Clinical chemistry最新文献

{"title":"Low-Pass Whole Genome Sequencing of Cell-Free DNA from Cerebrospinal Fluid: A Focus on Pediatric Central Nervous System Tumors.","authors":"Katrina O'Halloran, Eirini Christodoulou, Vera A Paulson, Bonnie L Cole, Ashley S Margol, Jaclyn A Biegel, Sarah E S Leary, Christina M Lockwood, Erin E Crotty","doi":"10.1093/clinchem/hvae140","DOIUrl":"https://doi.org/10.1093/clinchem/hvae140","url":null,"abstract":"<p><strong>Background: </strong>Cell-free DNA (cfDNA) technology has allowed for cerebrospinal fluid (CSF), a previously underutilized biofluid, to be analyzed in new ways. The interrogation of CSF-derived cfDNA is giving rise to novel molecular insights, particularly in pediatric central nervous system (CNS) tumors, where invasive tumor tissue acquisition may be challenging. Contemporary disease monitoring is currently restricted to radiographic surveillance by magnetic resonance imaging and CSF cytology to directly detect abnormal cells and cell clusters. Alternatively, cfDNA is often present in the CSF from pediatric patients with both malignant and nonmalignant CNS tumors and can be accessed by minimally invasive lumbar puncture and other CSF-liberating procedures, offering a promising alternative for longitudinal molecular disease analysis and surveillance.</p><p><strong>Content: </strong>This review explores the use of low-pass whole genome sequencing (LP-WGS) to analyze cfDNA from the CSF of pediatric patients with CNS tumors. This platform is uniquely poised for the detection of tumors harboring copy number variants, which are prevalent in this population. The utility and sensitivity of LP-WGS as a clinical tool is explored and discussed in the context of alternative CSF liquid biopsy interrogation modalities, including nanopore sequencing and methylation array.</p><p><strong>Summary: </strong>Analysis of CSF-derived cfDNA by LP-WGS has broad diagnostic, prognostic, and clinical implications for pediatric patients with CNS tumors. Careful interpretation of LP-WGS results may aid in therapeutic targeting of pediatric CNS tumors and may provide insight into tumor heterogeneity and evolution over time, without the need for invasive and potentially risky tissue sampling.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"87-96"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mate-Pair Sequencing Enables Identification and Delineation of Balanced and Unbalanced Structural Variants in Prenatal Cytogenomic Diagnostics.","authors":"Jicheng Qian, Huilin Wang, Hailei Liang, Yuting Zheng, Mingyang Yu, Wing Ting Tse, Angel Hoi Wan Kwan, Lo Wong, Natalie Kwun Long Wong, Isabella Yi Man Wah, So Ling Lau, Shuk Yi Annie Hui, Matthew Hoi Kin Chau, Xiaoyan Chen, Rui Zhang, Liona C Poon, Tak Yeung Leung, Pengfei Liu, Kwong Wai Choy, Zirui Dong","doi":"10.1093/clinchem/hvae146","DOIUrl":"https://doi.org/10.1093/clinchem/hvae146","url":null,"abstract":"<p><strong>Background: </strong>Mate-pair sequencing detects both balanced and unbalanced structural variants (SVs) and simultaneously informs in relation to both genomic location and orientation of SVs for enhanced variant classification and clinical interpretation, while chromosomal microarray analysis (CMA) only reports deletion/duplication. Herein, we evaluated its diagnostic utility in a prospective back-to-back prenatal comparative study with CMA.</p><p><strong>Methods: </strong>From October 2021 to September 2023, 426 fetuses with ultrasound anomalies were prospectively recruited for mate-pair sequencing and CMA in parallel for prenatal genetic diagnosis. Balanced/unbalanced SVs and regions with absence of heterozygosity (AOH) were detected and classified independently, and comparisons were made between mate-pair sequencing and CMA to assess concordance. In addition, novel SVs were investigated for potential RNA perturbations using cultured cells, whenever available.</p><p><strong>Results: </strong>Mate-pair sequencing and CMA successfully yielded results for all 426 fetuses without the need for cell culturing. In addition, mate-pair sequencing identified 19 cases with aneuploidies, 16 cases with pathogenic simple deletions/duplications, and 5 cases with pathogenic translocations/insertions, providing a 25% incremental diagnostic yield compared to CMA (9.4%, 40/426 vs 7.6%, 32/426). Furthermore, by identifying the location and orientation of SVs, mate-pair sequencing improved the variant interpretation and/or follow-up approach for 40.0% (12) of the 30 cases with likely clinically significant deletions/duplications reported by CMA. Lastly, both platforms reported 3 cases (3/426) with multiple regions of AOH likely attributable to parental consanguinity.</p><p><strong>Conclusions: </strong>Mate-pair sequencing detects additional balanced/unbalanced SVs and improves variant interpretation in comparison to CMA, indicating its potential to serve as a comprehensive prenatal cytogenomic diagnostic method.