Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Cell. 2018 Jun 14;173(7):1770-1782.e14. doi: 10.1016/j.cell.2018.04.034.
Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. CDK12 mutant cases are baseline diploid and do not exhibit DNA mutational signatures linked to defects in homologous recombination. CDK12 mutant cases are associated with elevated neoantigen burden ensuing from fusion-induced chimeric open reading frames and increased tumor T cell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy.
通过对 360 例转移性去势抵抗性前列腺癌（mCRPC）样本的综合基因组分析，我们鉴定出一种新型前列腺癌亚型，其特征为 CDK12 的双等位基因缺失，与由 DNA 修复缺陷、ETS 融合和 SPOP 突变驱动的肿瘤相互排斥。与临床局限性疾病相比，CDK12 缺失在 mCRPC 中更为丰富，其特征为导致基因融合增加和明显差异基因表达的焦点串联重复（FTD）。与 CDK12 缺失相关的 FTD 导致涉及细胞周期和 DNA 复制的基因的高频率获得性增益。CDK12 突变病例在基线时为二倍体，并且不表现出与同源重组缺陷相关的 DNA 突变特征。CDK12 突变病例与融合诱导的嵌合开放阅读框引起的新抗原负荷增加以及肿瘤 T 细胞浸润/克隆扩增相关。因此，CDK12 失活定义了一种独特的 mCRPC 类别，可能受益于免疫检查点免疫治疗。
