Dataset related to article "Targeted Mutational Analysis of Circulating Tumor DNA to Decipher Temporal Heterogeneity of High-Grade Serous Ovarian Cancer"

This record contains raw data related to article "Targeted Mutational Analysis of Circulating Tumor DNA to Decipher Temporal Heterogeneity of High-Grade Serous Ovarian Cancer".

We have previously demonstrated that longitudinal untargeted analysis of plasma samples withdrawn from patients with high-grade serous ovarian cancer (HGS-EOC) can intercept the presence of molecular recurrence (TRm) earlier than the diagnosis of clinical recurrence (TRc). This finding opens a clinical important temporal window to acquire through plasma sample analysis a real-time picture of those emerging molecular lesions that will drive and sustain the growth of relapsed disease and ultimately will confer resistance. In this proof of principle study, the same genomic libraries obtained at the diagnosis (T0), TRm and TRc were further analyzed by targeted resequencing approach to sequence the coding region of a panel of 65 genes to provide longitudinal analysis of clonal evolution as a novel strategy to support clinical decisions for the second-line treatment. Experiments were performed on plasma and tumor tissues withdrawn on a selection of previously analyzed cohorts of cases (i.e., 33 matched primary and synchronous lesions and 43 plasma samples from 18 patients). At T0, the median concordance of mutations shared by each tumor tissue biopsy and its matched plasma sample was 2.27%. This finding confirms the limit of a single tumor biopsy to be representative of the entire disease, while plasma analysis can recapitulate most of the main molecular lesions of the disease. A comparable scenario was observed during longitudinal analysis, where, with the exception of the TP53 gene and germline mutations in BRCA1/2 genes, no other gene shared the same locus specific gene mutation across T0, TRm and TRc time points. This high level of temporal heterogeneity has important implications for planning second-line treatment. For example, in three out of 13 cases, plasma ctDNA analysis at TRm or TRc reported acquired novel variants in the TP53BP1 gene not present at T0. In particular, patient 21564, potentially eligible for PARP-inhibitor (PARPi) treatment at the time of diagnosis (BRCA1 c.5182delA mutation), would unlikely respond to these drugs in second-line therapy due to the presence of eight distinct TP53BP1 variants in plasma samples collected TRc. This study demonstrates that liquid biopsy provides a real-time molecular picture to intercept those actionable genetic vulnerabilities or drug resistance mechanisms that could be used to plan a more rational second-line treatment.

本数据集包含与题为《循环肿瘤DNA靶向突变分析解析高级别浆液性卵巢癌的时间异质性》的学术论文相关的原始实验数据。
此前我们已证实，对高级别浆液性卵巢癌（High-Grade Serous Ovarian Cancer, HGS-EOC）患者采集的血浆样本进行纵向非靶向分析，可比临床复发诊断（TRc）更早检测到分子复发（TRm）的存在。这一发现开辟了一个具有重要临床价值的时间窗口：通过血浆样本分析，可实时获取驱动、维持复发疾病生长并最终导致耐药性产生的新发分子病灶信息。
在本原理验证研究中，我们对确诊时（T0）、分子复发（TRm）及临床复发（TRc）阶段获取的同一批基因组文库，采用靶向重测序技术进一步分析：对包含65个基因的组合的编码区进行测序，以实现克隆演化的纵向分析，以此作为支持二线治疗临床决策的新型策略。
本研究的实验样本取自此前已分析过的部分病例队列：包括33对匹配的原发及同步病灶样本，以及18名患者的43份血浆样本。
在确诊阶段（T0），每例肿瘤组织活检样本与其匹配血浆样本共有的突变中位一致性为2.27%。这一结果证实，单一体肿瘤活检样本无法代表整个肿瘤的全貌；而血浆分析则可覆盖该疾病绝大多数主要的分子病灶。
纵向分析中也观察到了类似的情况：除TP53基因及BRCA1/2基因的种系突变外，其余基因在T0、TRm及TRc三个时间点均未出现相同的位点特异性突变。这种高水平的时间异质性对二线治疗方案的制定具有重要指导意义。
例如，13例病例中有3例的TRm或TRc阶段血浆循环肿瘤DNA（circulating tumor DNA, ctDNA）分析显示，TP53BP1基因出现了确诊阶段（T0）未检测到的获得性新变异。以患者21564为例：其确诊时携带BRCA1 c.5182delA突变，本可接受PARP抑制剂（PARP inhibitor, PARPi）治疗；但由于其临床复发（TRc）阶段采集的血浆样本中存在8种不同的TP53BP1变异，该患者在二线治疗中大概率无法从这类药物中获益。
本研究证实，液体活检可提供实时的分子图谱，从而检测出可作为二线治疗制定依据的可靶向遗传脆弱性或耐药机制，助力制定更为合理的二线治疗方案。