Journal of Molecular Diagnostics最新文献

Allele, Diplotype, and Phenotype Frequency Distribution of CYP2B6, CYP2C19, and CYP2D6 in the Han Population in North China 华北汉族人群CYP2B6、CYP2C19和CYP2D6等位基因、二倍型及表型频率分布

IF 3.4 3区医学 Q1 PATHOLOGY

Journal of Molecular Diagnostics

Pub Date : 2026-03-01 Epub Date: 2025-12-18 DOI: 10.1016/j.jmoldx.2025.11.007

Yueyao Luan , Qixuan Sun , Yiyuan Wang , Binliang Tong , Liguang Duan , Jiaqi Wang , Yuhang Yan , Chaoli Chen , Yang Lun , Jing Yu , Yuanyuan Zhao , Mengqiang Zhao , Chunhua Zhou

This large-scale retrospective study investigated the allele, diplotype, and phenotype frequencies of CYP2B6, CYP2C19, and CYP2D6 in a Han Chinese population (N > 10,000), using real-world genetic data from The First Hospital of Hebei Medical University, assessed between March 2021 and April 2025. Single-nucleotide polymorphism genotyping was performed using the Agena MassARRAY assay. CYP2D6 copy number variation (CNV) was analyzed by TaqMan real-time quantitative PCR. The sample sizes were 9729 for CYP2B6, 11,479 for CYP2C19, and 11,315 for CYP2D6, all from the Han Chinese population. The high frequencies of alleles were CYP2B6∗6 (16.19%), CYP2C19∗2 (30.36%), and CYP2D6∗10 (41.67%), with the most common diplotypes being CYP2B6 ∗1/∗6 (23.65%), CYP2C19 ∗1/∗2 (37.62%), and CYP2D6 ∗1/∗10 (16.05%), respectively. At the phenotype level, normal metabolizer was most common for CYP2B6 (57.86%) and CYP2D6 (60.50%), whereas the intermediate metabolizer phenotype was noted for CYP2C19 (44.77%). CYP2D6 CNVs included zero copies (0.43%), one copy (13.64%), two copies (83.79%), three copies (2.11%), and more than three copies (0.03%). This large-scale, real-world study of a Northern Han Chinese cohort provides a valuable pharmacogenomic reference and demonstrates the necessity of integrating CNV analysis with single-nucleotide polymorphism genotyping to ensure accurate clinical phenotyping of CYP2D6.

这项大规模回顾性研究利用河北医科大学第一医院在2021年3月至2025年4月期间的真实遗传数据，调查了中国汉族人群（N bbb10 000）中CYP2B6、CYP2C19和CYP2D6的等位基因、二倍型和表型频率。使用Agena MassARRAY检测进行SNP基因分型。采用TaqMan实时qPCR分析CYP2D6拷贝数变异（CNV）。CYP2B6的样本量为9729例，CYP2C19为11479例，CYP2D6为11315例，均来自汉族人群。等位基因频率较高的是CYP2B6*6（16.19%）、CYP2C19*2（30.36%）和CYP2D6*10(41.67%)，最常见的二倍型分别是CYP2B6* 1/*6（23.65%）、CYP2C19* 1/*2（37.62%）和CYP2D6*1 /*10（16.05%）。在表型水平上，CYP2B6（57.86%）和CYP2D6（60.50%）为正常代谢表型，而CYP2C19（44.77%）为中间代谢表型。CYP2D6 CNVs包括0拷贝（0.43%）、1拷贝（13.64%）、2拷贝（83.79%）、3拷贝（2.11%）和>3拷贝（0.03%）。这项大规模的现实世界的北方汉族队列研究提供了有价值的药物基因组学参考，并证明了将CNV分析与SNP基因分型相结合的必要性，以确保准确的CYP2D6临床表型。

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引用次数: 0

Phenotypic POLE Variant Classification Identifies Patients Who May Have Favorable Prognosis and Benefit from Immunotherapy 表型POLE变异分类识别可能具有良好预后并受益于免疫治疗的患者。

