Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, IL, USA.
Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA.
Gynecol Oncol. 2024 Mar;182:82-90. doi: 10.1016/j.ygyno.2024.01.001. Epub 2024 Jan 22.
The genome-wide profiling of 5-hydroxymethylcytosines (5hmC) on circulating cell-free DNA (cfDNA) has revealed promising biomarkers for various diseases. The purpose of this study was to investigate 5hmC signals in serum cfDNA and identify novel predictive biomarkers for the development of chemoresistance in high-grade serous ovarian cancer (HGSOC). We hypothesized that 5hmC profiles in cfDNA reflect the development of chemoresistance and elucidate pathways that may drive chemoresistance in HGSOC. Moreover, we sought to identify predictors that would better stratify outcomes for women with intermediate-sensitive HGSOC.
Women diagnosed with HGSOC and known platinum sensitivity status were selected for this study. Nano-hmC-Seal was performed on cfDNA isolated from archived serum samples, and differential 5hmC features were identified using DESeq2 to establish a model predictive of chemoresistance.
A multivariate model consisting of three features (preoperative CA-125, largest residual implant after surgery, 5hmC level of OSGEPL), stratified samples from intermediate sensitive, chemo-naive women diagnosed with HGSOC into chemotherapy-resistant- and sensitive-like strata with a significant difference in overall survival (OS). Independent analysis of The Cancer Genome Atlas data further confirmed that high OSGEPL1 expression is a favorable prognostic factor for HGSOC.
We have developed a novel multivariate model based on clinico-pathologic data and a cfDNA-derived 5hmC modified gene, OSGEPL1, that predicted response to platinum-based chemotherapy in intermediate-sensitive HGSOC. Our multivariate model applies to chemo-naïve samples regardless if the patint was treated with adjuvant or neoadjuvant chemotherapy. These results merit further investigation of the predictive capability of our model in larger cohorts.
对循环游离 DNA（cfDNA）中的 5-羟甲基胞嘧啶（5hmC）进行全基因组分析，揭示了各种疾病有前景的生物标志物。本研究旨在研究血清 cfDNA 中的 5hmC 信号，并鉴定高级别浆液性卵巢癌（HGSOC）发生化疗耐药的新型预测性生物标志物。我们假设 cfDNA 中的 5hmC 谱反映了化疗耐药的发展，并阐明可能导致 HGSOC 化疗耐药的途径。此外，我们试图确定能够更好地分层具有中间敏感性 HGSOC 的女性结局的预测因子。
选择患有 HGSOC 且已知铂类敏感性状态的女性进行本研究。对来自存档血清样本的 cfDNA 进行纳米-hmC-Seal 处理，使用 DESeq2 鉴定差异 5hmC 特征，以建立预测化疗耐药的模型。
由三个特征（术前 CA-125、手术后最大残留植入物、OSGEPL1 的 5hmC 水平）组成的多变量模型，将来自诊断为 HGSOC 的中间敏感、化疗初治女性的样本分为化疗耐药和敏感样，在总生存期（OS）方面有显著差异。对癌症基因组图谱数据的独立分析进一步证实，高 OSGEPL1 表达是 HGSOC 的有利预后因素。
我们基于临床病理数据和 cfDNA 衍生的 5hmC 修饰基因 OSGEPL1 开发了一种新的多变量模型，该模型预测了中间敏感型 HGSOC 对铂类化疗的反应。我们的多变量模型适用于化疗初治样本，无论患者是否接受辅助或新辅助化疗。这些结果值得进一步研究我们模型在更大队列中的预测能力。