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"155-168"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 Diversity and Transmission on a University Campus across Two Academic Years during the Pandemic.","authors":"Amanda M Casto, Miguel I Paredes, Julia C Bennett, Kyle G Luiten, Peter D Han, Luis S Gamboa, Evan McDermot, Geoffrey S Gottlieb, Zachary Acker, Natalie K Lo, Devon McDonald, Kathryn M McCaffrey, Marlin D Figgins, Christina M Lockwood, Jay Shendure, Timothy M Uyeki, Lea M Starita, Trevor Bedford, Helen Y Chu, Ana A Weil","doi":"10.1093/clinchem/hvae194","DOIUrl":"https://doi.org/10.1093/clinchem/hvae194","url":null,"abstract":"<p><strong>Background: </strong>Institutions of higher education (IHE) have been a focus of SARS-CoV-2 transmission studies but there is limited information on how viral diversity and transmission at IHE changed as the pandemic progressed.</p><p><strong>Methods: </strong>Here we analyze 3606 viral genomes from unique COVID-19 episodes collected at a public university in Seattle, Washington from September 2020 to September 2022.</p><p><strong>Results: </strong>Across the study period, we found evidence of frequent viral transmission among university affiliates with 60% (n = 2153) of viral genomes from campus specimens genetically identical to at least one other campus specimen. Moreover, viruses from students were observed in transmission clusters at a higher frequency than in the overall dataset while viruses from symptomatic infections were observed in transmission clusters at a lower frequency. Although only a small percentage of community viruses were identified as possible descendants of viruses isolated in university study specimens, phylodynamic modeling suggested a high rate of transmission events from campus into the local community, particularly during the 2021-2022 academic year.</p><p><strong>Conclusions: </strong>We conclude that viral transmission was common within the university population throughout the study period but that not all university affiliates were equally likely to be involved. In addition, the transmission rate from campus into the surrounding community may have increased during the second year of the study, possibly due to return to in-person instruction.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"192-202"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating Pharmacogenomics into the Broader Construct of Genomic Medicine: Efforts by the ClinGen Pharmacogenomics Working Group (PGxWG).","authors":"Li Gong, Clarissa J Klein, Kelly E Caudle, Ann M Moyer, Stuart A Scott, Michelle Whirl-Carrillo, Teri E Klein","doi":"10.1093/clinchem/hvae181","DOIUrl":"10.1093/clinchem/hvae181","url":null,"abstract":"<p><p>Pharmacogenomics (PGx) is focused on the relationship between an individual's genetic makeup and their response to medications, with the overarching aim of guiding prescribing decisions to improve drug efficacy and reduce adverse events. The PGx and genomic medicine communities have worked independently for over 2 decades, developing separate standards and terminology, making implementation of PGx across all areas of genomic medicine difficult. To address this issue, the Clinical Genome Resource (ClinGen) Pharmacogenomics Working Group (PGxWG) was established by the National Institutes of Health (NIH)-funded ClinGen to initially create frameworks for evaluating gene-drug response clinical validity and actionability aligned with the ClinGen frameworks for evaluating monogenic gene-disease relationships, and a framework for classifying germline PGx variants similar to the American College of Medical Genetics (ACMG) and Association of Molecular Pathology (AMP) system for interpretation of disease-causing variants. These frameworks will leverage decades of work from well-established PGx resources facilitating buy-in among PGx stakeholders. In this report, we describe the background and major activities of the ClinGen PGxWG, and how this initiative will facilitate the critical inclusion of PGx into the larger context of genomic medicine.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"36-44"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commentary on Liquid Biopsy Detection of a TP53 Variant in a \"Disease-Free\" Pediatric Patient with a History of TP53-mutant Adrenocortical Carcinoma.","authors":"Sasha Witts, Nicholas J Clemons, David S Liu","doi":"10.1093/clinchem/hvae132","DOIUrl":"https://doi.org/10.1093/clinchem/hvae132","url":null,"abstract":"","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"30"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commentary on Liquid Biopsy Detection of a TP53 Variant in a \"Disease-Free\" Pediatric Patient with a History of TP53-Mutant Adrenocortical Carcinoma.","authors":"Christina M Lockwood","doi":"10.1093/clinchem/hvae171","DOIUrl":"https://doi.org/10.1093/clinchem/hvae171","url":null,"abstract":"","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"29"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Higher Cell-Free DNA Yields on Liquid Biopsy Testing in Glioblastoma Patients.","authors":"J Bryan Iorgulescu, Timothy Blewett, Kan Xiong, Andjela Crnjac, Ruolin Liu, Sainetra Sridhar, David A Braun, MacLean C Sellars, Ju Cheng, Justin Rhoades, David A Reardon, G Mike Makrigiorgos, Catherine J Wu, Viktor A Adalsteinsson","doi":"10.1093/clinchem/hvae178","DOIUrl":"https://doi.org/10.1093/clinchem/hvae178","url":null,"abstract":"<p><strong>Background: </strong>Minimally invasive molecular profiling using cell-free DNA (cfDNA) is increasingly important to the management of cancer patients; however, low sensitivity remains a major limitation, particularly for brain tumor patients. Transiently attenuating cfDNA clearance from the body-thereby, allowing more cfDNA to be sampled-has been proposed to improve the performance of liquid biopsy diagnostics. However, there is a paucity of clinical data on the effect of higher cfDNA recovery. Here, we investigated the impact of collecting greater quantities of cfDNA on circulating tumor DNA (ctDNA) sensitivity in the \"low-shedding\" cancer type glioblastoma by analyzing up to approximately 15-fold more plasma than routinely obtained clinically.