LBPO.BCS02 · 生物信息与计算 · Late-Breaking
从快速尸检对转移性前列腺癌演进进行多组学重建揭示多克隆播散及对液体活检的意义
Multi-omic reconstruction of metastatic prostate cancer evolution from rapid autopsy reveals polyclonal seeding and implications for liquid biopsy
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引言:转移性去势抵抗性前列腺癌(mCRPC)由于对雄激素受体信号抑制剂(ARSI)和紫杉烷化疗获得性抵抗而仍然无可避免地致命。虽然mCRPC的基因组驱动因素已被充分编目,但抵抗的时空演进以及谱系可塑性的精确结构——具体而言即从AR阳性腺癌(ARPC)向神经内分泌(NEPC)或双阴性(DNPC)表型的转变——由于多部位转移组织的稀缺仍知之甚少。我们呈现一个通过快速尸检项目构建的终末期mCRPC的全面基因组和转录组图谱,界定致命疾病的演化史。
方法:我们对通过华盛顿大学快速尸检项目采集的来自70例mCRPC患者的180个转移瘤(平均每位患者3个肿瘤)进行了全基因组测序(WGS,60×),并对其中58例患者的一个子集配有匹配的胚系及死后血浆ctDNA。我们的分析框架纳入了:共识体细胞变异检出(VarScan、Mutect2、Strelka2);结构变异检测(SVABA、Manta、GRIDSS);拷贝数分析(TitanCNA);突变特征分析(SigProfilerExtractor);系统发育重建(PyClone、LICHeE);以及ctDNA表型分类(Keraon)。
结果:系统发育重建揭示致命的mCRPC是由复杂的多克隆播散而非简单的线性进展驱动。我们鉴定出独特的演化轨迹:虽然ARPC转移瘤常共享晚期产生的亚克隆驱动因素,但NEPC肿瘤表现出以RB1和TP53同时缺失为特征的早期主干分歧。尸检ctDNA与同步肿瘤WGS之间的一致性分析表明,液体活检能准确恢复主干驱动事件(一致性>90%)。此外,来自ctDNA的Keraon表型分析在17%具有异质性的患者中揭示了混合的ARPC/NEPC表型。
结论:我们呈现迄今最大的mCRPC多部位基因组图谱,揭示致命抵抗由早期分支事件驱动并通过广泛的多克隆播散得以维持。关键的是,我们表明液体活检能准确勾勒复杂表型(包括混合的ARPC/NEPC状态),并在复现主干驱动因素的同时也检测出空间隔离的亚克隆异质性,尽管这受肿瘤分数的影响。
查看英文原文 English abstract
Introduction: Metastatic castration-resistant prostate cancer (mCRPC) remains invariably lethal due to acquired resistance to androgen receptor signaling inhibitors (ARSIs) and taxane chemotherapy. While genomic drivers of mCRPC are well-cataloged, the spatiotemporal evolution of resistance and the precise architecture of lineage plasticity-specifically the transition from AR-positive adenocarcinoma (ARPC) to neuroendocrine (NEPC) or double-negative (DNPC) phenotypes-remain poorly understood due to the scarcity of multi-site metastatic tissue. We present a comprehensive genomic and transcriptomic atlas of end-stage mCRPC constructed via a rapid autopsy program, defining the evolutionary history of lethal disease.
Methods: We performed whole-genome sequencing (WGS, 60×) on 180 metastatic tumors from 70 mCRPC patients (average 3 tumors/patient) collected through the University of Washington Rapid Autopsy Program, with matched germline and post-mortem plasma ctDNA for a subset of 58 patients. Our analytical framework incorporated: consensus somatic variant calling (VarScan, Mutect2, Strelka2); structural variant detection (SVABA, Manta, GRIDSS); copy number analysis (TitanCNA); mutational signature analysis (SigProfilerExtractor); phylogenetic reconstruction (PyClone, LICHeE); and ctDNA phenotype classification (Keraon).
Results: Phylogenetic reconstruction revealed that lethal mCRPC is driven by complex, polyclonal seeding rather than simple linear progression. We identified distinct evolutionary trajectories: while ARPC metastases frequently shared late-arising subclonal drivers, NEPC tumors demonstrated early, truncal divergence characterized by simultaneous RB1 and TP53 loss. Concordance analysis between autopsy ctDNA and synchronous tumor WGS demonstrated that liquid biopsy accurately recovers truncal driver events (>90% concordance). Additionally, Keraon phenotype analysis from ctDNA revealed mixed ARPC/NEPC phenotypes in 17% of patients with heterogeneity.
Conclusions: We present the largest multi-site genomic atlas of mCRPC to date, revealing that lethal resistance is driven by early branching events and maintained through extensive polyclonal seeding. Critically, we show that liquid biopsy accurately delineates complex phenotypes (including mixed ARPC/NEPC states), and recapitulates truncal drivers while also detecting spatially segregated subclonal heterogeneity, although this is mediated by tumor fraction.
利益披露 Disclosure
A. Khandekar, None..
M. Vashisth, None..
P. Itagi, None..
R. Patton, None..
M. Adil, None..
P. Galipeau, None..
M. Haffner, None..
C. Morrisey, None..
P. Nelson, None..
G. Ha, None.