通过链接读取基因组测序揭示推动去势抵抗性前列腺癌的结构改变。
Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing.
机构信息
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
出版信息
Cell. 2018 Jul 12;174(2):433-447.e19. doi: 10.1016/j.cell.2018.05.036. Epub 2018 Jun 18.
Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%-87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered.
几乎所有的前列腺癌死亡都是由转移性去势抵抗性前列腺癌（mCRPC）引起的，但针对这种疾病状态的全基因组测序（WGS）研究很少。我们对 23 个 mCRPC 活检标本进行了连接读取 WGS，并对 86 名 mCRPC 患者的游离 DNA 测序数据进行了分析。除了影响已知前列腺癌基因的常见重排外，我们在大多数情况下还观察到 AR 基因座的复杂重排。出乎意料的是，与<2%的原发性前列腺癌相比，这些重排包括涉及 AR 上游增强子的高频串联重复，在 70%-87%的病例中发生。一部分病例在与 CDK12 失活相关的全基因组串联重复子表型背景下显示 AR 或 MYC 增强子重复，我们的发现强调了 mCRPC 的复杂基因组结构，确定了可能为前列腺癌治疗提供信息的改变，并表明非编码 mCRPC 基因组中仍有其他反复发生的事件有待发现。
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