Molecular Diagnosis & Therapy最新文献

{"title":"Making Sense of Missense: Benchmarking MutScore for Variant Interpretation in Inherited Cardiac Diseases.","authors":"Alessandra Pia Porretta, Véronique Fressart, Elodie Surget, Charles Morgat, Adrien Bloch, Anne Messali, Vincent Algalarrondo, Géraldine Vedrenne, Etienne Pruvot, Antoine Leenhardt, Isabelle Denjoy, Fabrice Extramiana","doi":"10.1007/s40291-025-00784-8","DOIUrl":"https://doi.org/10.1007/s40291-025-00784-8","url":null,"abstract":"<p><strong>Background: </strong>Accurate interpretation of genetic variants still represents a major challenge. According to current recommendations from the American College of Medical Genetics and Genomics (ACMG), variant interpretation relies on a comprehensive analysis including, among others, computational data for prediction of variant pathogenicity. However, the predictive accuracy of in silico tools is often limited, and results are frequently inconsistent. In the current study, we evaluated the predictive performance of a previously described innovative classifier (MutScore) for missense variants in our cohort of probands with inherited cardiac diseases (InCDs).</p><p><strong>Methods: </strong>We retrospectively reviewed missense variants detected in our cohort of probands with InCDs. Variants were analyzed with four in silico tools commonly used in our diagnostic pipelines (CADD, Polyphen-2, Alpha-missense and Revel) and with MutScore, a new meta-predictor combining data on variant location with the output of 16 existing predictors. For each variant, we recorded the original classification (established according to scientific evidence available at the time of molecular diagnosis) and the updated classification performed at the present time, according to ACMG standards.</p><p><strong>Results: </strong>We detected 252 missense variants in our cohort of 517 patients affected by InCDs. MutScore was the most proficient tool in classifying variants (0.89 maximum area under the curve [95% confidence interval (CI) 0.85-0.94]). Compared to Revel, the second-best predictor, MutScore showed superior sensitivity (73% vs 57%) at the maximum tolerated false-positive rate of 10%, higher specificity (0.83 vs 0.36) and a markedly lower false-positive rate (0.17 vs 0.64), supporting a more nuanced and accurate assessment, especially for benign or likely benign variants. MutScore also appeared to perform better for variants located in genes associated with channelopathies than for variants in cardiomyopathy-related genes. Notably, when comparing the original and updated classification, 27% (69/252) of missense variants underwent a change in classification over the 9-year follow-up period. Among these, reclassification had a significant impact on clinical management in one third of cases (i.e., variants of uncertain significance upgraded to pathogenic or likely pathogenic variants or vice versa), with a 4.8% increase in molecular diagnosis of InCDs over the 9-year period.</p><p><strong>Conclusion: </strong>Our study supports the excellent performance of MutScore in a real-life dataset of missense variants associated with the rare subset of InCDs. MutScore represents a promising application of artificial intelligence with major potential in cardiogenetics to improve diagnostic precision in clinical practice. In addition, our results highlight the importance of periodic reanalysis of variants, incorporating newly available scientific evidence, as attested by","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recurrent and Novel Pathogenic Variants in Genes Involved with Hearing Loss in the Pakistani Population.","authors":"Madiha Shadab, Afif Ben-Mahmoud, Luis Nicolás Martínez Völter, Ansar Ahmed Abbasi, Bonsu Ku, Ahsan Ejaz, Zahid Latif, Vijay Gupta, Daniel Owrang, Mi-Hyeon Jang, Zijin Zhang, Rahema Mohammad, Henry Houlden, Hyung-Goo Kim, Barbara Vona","doi":"10.1007/s40291-025-00782-w","DOIUrl":"https://doi.org/10.1007/s40291-025-00782-w","url":null,"abstract":"<p><strong>Background: </strong>Molecular diagnostic rates for hereditary hearing loss vary by genetic ancestry, highlighting the importance of population-specific studies. In Pakistan, where consanguineous marriages are prevalent, genetic research has identified many autosomal recessive genes, advancing understanding of rare and novel hearing loss mechanisms. This study aimed to identify pathogenic genetic variants in 31 families from Azad Kashmir, Pakistan, presenting non-syndromic hearing loss.</p><p><strong>Methods: </strong>We conducted exome sequencing and bioinformatics analysis, and targeted gene sequencing on 31 Pakistani families with hearing loss.