PO.CL01.10 · 临床研究
通过对原发肿瘤和纵向循环肿瘤DNA进行深度全基因组测序追踪前列腺癌进展
Tracking prostate cancer progression by deep whole genome sequencing of primary tumors and longitudinal circulating tumor DNAs
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：尽管前列腺癌（PCa）总体生存率较高，但部分患者会发展为侵袭性疾病。识别可靠的进展和治疗应答标志物对于改善疾病管理至关重要。血液中的游离DNA（cfDNA）提供了一种微创手段，可通过液体活检监测肿瘤演变。在本研究中，我们比较了重症PCa患者的原发肿瘤与长期无病个体，以识别与侵袭性相关的基因组改变。我们还在循环肿瘤DNA（ctDNA）中追踪肿瘤共有的改变，并发现进展过程中出现的独有修饰。方法：对根治性前列腺切除术病例（致死性PCa=80例，无病=35例）的库存新鲜冷冻前列腺组织进行处理，以识别肿瘤病灶并宏观解剖高细胞含量（>75%）的核心组织用于DNA提取。使用来自六例致死性病例的系列血浆采集分离cfDNA。对肿瘤、匹配的种系血液DNA和cfDNA进行测序，以识别拷贝数变异（CNV）和突变。结果：在致死性和无病病例的肿瘤中均发现了已确立的和新的CNV。比较其CNV显示存在与PCa发生和疾病复发相关的共有改变，同时也指出了特异性地与PCa严重程度相关的基因组特征。对致死性病例的临床分析揭示了与快速复发、转移、去势抵抗和短总生存期相关的基因组缺失。纵向cfDNA分析揭示了当患者进入转移期和晚期时ctDNA分数升高。尽管基因组扩增在原发肿瘤中罕见，但在进展过程中很常见。在进展过程中的ctDNA中发现了肿瘤共有的改变，以及新发现的ctDNA独有的修饰。此外，克隆性ctDNA改变在治疗期间变为亚克隆性，并在两年后与治疗耐药相关地重新出现于血液中。在晚期疾病阶段识别出肿瘤共有和独特克隆性演变的证据，说明存在瘤内和转移性细胞异质性。结论：在晚期疾病中识别肿瘤DNA和ctDNA中的新基因组变化正在增进我们对PCa严重程度的认识。关于ctDNA的发现凸显了纵向液体活检对于监测疾病进展的重要意义。它们可能有助于开发新的诊断检测，从而实现更早、更有效的治疗，并最终降低PCa的致死率。
查看英文原文 English abstract
Background: Although prostate cancer (PCa) generally has a high survival rate, some patients develop aggressive disease. Identifying reliable markers of progression and therapeutic response is essential for improving management. Cell-free DNA (cfDNA) in blood provides a minimally invasive means to monitor tumor evolution through liquid biopsy. In this study, we compared primary tumors from severe PCa patients versus long-term disease-free individuals to identify genomic alterations linked to aggressiveness. We also tracked tumor-shared alterations in circulating tumor DNA (ctDNA) and discovered exclusive modifications emerging during progression. Methods: Banked fresh frozen prostate tissues from radical prostatectomy cases (lethal PCa=80, disease-free=35) were processed to identify tumor foci and macro-dissect cores of high cellularity (>75%) for DNA extraction. Serial plasma collections from six lethal cases were used to isolate cfDNA. Sequencing of tumors, matched germline blood DNAs, and cfDNAs was performed to identify copy number variations (CNVs) and mutations. Results: Already established and novel CNVs were found in tumors of both lethal and disease-free cases. Comparing their CNVs showed shared alterations associated with PCa development and disease recurrence, also pinpointing genomic signatures specifically associated with PCa severity. Clinical analysis of lethal cases revealed genomic deletions associated with rapid recurrence, metastases, castration-resistance, and short overall survival. Longitudinal cfDNA analysis unveiled rising ctDNA fractions when patients reached the metastatic and late stages. Although genomic amplifications were rare in primary tumors, they were common during progression. Tumor-shared alterations were found in the ctDNA during progression, along with newly discovered ctDNA-exclusive modifications. Furthermore, clonal ctDNA alterations became sub-clonal during treatment and re-emerged in the blood two years later in relation to treatment resistance. Evidence of tumor-shared and unique clonal evolutions was identified in the advanced disease stages, speaking for intra-tumoral and metastatic cellular heterogeneity. Conclusion: The identification of novel genomic changes in tumor DNA and ctDNAs in advanced disease is enhancing our knowledge of PCa severity. Findings on ctDNA underscore the significance of longitudinal liquid biopsy for monitoring disease progression. They could contribute to the development of novel diagnostic tests that enable earlier, more effective treatment and ultimately reduce PCa lethality.
利益披露 Disclosure
S. Rahimirad, None..
E. Scarlata, None..
L. Hamel, None..
S. Derderian, None..
G. McKercher, None..
F. Brimo, None..
F. Saad, None..
A. Aprikian, None..
S. Chevalier, None.