Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
JCI Insight. 2022 Sep 8;7(17):e161370. doi: 10.1172/jci.insight.161370.
The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation shapes the genomic landscape of this disease across disease states. We uniformly characterized structural alterations across 531 localized and 143 metastatic prostate cancers profiled by whole genome sequencing, 125 metastatic samples of which were also profiled via whole transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes enriched in mCRPC and TMPRSS2-ERG rearrangements enriched in localized prostate cancer. We defined 9 subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.
在针对抑制雄激素受体 (AR) 信号的治疗压力下，前列腺癌的复杂基因组景观在疾病状态下不断演变。虽然已经广泛定义了前列腺癌中显著改变的基因，但对于结构变异如何在疾病状态下塑造这种疾病的基因组景观，系统分析较少。我们通过全基因组测序对 531 例局部前列腺癌和 143 例转移性前列腺癌进行了一致的结构改变特征分析，其中 125 例转移性样本还通过全转录组测序进行了分析。我们观察到局部和转移性去势抵抗性前列腺癌 (mCRPC) 中存在明显的显著重现断点，AR、MYC、FOXA1 和 LSAMP 基因侧翼的非编码区域普遍存在改变，mCRPC 中富集，局部前列腺癌中富集 TMPRSS2-ERG 重排。我们根据结构变异的特征定义了 9 种 mCRPC 亚类，每个亚类都与独特的遗传特征和临床结果相关。我们的研究结果全面定义了前列腺癌中结构变异的模式，并根据全基因组分析确定了具有临床可操作性的亚组。