</p><p><strong>Results: </strong>We identified ten pathogenic, three likely pathogenic variants, and one variant of uncertain significance, comprising six nonsense, four missense, three frameshift, and one deep intronic variant, across ten hearing loss-associated genes (MYO15A, GJB2, SLC26A4, TMC1, HGF, TMIE, SLC19A2, KCNE1, ILDR, PCDH15 and MYO6) in 25 families. The overall diagnostic rate, including families with pathogenic and likely pathogenic variants, was 77.4%. GJB2 was the most frequently affected gene, identified in seven families. Thirteen out of 14 identified variants were homozygous. Notably, we identified two novel variants: MYO15A (NM_016239.4, DFNB3) c.870C>G, p.(Tyr290*) and MYO6 (NM_016239.4, DFNB37) c.3465del, p.(Pro1156Leufs*9). Additionally, we identified c.10475dupA, p.(Leu3493Alafs*25) in MYO15A (NM_016239.4, DFNB3) and c.617T>A, p.(Leu206*) in SLC26A4 (NM_000441.2, DFNB4), previously documented in ClinVar but unpublished. We also propose SLC19A2 as a candidate gene presenting as non-syndromic hearing loss, despite its association with thiamine-responsive megaloblastic anemia syndrome.</p><p><strong>Conclusion: </strong>Our work expands the genotypic and phenotypic spectrum of hearing loss by emphasizing the importance of investigating under-represented groups to identify unique genetic variants and clinical characteristics. Such efforts deepen understanding of genetic diversity in under-represented populations to improve diagnosis and treatment strategies.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorescence Imaging-Assessed Surgical Margin Detection in Head and Neck Oncology by Passive and Active Targeting.","authors":"L Dirheimer, S Cortese, G Dolivet, J L Merlin, F Marchal, R Mastronicola, L Bezdetnaya","doi":"10.1007/s40291-025-00781-x","DOIUrl":"https://doi.org/10.1007/s40291-025-00781-x","url":null,"abstract":"<p><p>Surgery remains the gold standard in the management of head and neck squamous cell carcinoma (HNSCC). However, the anatomical complexity of these cancers, combined with the difficulty in discriminating between healthy and cancerous tissue and the detection of microlesions, complicates tumor resection, resulting in positive surgical margins, which are associated with a poor patient prognosis. Fluorescence-guided surgery (FGS) has emerged as a promising technique in the management of HNSCC, improving tumor resection and margin assessment. FGS strategies can be roughly divided into three approaches; namely, natural tissue autofluorescence, passive delivery of fluorescent contrast agents, and active targeting. This review provides a comprehensive overview of the advances made in FGS of head and neck cancers, particularly aiming to improve surgical margin assessment. Recently, the field has shown promising results by addressing contrast agents targeted to the overexpressed epidermal growth factor receptor (EGFR), both in preclinical and clinical settings. The identification of new targets such as αVβ6 integrin, uPAR, PARP1, and so on, as well as the development of contrast agents, are key steps in the further development of FGS of head and neck cancers, making it an essential tool in precision oncology. Among these, as was demonstrated in preclinical studies, the αVβ6 integrin is emerging as a promising target due to its high and specific expression in tumor and tumor margins.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Potential of a Cell-Free DNA Methylation-Based Blood Test in Colorectal Cancer Screening.","authors":"Angeliki Margoni, Athanasios G Papavassiliou","doi":"10.1007/s40291-025-00783-9","DOIUrl":"https://doi.org/10.1007/s40291-025-00783-9","url":null,"abstract":"","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Actionability of Molecular Targets in Multi-Ethnic Breast Cancer Patients: A Retrospective Single-Institutional Study.","authors":"Irene Kang, Leah Naghi, Susan E Yost, Joanne Mortimer","doi":"10.1007/s40291-025-00777-7","DOIUrl":"10.1007/s40291-025-00777-7","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Precision oncology is making remarkable advancements in optimizing patient care by personalizing treatments. To date, the US Food and Drug Administration (FDA) has approved poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib (Lynparza, AstraZeneca and Merck) and talazoparib (Talzenna, Pfizer Oncology Together™) for germline or somatic BRCA1/2-mutated metastatic breast cancer (BC) patients, and PI3K inhibitor alpelisib (Piqray, Novartis) plus fulvestrant for patients with hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+HER2-) PIK3CA-mutated advanced BC. In addition, the FDA approved capivasertib (Trucap, AstraZeneca) for HR+HER2- locally