Bancroft Elizabeth K, Raghallaigh Holly Ni, Page Elizabeth C, Eeles Rosalind A
Urology Genetics, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, SM2 5PT, UK.
Oncogenetics Team, The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, UK.
Curr Genet Med Rep. 2021;9(4):47-58. doi: 10.1007/s40142-021-00202-5. Epub 2021 Oct 8.
Prostate cancer (PrCa) is the most common cancer in men in the western world and is a major source of morbidity and mortality. Currently, general population PrCa screening is not recommended due to the limitations of the prostate-specific antigen (PSA) test. As such, there is increasing interest in identifying and screening higher-risk groups. The only established risk factors for PrCa are age, ethnicity, and having a family history of PrCa. A significant proportion of PrCa cases are caused by genetic factors.
Several rare germline variants have been identified that moderately increase risk of PrCa, and targeting screening to these men is proving useful at detecting clinically significant disease. The use of a "polygenic risk score" (PRS) that can calculate a man's personalized risk based on a number of lower-risk, but common genetic variants is the subject of ongoing research. Research efforts are currently focusing on the utility of screening in specific at-risk populations based on ethnicity, such as men of Black Afro-Caribbean descent. Whilst most screening studies have focused on use of PSA testing, the incorporation of additional molecular and genomic biomarkers alongside increasingly sophisticated imaging modalities is being designed to further refine and individualise both the screening and diagnostic pathway. Approximately 10% of men with advanced PrCa have a germline genetic predisposition leading to the opportunity for novel, targeted precision treatments.
The mainstreaming of genomics into the PrCa screening, diagnostic and treatment pathway will soon become standard practice and this review summarises current knowledge on genetic predisposition to PrCa and screening studies that are using genomics within their algorithms to target screening to higher-risk groups of men. Finally, we evaluate the importance of germline genetics beyond screening and diagnostics, and its role in the identification of lethal PrCa and in the selection of targeted treatments for advanced disease.
前列腺癌（PrCa）是西方世界男性中最常见的癌症，是发病和死亡的主要原因。目前，由于前列腺特异性抗原（PSA）检测的局限性，不建议对普通人群进行PrCa筛查。因此，识别和筛查高危人群的兴趣日益增加。PrCa唯一已确定的风险因素是年龄、种族和有PrCa家族史。相当一部分PrCa病例是由遗传因素引起的。
已鉴定出几种罕见的种系变异，它们适度增加了PrCa的风险，事实证明针对这些男性进行筛查有助于检测具有临床意义的疾病。使用“多基因风险评分”（PRS），根据一些低风险但常见的基因变异来计算男性的个性化风险，是正在进行的研究课题。目前的研究工作集中在基于种族的特定高危人群筛查的效用上，例如非洲加勒比裔黑人男性。虽然大多数筛查研究都集中在PSA检测的使用上，但越来越复杂的成像模式与额外的分子和基因组生物标志物相结合，旨在进一步优化和个性化筛查及诊断途径。大约10%的晚期PrCa男性有生殖系遗传易感性，这为新型靶向精准治疗提供了机会。
基因组学在PrCa筛查、诊断和治疗途径中的主流化将很快成为标准做法，本综述总结了目前关于PrCa遗传易感性的知识以及在其算法中使用基因组学将筛查目标对准高危男性群体的筛查研究。最后，我们评估了生殖系遗传学在筛查和诊断之外的重要性，及其在识别致命性PrCa和选择晚期疾病靶向治疗中的作用。
