Sandra and Edward Meyer Cancer Center and.
Department of Urology, Weill Cornell Medicine, New York, New York, USA.
J Clin Invest. 2021 May 17;131(10). doi: 10.1172/JCI147878.
BACKGROUNDMolecular characterization of prostate cancer (PCa) has revealed distinct subclasses based on underlying genomic alterations occurring early in the natural history of the disease. However, how these early alterations influence subsequent molecular events and the course of the disease over its long natural history remains unclear.METHODSWe explored the molecular and clinical progression of different genomic subtypes of PCa using distinct tumor lineage models based on human genomic and transcriptomic data. We developed transcriptional classifiers, and defined "early" and "late" categories of molecular subclasses from 8,158 PCa patients. Molecular subclasses were correlated with clinical outcomes and pathologic characteristics using Kaplan-Meier and logistic regression analyses.RESULTSWe identified PTEN and CHD1 alterations as subtype-specific late progression events specifically in ERG-overexpressing (ERG+) and SPOP-mutant tumors, respectively, and 2 distinct progression models consisting of ERG/PTEN (normal to ERG+ to PTEN-deleted) and SPOP/CHD1 (normal to SPOP-mutated to CHD1-deleted) with shared early tumorigenesis but distinct pathways toward progression. We found that within ERG+ and SPOP-mutant subtypes, late events were associated with worse prognosis. Importantly, the clinical and pathologic features associated with distinct late events at radical prostatectomy were strikingly different; PTEN deletions were associated with increased locoregional stage, while CHD1 deletions were only associated with increased grade, despite equivalent metastatic potential.CONCLUSIONThese findings suggest a paradigm in which specific subtypes of PCa follow distinct pathways of progression, at both the molecular and clinical levels. Therefore, the interpretation of common clinical parameters such as locoregional tumor stage may be influenced by the underlying tumor lineage, and potentially influence management decisions.FUNDINGProstate Cancer Foundation, National Cancer Institute, Urology Care Foundation, Damon Runyon Cancer Research Foundation, US Department of Defense, and the AIRC Foundation.
基于疾病自然史早期发生的潜在基因组改变，前列腺癌 (PCa) 的分子特征已经揭示了不同的亚型。然而，这些早期改变如何影响随后的分子事件以及疾病在其漫长自然史中的进程尚不清楚。
我们使用基于人类基因组和转录组数据的不同肿瘤谱系模型，探索了不同基因组亚型 PCa 的分子和临床进展。我们开发了转录分类器，并从 8158 例 PCa 患者中定义了“早期”和“晚期”分子亚型类别。使用 Kaplan-Meier 和逻辑回归分析，将分子亚型与临床结局和病理特征相关联。
我们发现 PTEN 和 CHD1 改变分别是 ERG 过表达 (ERG+) 和 SPOP 突变肿瘤特有的晚期进展事件，并且存在 2 种不同的进展模型，包括 ERG/PTEN（正常到 ERG+到 PTEN 缺失）和 SPOP/CHD1（正常到 SPOP 突变到 CHD1 缺失），它们具有共同的早期肿瘤发生，但进展途径不同。我们发现，在 ERG+和 SPOP 突变亚型中，晚期事件与预后较差相关。重要的是，在根治性前列腺切除术中与不同晚期事件相关的临床和病理特征明显不同；PTEN 缺失与局部区域分期增加相关，而 CHD1 缺失仅与分级增加相关，尽管转移潜能相当。
这些发现表明，PCa 的特定亚型在分子和临床水平上遵循不同的进展途径。因此，常见的临床参数（如局部区域肿瘤分期）的解释可能受肿瘤谱系的影响，并可能影响管理决策。
前列腺癌基金会、美国国立卫生研究院、美国泌尿科基金会、达蒙·鲁尼恩癌症研究基金会、美国国防部和 AIRC 基金会。
