PO.CL01.10 · 临床研究
基于数字PCR的血浆DNA甲基化检测用于小细胞肺癌的无创分子分型：一项前瞻性可行性研究
Digital PCR-based plasma DNA methylationassayfor noninvasive molecular subtyping of small cell lung cancer: A prospective feasibility study
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：小细胞肺癌（SCLC）是一种侵袭性神经内分泌肿瘤，治疗选择有限，生存预后差。尽管近期研究强调了分子亚型对治疗分层的临床意义，但基于组织的分型往往不可行，因为大多数患者接受化疗而非手术切除。本研究旨在开发并临床评价一种利用血浆样本进行亚型特异性甲基化谱分析的数字PCR检测。
方法：2023年4月至2025年9月，在首尔国立大学Boramae医疗中心前瞻性纳入20例经病理确诊的SCLC患者。在系统治疗前采集血浆样本，分子亚型分类为NEUROD1型（N型；n = 1）、ASCL1型（A型；n = 16）、POU2F3型（P型；n = 3）或SCLC-I型（I型；n = 0）。将基于数字PCR甲基化检测确定的血浆来源分子亚型与上述临床分类进行比较。
结果：通过对美国国家癌症研究所小细胞肺癌筛查项目中公开可得的甲基化芯片和表达数据集进行整合分析，鉴定出与亚型相关的甲基化标志物。这些候选位点被整合到一个4重数字PCR检测中，该检测在具有代表性的SCLC细胞系中显示出清晰的亚型富集甲基化模式。在20份前瞻性采集的血浆样本中，所有靶标均成功定量，具有足够的临床性能。血浆来源的分子亚型与临床分类的总体一致性为85.0%（17/20），其中N型的检测灵敏度为100.0%（1/1），A型为87.5%（14/16），P型为66.7%（2/3）。这些发现支持了基于血浆的甲基化谱分析用于SCLC无创分子分型的可行性。
结论：本研究证明了利用基于数字PCR的甲基化检测从血浆中对SCLC分子亚型进行分类的可行性。有必要开展更大规模的验证队列以优化临界值并确认临床实用性。
查看英文原文 English abstract
Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with limited treatment options and poor survival outcomes. Although recent studies highlight the clinical relevance of molecular subtypes for therapeutic stratification, tissue-based subtyping is often infeasible because most patients receive chemotherapy rather than surgical resection. This study aimed to develop and clinically evaluate a digital PCR assay for subtype-specific methylation profiling using plasma samples.
Methods: Twenty patients with pathologically confirmed SCLC were prospectively enrolled at Seoul National University Boramae Medical Center from April 2023 to September 2025. Plasma samples were collected prior to systemic therapy, and molecular subtypes were classified as NEUROD1-type (N-type; n = 1), ASCL1-type (A-type; n = 16), POU2F3-type (P-type; n = 3), or SCLC-I type (I-type; n = 0). Plasma-derived molecular subtypes determined by the digital PCR-based methylation assay were compared with these clinical classifications.
Results: Subtype-associated methylation markers were identified through integrative analysis of publicly available methylation array and expression datasets from the National Cancer Institute Small Cell Lung Cancer Screening Project. These candidate loci were integrated into a 4-plex digital PCR assay, which demonstrated clear subtype-enriched methylation patterns across representative SCLC cell lines. In 20 prospectively collected plasma samples, all targets were successfully quantified with sufficient clinical performance. Plasma-derived molecular subtypes showed overall concordance of 85.0% (17/20) with clinical classifications, with detection sensitivities of 100.0% (1/1) for N-type, 87.5% (14/16) for A-type, and 66.7% (2/3) for P-type cases. These findings support the feasibility of plasma-based methylation profiling for noninvasive SCLC molecular subtyping.
Conclusion: This study demonstrates the feasibility of using a digital PCR-based methylation assay to classify SCLC molecular subtypes from plasma. Larger validation cohorts are warranted to refine cutoffs and confirm clinical utility.
利益披露 Disclosure
J. Kim,
Gencurix, Inc. ).
M. Kim, None..
J. Yim, None.
Y. Lee,
Gencurix, Inc. Employment, Stock, Stock Option.
J. An,
Gencurix, Inc. Employment, Stock, Stock Option.
J. Han,
Gencurix, Inc. Employment, Stock, Stock Option.
J. Kim, None.
Y. Moon,
Gencurix, Inc. Employment, Stock, Stock Option.