前列腺癌的颅内转移虽不常见，但其临床侵袭性较强。对前列腺癌颅内转移进行详细的分子特征描述将有助于我们理解其发病机制，并寻找新的治疗策略。我们评估了36名转移至硬脑膜或脑实质的前列腺癌患者的临床和分子特征。我们对10个颅内前列腺癌转移灶进行了全基因组测序（WGS），并对后来发展为转移性疾病（n = 6）以及非脑前列腺癌转移灶（n = 36）的男性原发前列腺肿瘤进行了WGS。这项首次对前列腺颅内转移进行的全基因组测序研究得出了几个新见解。首先，与原发肿瘤组织相比，前列腺癌颅内转移显示出更高的复杂结构变异多样性。染色体断裂和染色体重排事件似乎较为常见，但与非脑转移灶相比，特定结构变异类别的富集较少。其次，我们观察到7/10（70％）颅内转移灶中存在与AR基因相关的异常，包括AR增强子增益；8/10（80％）颅内转移灶出现涉及TP53的功能缺失异常，2/10（20％）颅内转移灶有RB1的缺失功能异常，2/10（20％）颅内转移灶有BRCA2的缺失功能异常，8/10（80％）颅内转移灶引起PI3K/AKT/PTEN通路的激活。这些变异在被同时或连续得到的来自同一患者的其它疾病部位的肿瘤组织中也经常存在。第三，克隆分析指出了在前列腺癌患者的转移扩散中起作用的基因组因素和进化瓶颈。这些结果描述了颅内转移背后的侵袭性分子特征，可能为未来的诊断和治疗方法提供了指导。© 2023. Nature Publishing Group UK.

Intracranial metastases in prostate cancer are uncommon but clinically aggressive. A detailed molecular characterization of prostate cancer intracranial metastases would improve our understanding of their pathogenesis and the search for new treatment strategies. We evaluated the clinical and molecular characteristics of 36 patients with metastatic prostate cancer to either the dura or brain parenchyma. We performed whole genome sequencing (WGS) of 10 intracranial prostate cancer metastases, as well as WGS of primary prostate tumors from men who later developed metastatic disease (n = 6) and nonbrain prostate cancer metastases (n = 36). This first whole genome sequencing study of prostate intracranial metastases led to several new insights. First, there was a higher diversity of complex structural alterations in prostate cancer intracranial metastases compared to primary tumor tissues. Chromothripsis and chromoplexy events seemed to dominate, yet there were few enrichments of specific categories of structural variants compared with non-brain metastases. Second, aberrations involving the AR gene, including AR enhancer gain were observed in 7/10 (70%) of intracranial metastases, as well as recurrent loss of function aberrations involving TP53 in 8/10 (80%), RB1 in 2/10 (20%), BRCA2 in 2/10 (20%), and activation of the PI3K/AKT/PTEN pathway in 8/10 (80%). These alterations were frequently present in tumor tissues from other sites of disease obtained concurrently or sequentially from the same individuals. Third, clonality analysis points to genomic factors and evolutionary bottlenecks that contribute to metastatic spread in patients with prostate cancer. These results describe the aggressive molecular features underlying intracranial metastasis that may inform future diagnostic and treatment approaches.© 2023. Nature Publishing Group UK.