Cell-free DNA from ascites identifies clinically relevant variants and tumour evolution in patients with advanced ovarian cancer.

IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Molecular Oncology Pub Date : 2024-11-01 Epub Date: 2024-08-08 DOI:10.1002/1878-0261.13710
Bonnita Werner, Elyse Powell, Jennifer Duggan, Marilisa Cortesi, Yeh Chen Lee, Vivek Arora, Ramanand Athavale, Michael Dean, Kristina Warton, Caroline E Ford
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Abstract

The emergence of targeted therapies has transformed ovarian cancer treatment. However, biomarker profiling for precision medicine is limited by access to quality, tumour-enriched tissue samples. The use of cell-free DNA (cfDNA) in ascites presents a potential solution to this challenge. In this study, next-generation sequencing was performed on ascites-derived cfDNA samples (26 samples from 15 human participants with ovarian cancer), with matched DNA from ascites-derived tumour cells (n = 5) and archived formalin-fixed paraffin-embedded (FFPE) tissue (n = 5). Similar tumour purity and variant detection were achieved with cfDNA compared to FFPE and ascites cell DNA. Analysis of large-scale genomic alterations, loss of heterozygosity and tumour mutation burden identified six cases of high genomic instability (including four with pathogenic BRCA1 and BRCA2 mutations). Copy number profiles and subclone prevalence changed between sequential ascites samples, particularly in a case where deletions and chromothripsis in Chr17p13.1 and Chr8q resulted in changes in clinically relevant TP53 and MYC variants over time. Ascites cfDNA identified clinically actionable information, concordant to tissue biopsies, enabling opportunistic molecular profiling. This advocates for analysis of ascites cfDNA in lieu of accessing tumour tissue via biopsy.

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从腹水中提取的无细胞 DNA 可识别晚期卵巢癌患者的临床相关变异和肿瘤演变。
靶向疗法的出现改变了卵巢癌的治疗。然而,用于精准医疗的生物标志物分析受限于获取高质量、富含肿瘤的组织样本。腹水中无细胞 DNA(cfDNA)的使用为这一挑战提供了潜在的解决方案。在这项研究中,对来自腹水的cfDNA样本(来自15名卵巢癌患者的26个样本)进行了下一代测序,并对来自腹水的肿瘤细胞(n = 5)和归档的福尔马林固定石蜡包埋(FFPE)组织(n = 5)的DNA进行了比对。与 FFPE 和腹水细胞 DNA 相比,cfDNA 的肿瘤纯度和变异检测结果相似。对大规模基因组改变、杂合性缺失和肿瘤突变负荷的分析发现了六例基因组高度不稳定的病例(其中四例存在致病性 BRCA1 和 BRCA2 突变)。拷贝数图谱和亚克隆流行率在连续腹水样本之间发生了变化,特别是在一个病例中,Chr17p13.1 和 Chr8q 的缺失和染色体三分裂导致临床相关的 TP53 和 MYC 变异随时间发生变化。腹水 cfDNA 鉴定出了与组织活检一致的临床可操作信息,从而实现了机会性分子剖析。这提倡用腹水 cfDNA 分析来代替通过活检获取肿瘤组织。
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来源期刊
Molecular Oncology
Molecular Oncology Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
11.80
自引率
1.50%
发文量
203
审稿时长
10 weeks
期刊介绍: Molecular Oncology highlights new discoveries, approaches, and technical developments, in basic, clinical and discovery-driven translational cancer research. It publishes research articles, reviews (by invitation only), and timely science policy articles. The journal is now fully Open Access with all articles published over the past 10 years freely available.
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