advanced or metastatic BC patients with one or more AKT1, PIK3CA, or PTEN alterations. Finally, the FDA recently approved elacestrant (Orserdu, Stemline Therapeutics, Inc.) for postmenopausal patients with ER+ HER2- ESR1-mutated advanced or metastatic BC with disease progression following at least one line of endocrine therapy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This study presents a single institutional retrospective review of genomic reports of patients with BC. Analysis of genomic reports of 1361 BC sequencing reports was performed for 1010 patients with BC from 2013 to 2023 (23% of patients had multiple reports). Eligible patients had at least one primary or metastatic tumor. Multiple sequencing platforms were used for FFPE specimens including Tempus xT targeted next-generation sequencing (NGS), Foundation One Medicine, HopeSeq, Ashion Analytics GEM ExTra, and Exact Sciences Oncomap. Liquid biopsies were performed by Guardant, Tempus, and Foundation One Medicine. Chart reviews were performed to collect patient characteristics. BRCA1/2-mutated, metastatic BC patients who initiated treatment with olaparib or talazoparib, and PIK3CA-mutated, HR+ metastatic BC patients who initiated treatment with alpelisib were reported. In addition, patients with ESR1 or AKT1/PIK3CA/PTEN mutations were identified. Clinical outcomes, including progression-free survival (PFS) and overall survival (OS) were analyzed for BRCA1/2 and PIK3CA-mutated patients who received PARPi or alpelisib. Survival curves were generated using the Kaplan Meier method.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A cohort of 1010 BC patients with 1361 genomic reports was identified. A total of 935/1361 (69%) specimens were formalin-fixed paraffin-embedded (FFPE) tumor biopsies and 426/1361 (31%) were liquid biopsies. Receptor status included 65% HR+HER2-, 8% HR+HER2+, 4% HR-HER2+, and 23% TNBC. Racial and ethnic distribution of these patients included 50% non-Hispanic White, 26% Hispanic, 17% Asian, 6% African American, 1% other (Native Hawaiian or Other Pacific Islander, American Indian or Alaska Native, or unknown). Sequencing platforms included 30% Tempus xT, 31% Foundation One, 10% HopeSeq, 20% GEM ExTra, and 9% Exact Sciences. Liquid biopsies included 79% Guardant, 20% Tempus, and 1% Foundation O","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"393-405"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Somatic Genetic Variants in Superficial Vascular Malformations by Liquid Biopsy in a Cohort of 88 Patients from a French Hospital.","authors":"Franck Neil El Sissy, Annouk Bisdorff, Alexandre Perrier, Erell Guillerm, Jérôme Denis, Löetitia Favre, Mathilde Aubertin, Mélanie Eyries, Florence Coulet","doi":"10.1007/s40291-025-00770-0","DOIUrl":"10.1007/s40291-025-00770-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;Superficial vascular anomalies are complex disorders characterized by abnormal vascular growth. Next-generation sequencing has recently identified somatic genetic alterations associated with these malformations, offering new insights for targeted treatments. However, tissue biopsies for genetic testing can be invasive and difficult to obtain, especially in arteriovenous malformations (AVM) with hemorrhagic risks. A liquid biopsy, a non-invasive approach, offers a promising solution by detecting genetic mutations in cell-free DNA. This pilot study aimed to evaluate the feasibility of using a liquid biopsy for the genetic analysis of patients with superficial vascular anomalies through cell-free DNA sampling. Additionally, it explored whether specific sampling sites, such as the afferent artery, nidus, and efferent vein, could enhance the sensitivity of detecting pathogenic variants in patients with AVM.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A total of 88 patients were enrolled, including 55 with AVM and 33 with lymphatic malformations. For patients with AVM, cell-free DNA samples were collected from peripheral blood, efferent veins, afferent arteries, and the AVM nidus. In patients with lymphatic malformations, cystic lymphatic fluid was collected by a direct puncture during diagnostic procedures. A molecular analysis was performed using a targeted gene panel relevant to somatic alterations in solid tumors. Pathogenic variants were validated by digital polymerase chain reaction for patients with lymphatic malformations.