PO.CL01.11 · 临床研究
实体瘤中CHIP的检测在不同液体活检检测方法之间存在差异
CHIP detection in solid tumors differs between liquid biopsy testing approaches
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：意义未明的克隆性造血（CHIP）源于造血祖细胞中的体细胞变异，在老年个体中更为常见。CHIP可作为偶然发现出现在实体瘤患者的游离DNA（cfDNA）中，引入生物学背景噪声，可能混淆结果解读。MSK-ACCESS®（由SOPHiA DDM™赋能）纳入了配对的白细胞（WBC）DNA测序，以实现对CHIP和胚系变异的过滤。本研究评估了不同cfDNA检测方法中实体瘤患者的CHIP检测情况。
材料与方法：我们开展了一项多中心回顾性观察研究；此处呈现一家中心的结果。分析了102例结直肠癌、前列腺癌、胰腺癌或乳腺癌个体的样本。使用MSK-ACCESS®（由SOPHiA DDM™赋能）处理cfDNA和配对的WBC gDNA，该方法可检测SNVs/INDELs、CNVs和结构变异。同时还获得了来自集中化外送cfDNA-only检测的正交结果，包括对推定胚系变异和CHIP变异的注释。评估了一致性（阳性符合率，PPA），同时也聚焦于因纳入WBC测序而产生的不一致CHIP判定。
结果：MSK-ACCESS®（由SOPHiA DDM™赋能）对所有变异等位基因频率（VAF）≥0.5%的变异（不论分类）实现了95%的PPA，与其检测限一致。检测到的VAF与正交检测显示出强相关性（R2=0.86）。cfDNA-only方法与MSK-ACCESS®（由SOPHiA DDM™赋能）之间观察到不一致的CHIP和肿瘤特异性判定。这些受到cfDNA与WBC的VAF比值阈值、基因集组成（例如DNMT3A vs. TP53）和统计过滤标准等因素的影响。CHIP判定的总体符合率（OPA）正在评估中。
结论：如MSK-ACCESS®（由SOPHiA DDM™赋能）所实施的那样，纳入配对的WBC测序，在解决CHIP相关模糊性方面相比仅肿瘤cfDNA方法具有潜在优势。有必要在各方法之间持续评估并进一步验证。
查看英文原文 English abstract
Objective: Clonal hematopoiesis of indeterminate potential (CHIP) arises from somatic variants in hematopoietic progenitor cells and is more frequent in older individuals. CHIP can appear as incidental findings in cell-free DNA (cfDNA) from patients with solid tumors, introducing biological background noise that may confound result interpretation. MSK-ACCESS® powered with SOPHiA DDM™ incorporates matched white blood cell (WBC) DNA sequencing to allow filtering of CHIP and germline variants. This study evaluated CHIP detection in patients with solid tumors across different cfDNA testing approaches.
Materials and Methods: We conducted a multicenter, retrospective observational study; results from one center are presented here. Samples from 102 individuals with colorectal, prostate, pancreatic, or breast cancer were analyzed. cfDNA and matched WBC gDNA were processed using MSK-ACCESS® powered with SOPHiA DDM™, which detects SNVs/INDELs, CNVs, and structural variants. Orthogonal results from a centralized, send-out cfDNA-only assay were also available, including annotations for putative germline and CHIP variants. Concordance (percent positive agreement, PPA) was assessed while also focusing on discordant CHIP calls attributable to the inclusion of WBC sequencing.
Results: MSK-ACCESS® powered with SOPHiA DDM™ achieved 95% PPA for all variants with variant allele frequencies (VAF) ≥ 0.5% independent of classification, consistent with its limit of detection. Detected VAF showed strong correlation with the orthogonal assay (R 2 = 0.86). Discordant CHIP and tumor-specific calls were observed between the cfDNA-only approach and MSK-ACCESS® powered with SOPHiA DDM™. These were influenced by factors such as cfDNA-to-WBC VAF ratio thresholds, gene set composition (e.g., DNMT3A vs. TP53 ), and statistical filtering criteria. Overall percent agreement (OPA) for CHIP calls is under evaluation.
Conclusion: Incorporating matched WBC sequencing, as implemented in MSK-ACCESS® powered with SOPHiA DDM™, yields a potential advantage in resolving CHIP-related ambiguity compared to tumor-only cfDNA approaches. Continued assessment across methodologies and further evaluation are warranted.
利益披露 Disclosure
F. Klemm,
SOPHiA GENETICS Employment, Stock, Stock Option, Travel, Other Intellectual Property.
F. Mohammad,
SOPHiA GENETICS Employment, Stock, Stock Option, Travel, Other Intellectual Property.
A. C. Tuck,
SOPHiA GENETICS Employment, Stock, Stock Option, Travel, Patent, Other Intellectual Property.
G. Morales,
SOPHiA GENETICS Employment, Travel.
R. Awuku, None..
K. Mokretar, None..
A. Heasman, None..
G. Gerrard, None..
P. du Parcq, None.
Z. Xu,
SOPHiA GENETICS Employment, Stock, Stock Option, Patent, Other Intellectual Property.