IF 3.4 3区医学 Q1 PATHOLOGY

Journal of Molecular Diagnostics

Pub Date : 2026-03-01 Epub Date: 2026-01-02 DOI: 10.1016/j.jmoldx.2025.12.004

Rachel B. Keller-Evans , Zoe Fleischmann , Smruthy Sivakumar , Radwa Sharaf , Erik A. Williams , Benjamin Kaplan , Ethan S. Sokol , Alexa B. Schrock , Hanna Tukachinsky , Douglas A. Mata , Tyler Janovitz , Douglas I. Lin , Lei Zhong , Lyle Lopez , Nimesh R. Patel , Garrett M. Frampton , Geoffrey R. Oxnard , Julia A. Elvin , Brennan Decker

Pathogenic POLE mutations (pPOLE) undermine mismatch error correction by polymerase ε during DNA replication, and the resulting somatic ultramutation predicts response to immunotherapy. Beyond frequently recurrent alleles, historical pPOLE classification has been largely based on exonuclease domain localization. A POLE-specific phenotypic classification model was developed, encompassing tumor mutational burden (TMB), mutational signatures, germline frequency, and consideration of comutation with other POLE mutations to identify pPOLE. This model was applied to >490,000 samples and identified 29 predicted pPOLE, including 16 not previously reported. A total of 748 tumors (0.2%) had one or more pPOLE, most commonly in endometrial and colorectal cancers, although pPOLE were observed in many additional cancer types. pPOLE were associated with ultramutation [median TMB, 186.3 mutations per megabase (mut/Mb)] across tumor types. Concurrent pPOLE and microsatellite instability were more common than previously appreciated and produced a synergistic TMB impact, with medians of 135.7 mut/Mb for pPOLE/microsatellite stable samples compared with 325.6 mut/Mb for pPOLE/microsatellite instability-high samples. Comutation analysis in endometrial and colorectal cancers highlighted associations with homologous recombination pathway gene mutations that were predominantly monoallelic passengers that are unlikely to predict response to therapies targeting DNA repair deficiencies. pPOLE have been incorporated into treatment guidelines for several malignancies and are an important predictor of immunotherapy response. This study provides biological insight to guide classification and clinical management of patients with tumors harboring pPOLE.

致病性极点突变（pPOLE）在DNA复制过程中破坏了极点ε对错配错误的纠正，由此产生的体细胞超突变预测了对免疫治疗的反应。除了经常复发的等位基因外，历史上的极点分类主要基于外切酶结构域的定位。建立了一种POLE特异性表型分类模型，包括肿瘤突变负担（TMB）、突变特征、种系频率以及与其他POLE突变的共突变的考虑来识别POLE。该模型应用于bbbb49万个样本，确定了29个预测的极点，其中包括16个以前未报道的极点。748个肿瘤（0.2%）有一个或多个pPOLE，最常见的是子宫内膜癌和结直肠癌，尽管在许多其他癌症类型中也观察到pPOLE。pPOLE与各种肿瘤类型的超突变相关（中位TMB为186.3 mut/Mb）。pPOLE和微卫星同时不稳定性（MSI）比之前认识到的更为普遍，并产生协同TMB影响，pPOLE/微卫星稳定样品的中位数为135.7 mut/Mb，而pPOLE/MSI-高样品的中位数为325.6 mut/Mb。子宫内膜癌和结直肠癌的共突变分析强调了同源重组（HR）途径基因突变的相关性，这些基因突变主要是单等位基因乘客，不太可能预测针对DNA修复缺陷的治疗反应。pPOLE已被纳入几种恶性肿瘤的治疗指南，是免疫治疗反应的重要预测指标。本研究为指导pPOLE肿瘤的分型及临床治疗提供生物学依据。

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引用次数: 0

Piloting an Interpretive External Quality Assurance Model for Genomic Testing for Childhood Syndromes and Intellectual Disability 为儿童综合症和智力残疾的基因组检测试行解释性外部质量保证模型。

IF 3.4 3区医学 Q1 PATHOLOGY

Journal of Molecular Diagnostics

Pub Date : 2026-03-01 Epub Date: 2025-12-18 DOI: 10.1016/j.jmoldx.2025.11.006

Ben Lundie , Sze Yee Chai , Alicia B. Byrne , Dimitar Azmanov , John Christodoulou , Matilda A. Haas , Karin S. Kassahn , Sebastian Lunke , Ami Stott , Bryony A. Thompson , Tony Badrick , Bruce Bennetts

