Inter- and intra-patient molecular heterogeneity of primary and metastatic prostate cancer (PCa) confers variable clinical outcome and poses a formidable challenge in disease management. High-throughput integrative genomics and functional approaches have untangled the complexity involved in this disease and revealed a spectrum of diverse aberrations prevalent in various molecular subtypes, including ETS fusion negative. Emerging evidence indicates that SPINK1 upregulation, mutations in epigenetic regulators or chromatin modifiers, and SPOP are associated with the ETS-fusion negative subtype. Additionally, patients with defects in a DNA-repair pathway respond to poly-(ADP-ribose)-polymerase (PARP) inhibition therapies. Furthermore, a new class of immunogenic subtype defined by CDK12 biallelic loss has also been identified in ETS-fusion-negative cases. This review focuses on the emerging molecular underpinnings driving key oncogenic aberrations and advancements in therapeutic strategies of this disease.

中文翻译：

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控制 ETS-融合阴性前列腺癌遗传复杂性的分子基础。

原发性和转移性前列腺癌 (PCa) 的患者间和患者内分子异质性带来了可变的临床结果，并对疾病管理提出了巨大的挑战。高通量整合基因组学和功能方法解开了这种疾病的复杂性，并揭示了各种分子亚型中普遍存在的各种畸变谱，包括 ETS 融合阴性。新出现的证据表明 SPINK1 上调、表观遗传调节剂或染色质修饰剂的突变以及 SPOP 与 ETS 融合阴性亚型有关。此外，DNA 修复途径缺陷的患者对多聚 (ADP-核糖)-聚合酶 (PARP) 抑制疗法有反应。此外，在 ETS 融合阴性病例中也发现了由 CDK12 双等位基因缺失定义的一类新的免疫原性亚型。本综述重点关注推动关键致癌畸变的新兴分子基础和该疾病治疗策略的进展。