Improving cell-free DNA detection in advanced-stage high-grade serous ovarian cancer using combined TP53 mutational status and copy number changes

IF 2.9 4区医学 Q2 PATHOLOGY

Pathology, research and practice Pub Date : 2025-05-31 DOI:10.1016/j.prp.2025.156038

Hein S. Zelisse , Ymke van der Pol , Florent Mouliere , Frederike Dijk , Johannes B.G. Halfwerk , Banafsche Mearadji , Ludo F.M. Beenen , Roy J. Reinten , Saskia A.G.M. Cillessen , Gerrit K.J. Hooijer , Malou L.H. Snijders , Marc J. van de Vijver , Mignon D.J.M. van Gent , Constantijne H. Mom

{"title":"Improving cell-free DNA detection in advanced-stage high-grade serous ovarian cancer using combined TP53 mutational status and copy number changes","authors":"Hein S. Zelisse , Ymke van der Pol , Florent Mouliere , Frederike Dijk , Johannes B.G. Halfwerk , Banafsche Mearadji , Ludo F.M. Beenen , Roy J. Reinten , Saskia A.G.M. Cillessen , Gerrit K.J. Hooijer , Malou L.H. Snijders , Marc J. van de Vijver , Mignon D.J.M. van Gent , Constantijne H. Mom","doi":"10.1016/j.prp.2025.156038","DOIUrl":null,"url":null,"abstract":"<div><div>Circulating tumor DNA (ctDNA) is a promising biomarker in patients with high-grade serous ovarian cancer (HGSOC). However, the detection rate of <em>TP53</em> mutations in ctDNA of HGSOC patients has previously been shown to be inadequate. Given the prevalence of copy number aberrations (CNAs) in HGSOC, this study aimed to improve ctDNA detection by combining <em>TP53</em> sequencing with shallow whole-genome sequencing (sWGS), and to evaluate the correlation with clinicopathological features and survival outcomes. This exploratory, retrospective cohort study included 53 advanced-stage HGSOC patients, comprising 18 treatment-naive patients and 35 patients treated with two neoadjuvant chemotherapy cycles. <em>TP53</em> targeted sequencing was integrated with sWGS (<5x coverage) for CNA estimation using ichor copy number aberration tumor fraction (ichorCNA TF). <em>TP53</em> mutations were detected in 28 patients (52.8 %), and 17 patients (32.1 %) showed positive ichorCNA TF. Combining <em>TP53</em> mutation detection with ichorCNA TF identified 62.3 % (n = 33) of patients as ctDNA-positive, showing a trend towards improved detection compared to <em>TP53</em> mutation alone (p = .063). Treatment-naive patients exhibited higher <em>TP53</em> mutation (72.2 % vs. 42.9 %, p = .043) and ichorCNA TF (66.7 % vs. 14.3 %, p < .001) detection rates compared to chemotherapy-treated patients. No correlations between ctDNA metrics and clinicopathological characteristics or survival outcomes were found. In conclusion, the integration of ichorCNA TF with <em>TP53</em> mutation analysis showed a trend towards improved ctDNA detection in advanced-stage HGSOC patients. Future studies should further explore ctDNA detection rates by ichorCNA TF and its potential clinical implications in HGSOC.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"272 ","pages":"Article 156038"},"PeriodicalIF":2.9000,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pathology, research and practice","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0344033825002316","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PATHOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Circulating tumor DNA (ctDNA) is a promising biomarker in patients with high-grade serous ovarian cancer (HGSOC). However, the detection rate of TP53 mutations in ctDNA of HGSOC patients has previously been shown to be inadequate. Given the prevalence of copy number aberrations (CNAs) in HGSOC, this study aimed to improve ctDNA detection by combining TP53 sequencing with shallow whole-genome sequencing (sWGS), and to evaluate the correlation with clinicopathological features and survival outcomes. This exploratory, retrospective cohort study included 53 advanced-stage HGSOC patients, comprising 18 treatment-naive patients and 35 patients treated with two neoadjuvant chemotherapy cycles. TP53 targeted sequencing was integrated with sWGS (<5x coverage) for CNA estimation using ichor copy number aberration tumor fraction (ichorCNA TF). TP53 mutations were detected in 28 patients (52.8 %), and 17 patients (32.1 %) showed positive ichorCNA TF. Combining TP53 mutation detection with ichorCNA TF identified 62.3 % (n = 33) of patients as ctDNA-positive, showing a trend towards improved detection compared to TP53 mutation alone (p = .063). Treatment-naive patients exhibited higher TP53 mutation (72.2 % vs. 42.9 %, p = .043) and ichorCNA TF (66.7 % vs. 14.3 %, p < .001) detection rates compared to chemotherapy-treated patients. No correlations between ctDNA metrics and clinicopathological characteristics or survival outcomes were found. In conclusion, the integration of ichorCNA TF with TP53 mutation analysis showed a trend towards improved ctDNA detection in advanced-stage HGSOC patients. Future studies should further explore ctDNA detection rates by ichorCNA TF and its potential clinical implications in HGSOC.

查看原文本刊更多论文

结合TP53突变状态和拷贝数变化改善晚期高级别浆液性卵巢癌的无细胞DNA检测

循环肿瘤DNA （ctDNA）在高级别浆液性卵巢癌（HGSOC）患者中是一个很有前景的生物标志物。然而，HGSOC患者ctDNA中TP53突变的检出率之前被证明是不足的。鉴于HGSOC中拷贝数畸变（copy number aberrations, CNAs）的普遍存在，本研究旨在通过TP53测序与浅全基因组测序（sWGS）的结合来提高ctDNA的检测水平，并评估其与临床病理特征和生存结局的相关性。这项探索性、回顾性队列研究纳入了53例晚期HGSOC患者，其中18例未接受治疗，35例接受了两个新辅助化疗周期。TP53靶向测序与sWGS （<；5倍覆盖率）相结合，使用肿瘤拷贝数畸变分数（ichorCNA TF）估计CNA。TP53突变28例（52.8% %），ichorCNA TF阳性17例（32.1% %）。结合TP53突变检测与ichorCNA TF检测，62.3 % （n = 33）的患者ctdna呈阳性，与单独检测TP53突变相比，有提高检测的趋势（p = .063）。与化疗患者相比，未接受治疗的患者表现出更高的TP53突变（72.2 %对42.9 %,p = .043）和ichorCNA TF（66.7 %对14.3 %,p <； .001）检出率。ctDNA指标与临床病理特征或生存结果之间没有相关性。综上所述，ichorCNA TF结合TP53突变分析显示晚期HGSOC患者ctDNA检测有改善的趋势。未来的研究应进一步探讨ichorCNA TF对ctDNA的检出率及其在HGSOC中的潜在临床意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Pathology, research and practice 医学-病理学

CiteScore

5.00

自引率

3.60%

发文量

405

审稿时长

24 days

期刊介绍： Pathology, Research and Practice provides accessible coverage of the most recent developments across the entire field of pathology: Reviews focus on recent progress in pathology, while Comments look at interesting current problems and at hypotheses for future developments in pathology. Original Papers present novel findings on all aspects of general, anatomic and molecular pathology. Rapid Communications inform readers on preliminary findings that may be relevant for further studies and need to be communicated quickly. Teaching Cases look at new aspects or special diagnostic problems of diseases and at case reports relevant for the pathologist''s practice.