</p><p><strong>Methods: </strong>We tested 70 plasma samples (median 17.0 mL, range 2.5-66.5) from 8 IDH-wild-type glioblastoma patients using an optimized version of the MAESTRO-Pool ctDNA assay. Results were compared with simulated single-blood-tube equivalents of cfDNA. ctDNA results were then compared with magnetic resonance imaging (MRI) and pathology assessments of true progression vs pseudoprogression in glioblastoma patients.</p><p><strong>Results: </strong>Larger cfDNA yields exhibited a doubling in ctDNA-positivity while achieving a median specificity of 99% and more precise ctDNA quantification. In 8 glioblastoma patients, ctDNA was detected in 88%, including at multiple timepoints in 6/7. In the setting of indeterminate progression by MRI, our data suggested that MAESTRO-Pool with large plasma volumes can help distinguish true glioblastoma progression from pseudoprogression.</p><p><strong>Conclusions: </strong>Our findings provide a proof-of-principle that most glioblastomas shed ctDNA into plasma and that greater ctDNA yields could help improve liquid biopsies for \"low-shedding\" cancer types such as glioblastoma.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"215-225"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Routine Prenatal cfDNA Screening for Autosomal Dominant Single-Gene Conditions.","authors":"Sophie Adams, Olivia Maher Trocki, Christina Miller, Courtney Studwell, Meghan Bombalicki, Lori Dobson, Sofia Horan, Jordan Sargent, Michael Duyzend, Kathryn J Gray, Stephanie Guseh, Louise Wilkins-Haug","doi":"10.1093/clinchem/hvae189","DOIUrl":"https://doi.org/10.1093/clinchem/hvae189","url":null,"abstract":"<p><strong>Background: </strong>Genetic screening has advanced from prenatal cell-free DNA (cfDNA) screening for aneuploidies (cfDNA-ANP) to single-gene disorders (cfDNA-SGD). Clinical validation studies have been promising in pregnancies with anomalies but are limited in the general population.</p><p><strong>Methods: </strong>Chart review and laboratory data identified pregnancies with cfDNA-SGD screening for 25 autosomal dominant conditions at our academic center. Screening was identified as routine by International Classification of Diseases (ICD) 10 codes and chart review. Ultrasound anomalies or known family history of a condition on the panel were excluded. Retrospective chart review investigated test concordance, outcomes, and phenotypes.</p><p><strong>Results: </strong>cfDNA-SGD was completed for 3480/37 050 (9.4%) pregnancies, of which 2745 (78.9%) were for routine screening. Fourteen (0.51%, 14/2745) had high-risk results defined as pathogenic/likely pathogenic (P/LP) variants: 6 (0.22%) likely fetal variants, and 8 (0.29%) maternal variants with 50% risk for fetal inheritance. Diagnostic testing detected 6/6 fetal and 6/8 maternal cfDNA-SGD variants (2/8 pregnant individuals declined testing but had clinical features on physical exam). Variants were detected in 11/14 pregnancies/newborns and in 9/14 (64.3%) parents/gamete donors. There were no false positives identified by cfDNA-SGD; however, 2 variants were discrepantly classified between the cfDNA-SGD and diagnostic testing laboratories. All pregnancies had normal imaging and 9 had mild postnatal phenotypes. Three terminated pregnancy following diagnostic testing.</p><p><strong>Conclusions: </strong>Our study demonstrated that 0.51% of routine cfDNA-SGD was high risk, prompting comprehensive evaluation for pregnancies and parents. Routine cfDNA-SGD allowed for early identification and intervention, but raises counseling challenges due to variable expressivity, limited genotype-phenotype correlations, and discrepant variant classification.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"129-140"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges and Opportunities in Training Cytogenetics Laboratory Directors.","authors":"T Niroshi Senaratne","doi":"10.1093/clinchem/hvae172","DOIUrl":"https://doi.org/10.1093/clinchem/hvae172","url":null,"abstract":"","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"21-23"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming Barriers to Genomic Medicine Implementation.","authors":"Heidi L Rehm","doi":"10.1093/clinchem/hvae147","DOIUrl":"https://doi.org/10.1093/clinchem/hvae147","url":null,"abstract":"","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"4-9"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}