Few external quality assurance programs adequately address the complexity of largescale human genome or exome analysis. To bridge this gap, Australian Genomics and the Royal College of Pathologists of Australasia Quality Assurance Programs (QAP) developed a pilot interpretive module focused on genomic testing for childhood syndromes and intellectual disabilities. The program assessed laboratories' proficiency in interpreting complex genomic data for pediatric disorders. Six clinically accredited laboratories analyzed standardized genomic, phenotypic, and referral data. Reports were evaluated using a rubric adapted from the European Molecular Genetics Quality Network model, covering genotyping, variant classification, interpretation, and report content. Feedback included comparative performance results and individual recommendations. All laboratories correctly identified and classified target variants, but variation was observed in report structure, inclusion of genetic counseling advice, and application of the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework. Participants noted that data-sharing limitations and differences in local reporting practices contributed to scoring inconsistencies. The pilot demonstrated the feasibility of a disease-specific interpretive QAP for complex pediatric genomic testing. Future rounds will address logistical challenges, refine scoring criteria, and strengthen standardization, supporting broader implementation. This initiative lays the groundwork for integrating specialized QAP modules into routine practice to improve diagnostic accuracy and consistency across laboratories.

很少有外部质量保证程序充分解决大规模人类基因组或外显子组分析的复杂性。为了弥补这一差距，澳大利亚基因组学和澳大利亚皇家病理学家学院质量保证计划（QAP）开发了一个试点解释性模块，重点是儿童综合症和智力残疾的基因组测试。该项目评估了实验室在解释儿科疾病复杂基因组数据方面的熟练程度。六个临床认可的实验室分析了标准化的基因组、表型和转诊数据。报告采用欧洲分子遗传学质量网络模型的标准进行评估，包括基因分型、变异分类、解释和报告内容。反馈包括比较绩效结果和个人建议。所有实验室都正确地识别和分类了目标变异，但在报告结构、遗传咨询建议的纳入以及美国医学遗传学和基因组学学院/分子病理学协会分类框架的应用方面存在差异。与会者指出，数据共享的限制和当地报告做法的差异导致了得分不一致。该试点项目证明了用于复杂儿科基因组检测的疾病特异性解释性QAP的可行性。未来几轮将解决后勤方面的挑战，完善评分标准，加强标准化，支持更广泛的实施。这一举措为将专门的QAP模块整合到常规实践中奠定了基础，以提高各实验室诊断的准确性和一致性。

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引用次数: 0

Clinical Exome Sequencing 临床外显子组测序：遗传性视网膜营养不良的遗传诊断方法。

IF 3.4 3区医学 Q1 PATHOLOGY

Journal of Molecular Diagnostics

Pub Date : 2026-03-01 Epub Date: 2026-01-05 DOI: 10.1016/j.jmoldx.2025.11.008

Pilar Barberán-Martínez , Mar Balanzá , Belén García-Bohórquez , Sofia Escobar-Parra , Romana García-Gil , Anselmo Feliciano-Sánchez , Teresa Jaijo , Elena Aller , Gema García-García , José M. Millán

Inherited retinal dystrophies (IRDs) represent a diverse group of rare pathologies affecting vision, with significant genetic and clinical variability. Clinical exome sequencing was performed on 143 families clinically diagnosed with IRDs. The obtained variants were filtered and classified according to the American College of Medical Genetics and Genomics guidelines. Overall, a genetic diagnosis was achieved for 68.53% of the families in the cohort; 35 causative genes were identified, predominantly ABCA4 and USH2A. A total of 170 clinically relevant variants were identified, 45 (26.47%) of which were novel, with missense variants being the most common type (40.59%). This study reported aberrant splicing generated by the ABCA4 (NM_000350.2): c.1299A>G mutation through the functional assay of a minigene. Furthermore, the genes FAM161A and GUCY2D were associated with IRDs that are not typically linked to these genes. Consequently, this study expands the current understanding of IRDs and supports the use of clinical exome sequencing as an effective strategy for the genetic diagnosis of these pathologies.

