外显子芯片扫描，为本项目的开展奠定了基础，本课题基于前期数据结果：1）挑选出可能与前列腺癌进展相关的遗传位点进行验证，并对两阶段结果进行合并分析，寻找与前列腺癌进展相关的遗传位点；2）联合同样开展了前列腺癌GWAS的日本合作单位，共同开展meta－GWAS研究。最终成功鉴定到两个新的亚洲人群前列腺癌的风险基因位点11p15.4 (rs12791447, P＝3.59×10-8; PPFIBP2)和14q23.2 (rs58262369, P=6.05×10-10; ESR2)；3）基于这些在中国人群中已确定的人前列腺癌风险相关的SNPs，我们建立了一个用于评估前列腺癌风险的遗传分数，并在多个前列腺穿刺病人队列中展示了其预测阳性穿刺(前列腺癌)率的临床用途。