Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, 208016, U.P., India.
Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, 208016, U.P., India.
Trends Mol Med. 2019 Nov;25(11):1024-1038. doi: 10.1016/j.molmed.2019.07.001. Epub 2019 Jul 25.
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.
原发和转移性前列腺癌（PCa）的患者内和患者间分子异质性导致不同的临床结局，并对疾病管理构成了巨大挑战。高通量的整合基因组学和功能方法已经理清了该疾病的复杂性，并揭示了各种分子亚型中普遍存在的一系列不同的异常，包括 ETS 融合阴性。新出现的证据表明，丝氨酸蛋白酶抑制剂 K1（SPINK1）上调、表观遗传调节剂或染色质修饰剂突变以及 SPOP 与 ETS 融合阴性亚型相关。此外，存在 DNA 修复途径缺陷的患者对聚（ADP-核糖）聚合酶（PARP）抑制治疗有反应。此外，在 ETS 融合阴性病例中，还发现了一种新的免疫原性亚型，其特征是 CDK12 双等位基因缺失。本综述重点介绍了推动关键致癌异常的新兴分子基础，以及该疾病治疗策略的进展。