遗传性视网膜营养不良（IRDs）代表了一组影响视力的罕见病理，具有显著的遗传和临床变异性。对143个临床诊断为IRDs的家庭进行临床外显子组测序（CES）。根据美国医学遗传学学院的指导方针，对获得的变异进行筛选和分类。总体而言，该队列中68.53%的家庭获得了遗传诊断，鉴定出35个致病基因，主要是ABCA4和USH2A。共发现170个临床相关变异，其中45个（26.47%）为新变异，错义变异是最常见的类型（40.59%）。本研究通过一个小基因的功能分析证实了ABCA4 (NM_000350.2): c.1299A>G突变产生的异常剪接。此外，基因FAM161A和GUCY2D与通常不与这些基因相关的ird相关。因此，本研究扩展了目前对ird的理解，并支持将CES作为这些病理的有效遗传诊断策略。

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引用次数: 0

Dideoxy Sequencing Enhances Detection of KIT Mutations in Gastrointestinal Stromal Tumors Initially Evaluated by Next-Generation Sequencing Hotspot Panels 双脱氧测序增强了最初由NGS热点面板评估的gist中KIT突变的检测。

IF 3.4 3区医学 Q1 PATHOLOGY

Journal of Molecular Diagnostics

Pub Date : 2026-03-01 Epub Date: 2025-12-18 DOI: 10.1016/j.jmoldx.2025.11.005

Lisa Robinson, Sharleen Rapp, Weiwei Zhang, Jaclyn Pope, Allison M. Cushman-Vokoun

Gastrointestinal stromal tumors (GISTs) are predominantly characterized by mutations in KIT or PDGFRA. Mutation detection is important for optimal therapy. Next-generation sequencing (NGS) panels are useful in GIST assessment as they allow for simultaneous evaluation of multiple genes. However, inherent to use of NGS with short-read sequences on formalin-fixed specimens is the potential to miss larger insertion or deletion variants. Over 9 years, GIST testing was performed on specimens from 55 patients by amplicon-based, semiconductor NGS using the Ion AmpliSeq Cancer Hotspot Panel version 2, a Cancer Hotspot Panel version 2–based GIST panel, or the Oncomine Precision Assay. Negative cases were evaluated by dideoxy sequencing for detection of mutations in KIT and PDGFRA, as per the clinical protocol. Before reflexive sequencing, of 55 completed analyses, 47 (85%) were positive for KIT or PDGFRA mutations by NGS. Three cases were attributed to positivity for pathogenic variants in other genes. Of the five cases evaluated by dideoxy sequencing, all five (9% of all specimens) were positive for pathogenic or likely pathogenic KIT mutations. A total of 12% of KIT mutations required dideoxy sequencing for identification. Mutations were 12 to 39 nucleotide deletion or duplication variants. The results suggest that short-read, amplicon-based NGS assays may miss a significant number of clinically actionable KIT mutations and that follow-up of KIT and PDGFRA NGS-negative cases by alternative testing modalities should be considered.

gist主要以KIT或PDGFRA突变为特征。突变检测对于优化治疗非常重要。NGS面板在GIST评估中很有用，因为它们允许同时评估多个基因。然而，在福尔马林固定标本上使用短读序列的NGS的固有特点是有可能遗漏较大的indel变体。在9年多的时间里，通过基于扩增子的半导体NGS，使用离子AmpliSeq癌症热点面板v2 (CHPv2)，基于CHPv2的GIST面板或Oncomine精密测定法，对55名患者的标本进行了GIST检测。按照我们的临床方案，通过双脱氧测序检测KIT和PDGFRA突变来评估阴性病例。在反射性测序之前，在55个完成的分析中，47个（85%）通过NGS检测KIT或PDGFRA突变呈阳性。3例归因于其他基因致病性变异阳性。在通过双脱氧测序评估的5例病例中，所有5例（占所有标本的9%）均为致病性或可能致病性KIT突变阳性。12%的KIT突变需要双脱氧测序进行鉴定。突变为12 ~ 39个核苷酸缺失或重复变异。我们的研究结果表明，短读、基于扩增子的NGS检测可能会遗漏大量临床可操作的KIT突变，应该考虑采用其他检测方式对KIT和PDGFRA NGS阴性病例进行随访。

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引用次数: 0

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IF 3.4 3区医学 Q1 PATHOLOGY

Journal of Molecular Diagnostics

Pub Date : 2026-03-01 Epub Date: 2026-02-25 DOI: 10.1016/j.jmoldx.2026.01.001

引用次数: 0

A Laboratory-Adaptive Dynamic Quality Control Framework Reduces Targeted Capture Sequencing Failure in Solid Tumors by >90% 实验室自适应动态质量控制框架将实体肿瘤的靶向捕获测序失败减少了90%：临床基因组学的可扩展解决方案。

