Venken Tom, Miller Ian S, Arijs Ingrid, Thomas Valentina, Barat Ana, Betge Johannes, Zhan Tianzuo, Gaiser Timo, Ebert Matthias P, O'Farrell Alice C, Prehn Jochen, Klinger Rut, O'Connor Darran P, Moulton Brian, Murphy Verena, Serna Garazi, Nuciforo Paolo G, McDermott Ray, Bird Brian, Leonard Gregory, Grogan Liam, Horgan Anne, Schulte Nadine, Moehler Markus, Lambrechts Diether, Byrne Annette T
Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
VIB Center for Cancer Biology, Leuven, Belgium.
NPJ Genom Med. 2024 May 29;9(1):33. doi: 10.1038/s41525-024-00415-x.
To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.
为预测联合使用贝伐单抗（BVZ）治疗的结果，我们采用游离DNA（cfDNA）来确定转移性结直肠癌（mCRC）患者的染色体不稳定性（CIN）、核小体足迹（NF）和甲基化谱。对来自AC-ANGIOPREDICT II期试验（NCT01822444）的74例mCRC患者的配对肿瘤和血浆样本进行低覆盖全基因组测序（LC-WGS），并分析CIN和NFs。对来自曼海姆大学医学中心（UMM）的血浆样本验证队列进行了类似的分析。选择61份在BVZ治疗前后采集的AC-ANGIOPREDICT血浆样本进行靶向甲基化测序。利用cfDNA CIN谱，AC-ANGIOPREDICT样本以92.3%的准确率被分为低CIN和高CIN簇，配对血浆和肿瘤之间观察到良好的一致性。在高CIN患者中观察到生存期延长。基于血浆的CIN聚类在UMM队列中得到验证。甲基化分析确定了低CIN与高CIN之间的差异（AUC = 0.87）。此外，BVZ治疗后甲基化评分显著降低与预后改善相关（p = 0.013）。分析血浆样本中cfDNA的CIN、NFs和甲基化谱有助于分层为CIN簇，从而为患者的治疗反应提供信息。