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Pathogenic variants were identified in 23.6% of patients with AVM, predominantly in MAP2K1 and KRAS genes, with higher sensitivity near the AVM nidus. In addition, pathogenic variants were identified in 27.3% of patients with lymphatic malformations, all involving the PIK3CA gene. Despite the lower sensitivity of a cell-free DNA analysis compared with a tissue biopsy, especially in patients with AVM, the detection rate suggests the utility for a cell-free DNA analysis, particularly when a tissue biopsy is not feasible.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study confirms the feasibility of using a cell-free DNA liquid biopsy for genotyping patients with superficial vascular anomalies, although a tissue biopsy remains the gold standard for comprehensive genetic profiling because of its higher sensitivity. A liquid biopsy offers a non-invasive option for molecular analysis that is useful as a preliminary or alternative approach when direct tissue sampling is not possible. Importantly, the sensitivity of cell-free DNA sampling in AVM appeared highest when obtained close to the nidus, indicating an optimal sampling location for future studies. Further research is needed to improve detection sensitivity, especially for samples taken near the nidus, to validate and strengthen these findings. Although our study focused on superficial/extra-cranial AVM, further rese","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"367-380"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obecabtagene Autoleucel: First Approval.","authors":"Arnold Lee","doi":"10.1007/s40291-025-00771-z","DOIUrl":"10.1007/s40291-025-00771-z","url":null,"abstract":"<p><p>Obecabtagene autoleucel (AUCATZYL^®) is a CD19-directed genetically modified autologous T cell immunotherapy which is being developed by Autolus for the treatment of hematological cancers and systemic lupus erythematosus. In comparison with other chimeric antigen receptor T (CAR T) therapies, obecabtagene autoleucel has a fast off-rate binder for CD19. Obecabtagene autoleucel received approval following positive results from the FELIX phase I/II trial in adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), and it is the first CAR T therapy that does not have mandatory Risk Evaluation Mitigation Strategy monitoring requirements. This article summarizes the milestones in the development of obecabtagene autoleucel leading to this first approval for the treatment of adults with relapsed or refractory B-cell precursor ALL.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"419-423"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging the Gap: Cost-Effective Strategies for Detecting Ph-Like B-Lineage ALL in Resource-Limited Settings.","authors":"Dikshat Gopal Gupta, Monika, Neelam Varma","doi":"10.1007/s40291-025-00775-9","DOIUrl":"10.1007/s40291-025-00775-9","url":null,"abstract":"<p><p>Acute lymphoblastic leukemia (ALL) is a complex hematologic disorder primarily affecting children, characterized by genetic mutations that disrupt normal lymphoid cell differentiation and promote abnormal proliferation. A particularly high-risk subtype, Philadelphia chromosome-like ALL (Ph-like ALL), mirrors the genetic profile of Philadelphia chromosome-positive (Ph-positive) ALL but lacks the BCR::ABL1 fusion gene. While Ph-like ALL has been extensively studied in high-income countries (HICs), it remains under-researched in low- and middle-income countries (LMICs), where resource limitations hinder accurate diagnosis and targeted therapy. This review addresses this gap by providing a comprehensive overview of the incidence, genetic landscape, and detection strategies for Ph-like ALL, with a special focus on LMICs. It underscores the prevalence of Ph-like ALL and its association with poor clinical outcomes, emphasizing the critical need for cost-effective diagnostic methodologies tailored to resource-constrained settings. Despite advancements in diagnostic technologies, such as whole gene expression profiling and next-generation sequencing, their high cost and extended turnaround times limit their feasibility in LMICs. Innovative methods, such as the PGIMER In-House Rapid and Cost-Effective (PHi-RACE) classifier, which employs real-time quantitative polymerase chain reaction (PCR), offer promising solutions by delivering high sensitivity and specificity at a significantly reduced cost. This approach is further complemented using fluorescence in situ hybridization (FISH) to characterize kinase alterations, enabling the identification of targeted therapies. This method addresses the urgent need for accessible diagnostic tools in LMICs, enabling early detection and personalized treatment planning. As the landscape of Ph-like ALL detection evolves, integrating low-cost, rapid-turnaround approaches holds significant promise for improving patient outcomes globally. This review aims to highlight the challenges and opportunities in diagnosing and treating Ph-like ALL in LMICs, fostering efforts towards more accessible and effective diagnostic strategies to enhance patient care and prognosis.