IF 3.4 3区医学 Q1 PATHOLOGY

Journal of Molecular Diagnostics

Pub Date : 2026-03-01 Epub Date: 2026-02-25 DOI: 10.1016/j.jmoldx.2025.12.003

Jiang Wu , Jie Zhao , Xiaofeng Wang , Yifan Shen , Xin Liao , Zihan Yang , Shan Jiang , Fan Li , Wei Cheng , Lixue Chen , Xueping Chen

High failure rates in targeted capture sequencing of solid tumors—especially from formalin-fixed, paraffin-embedded samples—limit the clinical application of next-generation sequencing. Current wet-laboratory quality control (QC) relies on rigid, predefined thresholds, which are not adaptable to the heterogeneity of clinical samples and contribute significantly to sequencing failures. Retrospective analysis of QC parameters from 1146 tumor samples (425-gene panel; 2021 to 2023) identified five independent predictors of failure: total DNA amount, nucleic acid quality, DNA input, prelibrary total DNA, and prelibrary input (all P < 0.05). On the basis of these findings, the first laboratory-adaptive dynamic QC framework was developed to utilize sample-specific QC metrics for real-time adjustment of wet-laboratory workflows. Prospective validation in 2687 consecutive samples (March 2023 to the present) demonstrated a >90% reduction in sequencing failures, lowering the failure rate from 4.2% to 0.3% (P < 0.001), with significant improvements for high-risk samples. This approach also reduced projected costs by 257 RMB (Renminbi; Chinese Yuan) per sample, saving >230,000 RMB annually. By replacing static cutoffs with a dynamic, sample-specific strategy, this framework offers a scalable and cost-efficient solution, providing a paradigm shift in wet-laboratory QC for heterogeneous clinical specimens.

实体肿瘤靶向捕获测序的高失败率-特别是来自福尔马林固定，石蜡包埋的样品-限制了下一代测序的临床应用。目前的湿实验室质量控制（QC）依赖于严格的、预定义的阈值，这些阈值不适应临床样品的异质性，并且严重导致测序失败。回顾性分析来自1146份肿瘤样本（425个基因组，2021 - 2023年）的QC参数，发现5个独立的失败预测因子：总DNA量、核酸质量、DNA输入、库前总DNA和库前输入（均P < 0.05）。在这些发现的基础上，开发了第一个实验室自适应动态QC框架，利用样品特定的QC指标实时调整湿实验室工作流程。对2687个连续样本（2023年3月至今）的前瞻性验证表明，测序失败率降低了约90%，将失败率从4.2%降至0.3% (P < 0.001)，对高风险样本有显著改善。该方法还使每个样品的预计成本降低257元（人民币；中国元），每年节省bb23万元。通过用动态的、特定于样品的策略取代静态截止，该框架提供了一种可扩展且具有成本效益的解决方案，为异质临床标本的湿实验室质量控制提供了范式转变。

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引用次数: 0

Development and Clinical Validation of OncCNV OncCNV的开发和临床验证：使用TSO500试剂盒对肿瘤抑制基因的癌基因扩增、纯合缺失和双等位基因失活进行全基因组综合分析的管道。

IF 3.4 3区医学 Q1 PATHOLOGY

Journal of Molecular Diagnostics

Pub Date : 2026-03-01 Epub Date: 2025-12-18 DOI: 10.1016/j.jmoldx.2025.12.001

Stephanie A. Smoley , Gopinath Sivasankaran , Mallika Gandham , Beth A. Pitel , Shannon M. Knight , Stefan W. Nelson , Nipun A. Mistry , Katherine B. Geiersbach , Sounak Gupta , Kevin C. Halling , Robert B. Jenkins , Hussam Al-Kateb

Large-scale tumor molecular profiling has enabled the discovery of diagnostic, prognostic, and therapeutic biomarkers, and expanded the clinical utility of alterations such as gene amplifications (GAMPs), homozygous deletions (HMZ-Dels), and biallelic inactivation (BI) of tumor suppressor genes. Comprehensive clinical detection of these events is essential for optimal patient management. Illumina's TruSight Oncology 500 (TSO500) kit detects multiple biomarkers, including GAMPs for select genes, but does not assess HMZ-Del or BI events. To address this gap, OncCNV, a genome-wide copy number analysis and visualization pipeline that integrates both on-target and off-target probe data from TSO500 sequencing, was developed. Performance optimization evaluated copy number calling tools, on-target and off-target probe selection strategies, off-target bin sizes, and panel-of-normal configurations. Clinical validation was conducted using 132 unique solid tumors characterized by a clinically validated microarray assay. OncCNV showed >96% positive percentage agreement, >99% negative percentage agreement, and >99% accuracy at the assay's established limit of detection (40 ng DNA at 40% tumor content). Sensitivity for HMZ-Del and BI detection decreased to 62%–70% at tumor content of 20%–39% in in silico dilution experiments; however, intrarun, interrun, and interanalyst precision remained >99%. OncCNV extends the analytical capabilities of TSO500 by enabling robust and precise detection of GAMP, HMZ-Del, and BI events, enhancing solid tumor comprehensive molecular profiling.

