Abstract:
Circulating tumor DNA (ctDNA) is the fraction of cell-free DNA in patient blood that originates from a tumor. Advances in DNA sequencing technologies and our understanding of the molecular biology of tumors have increased interest in exploiting ctDNA to facilitate detection of molecular residual disease (MRD). Analysis of ctDNA as a promising MRD biomarker of solid malignancies has a central role in precision medicine initiatives exemplified by our CIRCULATE-Japan project involving patients with resectable colorectal cancer. Notably, the project underscores the prognostic significance of the ctDNA status at 4 weeks post-surgery and its correlation to adjuvant therapy efficacy at interim analysis. This substantiates the hypothesis that MRD is a critical prognostic indicator of relapse in patients with colorectal cancer. Despite remarkable advancements, challenges endure, primarily attributable to the exceedingly low ctDNA concentration in peripheral blood, particularly in scenarios involving low tumor shedding and the intrinsic error rates of current sequencing technologies. These complications necessitate more sensitive and sophisticated assays to verify the clinical utility of MRD across all solid tumors. Whole genome sequencing (WGS)-based tumor-informed MRD assays have recently demonstrated the ability to detect ctDNA in the parts-per-million range. This review delineates the current landscape of MRD assays, highlighting WGS-based approaches as the forefront technique in ctDNA analysis. Additionally, it introduces our upcoming endeavor, WGS-based pan-cancer MRD detection via ctDNA, in our forthcoming project, SCRUM-Japan MONSTAR-SCREEN-3.
摘要:
循环肿瘤DNA(ctDNA)是患者血液中源自肿瘤的无细胞DNA的部分。DNA测序技术的进步和我们对肿瘤分子生物学的理解增加了对利用ctDNA促进分子残留病(MRD)检测的兴趣。ctDNA作为实体恶性肿瘤的有希望的MRD生物标志物的分析在我们的RCULATE-Japan项目涉及可切除的结直肠癌患者的精准医学计划中具有核心作用。值得注意的是,该项目强调了术后4周时ctDNA状态的预后意义及其与中期分析时辅助治疗疗效的相关性.这证实了MRD是结直肠癌患者复发的关键预后指标的假设。尽管取得了显著进展,挑战持续,主要归因于外周血中ctDNA浓度极低,特别是在涉及低肿瘤脱落和当前测序技术固有错误率的情况下。这些并发症需要更灵敏和复杂的测定来验证MRD在所有实体瘤中的临床效用。基于全基因组测序(WGS)的基于肿瘤的MRD测定最近证明了检测百万分之一范围内的ctDNA的能力。这篇综述描绘了MRD测定的当前景观,强调基于WGS的方法作为ctDNA分析的前沿技术。此外,它介绍了我们即将到来的努力,基于WGS的泛癌症MRD通过ctDNA检测,在我们即将到来的项目中,SCRUM-日本MONSTAR-SCREEN-3。