Loss of androgen receptor (AR) signaling dependence occurs in approximately 15%-20% of advanced treatment-resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration-resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastatic tumor biopsy, which is invasive for patients and sometimes challenging to diagnose due to morphologic heterogeneity. By studying whole-exome sequencing and whole-genome bisulfite sequencing of cell free DNA (cfDNA) and of matched metastatic tumor biopsies from patients with metastatic prostate adenocarcinoma and CRPC-NE, we identified CRPC-NE features detectable in the circulation. Overall, there was markedly higher concordance between cfDNA and biopsy tissue genomic alterations in patients with CRPC-NE compared with castration-resistant adenocarcinoma, supporting greater intraindividual genomic consistency across metastases. Allele-specific copy number and serial sampling analyses allowed for the detection and tracking of clonal and subclonal tumor cell populations. cfDNA methylation was indicative of circulating tumor content fraction, reflective of methylation patterns observed in biopsy tissues, and was capable of detecting CRPC-NE-associated epigenetic changes (e.g., hypermethylation of ASXL3 and SPDEF; hypomethylation of INSM1 and CDH2). A targeted set combining genomic (TP53, RB1, CYLD, AR) and epigenomic (hypo- and hypermethylation of 20 differential sites) alterations applied to ctDNA was capable of identifying patients with CRPC-NE.

中文翻译：

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循环中的肿瘤DNA谱可识别向去势抵抗性神经内分泌前列腺癌的转化。

约15％-20％的晚期抗治疗性前列腺癌发生雄激素受体（AR）信号依赖性丧失，这在临床上可能表现为从前列腺腺癌组织学转变为去势抵抗性神经内分泌前列腺癌（CRPC-NE） 。CRPC-NE的诊断当前依赖于转移性肿瘤活检，该活检对患者具有侵入性，有时由于形态学异质性有时难以诊断。通过研究来自转移性前列腺腺癌和CRPC-NE患者的无细胞DNA（cfDNA）和匹配的转移性肿瘤活检的全基因组测序和全基因组亚硫酸氢盐测序，我们确定了循环中可检测到的CRPC-NE特征。总体，与去势抵抗性腺癌相比，CRPC-NE患者的cfDNA与活检组织基因组改变之间的一致性更高，支持了跨转移的更大的个体内基因组一致性。等位基因特异的拷贝数和连续采样分析可以检测和追踪克隆和亚克隆肿瘤细胞群。cfDNA甲基化指示循环肿瘤含量分数，反映活检组织中观察到的甲基化模式，并且能够检测CRPC-NE相关的表观遗传变化（例如ASXL3和SPDEF的甲基化过高； INSM1和CDH2的甲基化过低）。结合了基因组（TP53，RB1，CYLD，