大规模的肿瘤分子谱分析使得新的诊断、预后和治疗生物标志物的发现成为可能，同时扩大了已知改变的临床应用，如基因扩增（GAMP）、纯合缺失（HMZ-Del）和肿瘤抑制基因的双等位基因失活（BI）。对这些事件进行全面的临床检测对于优化患者管理至关重要。Illumina的TSO500试剂盒检测多种生物标志物，包括用于选择基因的GAMP，但不评估HMZ-Del或BI事件。为了解决这一问题，我们开发了OncCNV，这是一个全基因组拷贝数分析和可视化管道，集成了TSO500测序的靶标和非靶标探针数据。OncCNV的性能通过评估不同的工具包、靶探针和非靶探针来优化，用于CNV调用和可视化、非靶容器大小和正常配置面板。临床验证使用了132个独特的实体瘤，并通过临床验证的微阵列分析进行了表征。OncCNV在测定的检测限（40 ng DNA， 40%肿瘤含量）下，所有标记物的阳性一致性为b> 96%，阴性一致性为>99%，准确度为>99%。在硅稀释实验中，当肿瘤含量为20 ~ 39%时，HMZ-Del和BI的检测灵敏度降至62 ~ 70%；然而，运行内部和运行之间以及分析师之间的精度仍然保持在99%左右。OncCNV扩展了TSO500的分析能力，实现了对GAMP、HMZ-Del和BI事件的稳健、精确和准确的检测，增强了实体肿瘤的全面分子谱分析。

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引用次数: 0

Validation of the SOPHiA DDM HRD Solution as a Companion Diagnostic for Poly (ADP-Ribose) Polymerase Inhibitor Access in Australia SOPHiA DDM HRD解决方案作为澳大利亚PARPi接入的配套诊断的验证。

IF 3.4 3区医学 Q1 PATHOLOGY

Journal of Molecular Diagnostics

Pub Date : 2026-03-01 Epub Date: 2025-12-24 DOI: 10.1016/j.jmoldx.2025.12.002

Andrew P. Fellowes , David Y.H. Choong , Christopher R. McEvoy , Roxane A. Legaie , Anthony H. Bell , Stephen B. Fox

In this multilaboratory validation study of 145 ovarian cancer samples, the SOPHiA DDM HRD Solution was compared with the regulatory-approved Myriad myChoice HRD assay to assess clinical comparability for class 3 in-house in vitro diagnostic medical device companion diagnostic use. BRCA (BRCA1 and BRCA2) mutation status showed 100% concordance, and genomic instability (GI) measurements demonstrated strong linear agreement, absence of bias, and high analytical precision. Receiver operating characteristic analysis suggested a threshold adjustment from 0 to –1.5, improving overall accuracy to 91.2% when combined with BRCA mutation status to assign homologous recombination deficiency (HRD) status. Approximately 6% of samples were excluded because of inconclusive results, whereas GI classification discordance was concentrated near the clinical threshold. Neither inconclusiveness nor discordance was associated with sample-related factors. These findings indicate that the SOPHiA HRD assay can provide results broadly interchangeable with Myriad myChoice, although caution is warranted when assigning HRD status to borderline GI values.