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"329-344"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Therapeutics in Development to Treat Hyperlipoproteinemia.","authors":"Maud Ahmad, Robert A Hegele","doi":"10.1007/s40291-024-00768-0","DOIUrl":"10.1007/s40291-024-00768-0","url":null,"abstract":"<p><p>Clinical endpoints caused by hyperlipoproteinemia include atherosclerotic cardiovascular disease and acute pancreatitis. Emerging lipid-lowering therapies targeting proprotein convertase subtilisin/kexin 9 (PCSK9), lipoprotein(a), apolipoprotein C-III, and angiopoietin-like protein 3 represent promising advances in the management of patients with hyperlipoproteinemia. These therapies offer novel approaches for lowering pathogenic lipid and lipoprotein species, particularly in patients with serious perturbations who are not adequately controlled with conventional treatments or who are unable to tolerate them. Molecular targets for these novel therapeutic agents were identified and validated through genetic epidemiology studies. Proprotein convertase subtilisin/kexin 9 inhibitors (e.g., monoclonal antibodies and small interfering RNA) have revolutionized hypercholesterolemia management by significantly reducing both low-density lipoprotein cholesterol levels and major cardiovascular events. Genome editing of PCSK9 promises to provide a potential cure for patients with familial hypercholesterolemia. Several investigational lipoprotein(a)-targeting therapies aim to reduce the risk of atherosclerotic cardiovascular disease and aortic valve disease, although definitive clinical endpoint studies remain to be completed. Inhibition of APOC3 messenger RNA expression by olezarsen and plozasiran significantly lowers plasma triglyceride levels and markedly reduces pancreatitis risk in patients with familial chylomicronemia syndrome. Finally, angiopoietin-like protein 3 inhibition by the monoclonal antibody evinacumab has transformed management of patients with homozygous familial hypercholesterolemia. Together, these novel agents expand the therapeutic cache, offering personalized lipid-lowering strategies for high-risk patients with hyperlipoproteinemia, improving clinical outcomes and addressing previously unmet medical needs.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"291-305"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-Free DNA: Features and Attributes Shaping the Next Frontier in Liquid Biopsy.","authors":"Neeti Swarup, Ho Yeung Leung, Irene Choi, Mohammad Arshad Aziz, Jordan C Cheng, David T W Wong","doi":"10.1007/s40291-025-00773-x","DOIUrl":"https://doi.org/10.1007/s40291-025-00773-x","url":null,"abstract":"<p><p>Cell-free DNA (cfDNA) is changing the face of liquid biopsy as a minimally invasive tool for disease detection and monitoring, with its main applications in oncology and prenatal testing, and rising roles in transplant patient monitoring. However, the processes of cfDNA biogenesis, fragmentation, and clearance are complex and require further investigation. Evidence suggests that cfDNA production relates to mechanisms of cell death and DNA repair, both of which further influence fragment size and its applicability as a biomarker. An emerging domain, cfDNA fragmentomics is being explored for advancing the field of diagnostics using non-mutational signatures such as fragment size ratios and methylation patterns. Thus, this review examines structural diversity in cfDNA with various fragment sizes. In examining these cfDNA subsets, we discuss their distinct biological origins and potential clinical utility. Development of sequencing methodologies has broadened the application of cfDNA in diagnosing cancers and organ-specific pathologies, as well as directing personalized therapies. This has been achieved by identifying and uncovering different subsets of cfDNA in biofluids using different methodologies and biofluids. Different cfDNA subsets provide important insights regarding genomic and epigenetic features, enhancing the understanding of gene regulation, tissue-specific functions, and disease progression. Advancement of these key areas further asserts increasing clinical relevance for the use of cfDNA as a biomarker. Continued exploration of cfDNA subsets is expected to drive further innovation in liquid biopsy and its integration into routine clinical practice.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":"29 3","pages":"277-290"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}