在这项145例卵巢癌样本的多实验室验证研究中，SOPHiA DDM HRD溶液与监管部门批准的Myriad myChoice HRD检测进行了比较，以评估3类内部体外诊断医疗设备（IVD）配套诊断使用的临床可比性。BRCA1/2突变状态显示100%的一致性，基因组不稳定性（GI）测量显示出很强的线性一致性，没有偏差，分析精度高。接受者工作特征分析建议将阈值从0调整到-1.5，当结合BRCA突变状态来确定HRD状态时，总体准确率提高到91.2%。由于结果不确定，约6%的样本被排除，而GI分类不一致集中在临床阈值附近。不确定性和不一致性都与样本相关因素无关。这些发现表明，SOPHiA HRD检测可以提供与Myriad myChoice广泛互换的结果，尽管在将HRD状态分配给边缘GI值时需要谨慎。

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引用次数: 0

Different States of Lung Allograft Injury Assessed by Plasma Donor-Derived and Total Cell-Free DNA. 血浆供体来源和总游离细胞DNA评价同种异体肺移植损伤的不同状态。

IF 3.4 3区医学 Q1 PATHOLOGY

Journal of Molecular Diagnostics

Pub Date : 2026-02-26 DOI: 10.1016/j.jmoldx.2026.02.002

Alan Betensley, Katherine Vandervest, David J Ross, William S Ragalie, Kenneth W Presberg, Stephen Dolan, George Haasler, David Mason, Julie A Biller, Paula North, Gabriel D Ryan, Samir Sultan, Sangeeta Bhorade, Zachary Demko, Adam Prewett, Pippa Simpson, Mahua Dasgupta, Aoy Tomita-Mitchell, Michael E Mitchell

Lung allografts are susceptible to myriad injury types [including acute rejection (AR), infectious disease (ID), baseline lung allograft dysfunction (BLAD), and chronic lung allograft dysfunction (CLAD)] that affect outcomes. Donor-derived cell-free DNA (dd-cfDNA) is validated for detecting AR after lung transplantation (LT). However, data are limited regarding the ability of dd-cfDNA or total cell-free DNA (TcfDNA) to detect or differentiate other clinical conditions. This study stratified patients into Stable, AR, CLAD, and ID cohorts. Stable double LT recipients were further stratified into BLAD and non-BLAD over different periods posttransplantation. dd-cfDNA and TcfDNA results were associated with the various cohorts. cfDNA was measured in 354 plasma samples from 66 LT recipients. Median dd-cfDNA was elevated in AR (2.08%; P = 0.014) and ID (1.19%; P = 0.065) versus Stable (0.60%) but not CLAD; TcfDNA was only elevated in the ID cohort (P = 0.0078). dd-cfDNA was analyzed before and after treatment of eight episodes of AR, during which the median dd-cfDNA fraction decreased from 2.41% to 0.80% (P = 0.004). No differences were observed during early time points for BLAD versus non-BLAD, whereas median TcfDNA, but not dd-cfDNA, was elevated for BLAD beyond 12 months (13,842 vs 7767 cp/mL; P = 0.005). Overall, this was the first study that explored dd-cfDNA and TcfDNA levels across AR, ID, BLAD, and CLAD cohorts. These data suggest that cfDNA-based biomarkers have value in assessing allograft dysfunction beyond AR.

同种异体肺移植物易受多种损伤类型的影响，包括急性排斥反应（AR）、感染性疾病（ID）、基线肺移植物功能障碍（BLAD）和慢性肺移植物功能障碍（CLAD），这些都会影响结果。供体来源的无细胞DNA （dd-cfDNA）可用于检测肺移植（LT）后的AR。然而，关于dd-cfDNA或总游离细胞DNA （TcfDNA）检测或区分其他临床疾病的能力的数据有限。本研究将患者分为Stable、AR、CLAD和ID组。在移植后的不同时期，将稳定的双肝移植受体进一步分为BLAD和非BLAD。dd-cfDNA和TcfDNA结果与各个队列相关。在66名LT受体的354份血浆样本中测量cfDNA。与稳定组（0.60%）相比，AR组（2.08%,p=0.014）和ID组（1.19%,p=0.065）中位dd-cfDNA升高，但CLAD组没有升高；TcfDNA仅在ID中升高（p=0.0078）。分析8次AR治疗前后dd-cfDNA，治疗期间dd-cfDNA中位分数从2.41%下降到0.80% （p=0.004）。在BLAD与非BLAD的早期时间点没有观察到差异，而BLAD的中位TcfDNA（而不是dd-cfDNA）在12个月后升高（13,842 vs 7,767 cp/mL, p=0.005）。总的来说，这是第一个探索AR、ID、BLAD和CLAD队列中dd-cfDNA和TcfDNA水平的研究。这些数据表明，基于cfdna的生物标志物在评估AR以外的同种异体移植物功能障碍方面具有价值。

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