Am J Hum Genet. 2025 Jan 6:S0002-9297(24)00456-7. doi: 10.1016/j.ajhg.2024.12.014. Online ahead of print.

ABSTRACT

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European (EUR) ancestry group compared to other ancestries. We identify multiple loci associated with mLOY susceptibility and show that subsets of human hematopoietic stem cells are enriched for the activity of mLOY susceptibility variants. Finally, we found that certain alleles on chromosome Y are more likely to be lost than others in detectable mLOY clones.

PMID:39809269 | DOI:10.1016/j.ajhg.2024.12.014

Global Spine J. 2025 Jan;15(1_suppl):16S-28S. doi: 10.1177/21925682231222012.

ABSTRACT

STUDY DESIGN: Narrative review.

OBJECTIVES: This article aims to provide a narrative review of the current state of research for liquid biopsy in spinal tumors and to discuss the potential application of liquid biopsy in the clinical management of patients with spinal tumors.

METHODS: A comprehensive review of the literature was performed using PubMed, Google Scholar, Medline, Embase and Cochrane databases, and the review was limited to articles of English language. All the relevant articles which were identified to be related to liquid biomarker study in spinal tumors, were studied in full text.

RESULTS: Liquid biopsy has revolutionized the field of precision medicine by guiding personalized clinical management of cancer patients based on the liquid biomarker status. In recent years, more research has been done to investigate its potential utilization in patients with tumors from the spine. Herein, we review the liquid biomarkers that have been proposed in different spine malignancies including chordoma, chondrosarcoma, Ewing sarcoma, osteosarcoma, astrocytoma and ependymoma. We also discuss the wide window of opportunity to utilize these liquid biomarkers in diagnosis, treatment response, monitoring, and detection of minimal residual disease in patients with spinal tumors.

CONCLUSIONS: Liquid biomarkers, especially blood-derived circulating tumor DNA, has a promising clinical utility as they are disease-specific, minimally invasive, and the procedure is repeatable. Prospective studies with larger populations are needed to fully establish its use in the setting of spinal tumors.

PMID:39801114 | PMC:PMC11726521 | DOI:10.1177/21925682231222012

Respir Res. 2025 Jan 10;26(1):10. doi: 10.1186/s12931-024-03088-3.

ABSTRACT

BACKGROUND: In COPD, the balance between matrix metalloproteinases (MMPs) and their natural inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] is shifted towards excessive degradation, reflected in bronchoalveolar lavage (BAL) as increased MMP concentrations. Because of their critical role in lung homeostasis, MMP activity is tightly regulated, but to what extent this regulation occurs through epigenetic mechanisms remains unknown.

METHODS: To explore the interplay between MMPs, TIMPs, and DNA methylation (DNAm) we (1) analysed MMP-9, -12, and TIMP-1 concentrations in BAL fluid, and profiled DNAm in BAL cells from 18 COPD and 30 control subjects, (2) estimated protein-COPD relationships using multivariable regression, (3) identified protein quantitative trait methylation loci (pQTMs) with COPD as a potential modifier in a separate interaction model, and (4) integrated significant interactions with a previous COPD GWAS meta-analysis.

RESULTS: COPD was associated with higher levels of BAL MMP-12 (p = 0.016) but not with MMP-9 or TIMP-1. Further examination of MMP-12 identified association with DNAm at 34 loci (pQTMs), with TGFBR2 (p = 2.25 × 10^-10) and THBS4 (p = 1.11 × 10^-9) among the top ten pQTM genes. The interaction model identified 66 sites where the DNAm-MMP-12 association was significantly different in COPD compared to controls. Of these, one was colocalized with SNPs previously associated with COPD.

CONCLUSIONS: Our findings indicate that airway MMP-12 may partially be regulated by epigenetic mechanisms and that this regulation is disrupted in COPD. Furthermore, integration with COPD GWAS data suggests that this dysregulation is influenced by a combination of environmental factors, disease processes, and genetics, with the latter potentially playing a lesser role.

PMID:39794761 | PMC:PMC11724436 | DOI:10.1186/s12931-024-03088-3

Nat Commun. 2025 Jan 8;16(1):430. doi: 10.1038/s41467-024-55428-y.

ABSTRACT

The analysis of circulating tumour DNA (ctDNA) through minimally invasive liquid biopsies is promising for early multi-cancer detection and monitoring minimal residual disease. Most existing methods focus on targeted deep sequencing, but few integrate multiple data modalities. Here, we develop a methodology for ctDNA detection using deep (80x) whole-genome TET-Assisted Pyridine Borane Sequencing (TAPS), a less destructive approach than bisulphite sequencing, which permits the simultaneous analysis of genomic and methylomic data. We conduct a diagnostic accuracy study across multiple cancer types in symptomatic patients, achieving 94.9% sensitivity and 88.8% specificity. Matched tumour biopsies are used for validation, not for guiding the analysis, imitating an early detection scenario. Furthermore, in silico validation demonstrates strong discrimination (86% AUC) at ctDNA fractions as low as 0.7%. Additionally, we successfully track tumour burden and ctDNA shedding from precancerous lesions post-treatment without requiring matched tumour biopsies. This pipeline is ready for further clinical evaluation to extend cancer screening and improve patient triage and monitoring.

PMID:39779727 | PMC:PMC11711490 | DOI:10.1038/s41467-024-55428-y

Int J Mol Sci. 2024 Dec 20;25(24):13669. doi: 10.3390/ijms252413669.

ABSTRACT

Liquid biopsy (LB) involves the analysis of circulating tumour-derived DNA (ctDNA), providing a minimally invasive method for gathering both quantitative and qualitative information. Genomic analysis of ctDNA through next-generation sequencing (NGS) enables comprehensive genetic profiling of tumours, including non-driver alterations that offer prognostic insights. LB can be applied in both early-stage disease settings, for the diagnosis and monitoring of minimal residual disease (MRD), and advanced disease settings, for monitoring treatment response and understanding the mechanisms behind disease progression and tumour heterogeneity. Currently, LB has limited use in clinical practice, primarily due to its significant costs, limited diagnostic yield, and uncertain prognostic role. The application of artificial intelligence (AI) in the medical field is a promising approach to processing extensive information and applying it to individual cases to enhance therapeutic decision-making and refine risk assessment.

PMID:39769431 | PMC:PMC11727717 | DOI:10.3390/ijms252413669

Front Immunol. 2024 Dec 6;15:1517312. doi: 10.3389/fimmu.2024.1517312. eCollection 2024.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor, and the development of accurate predictive models for prognosis and drug sensitivity remains challenging.

METHODS: We integrated laboratory data and public cohorts to conduct a multi-omics analysis of HCC, which included bulk RNA sequencing, proteomic analysis, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics sequencing (ST-seq), and genome sequencing. We constructed a tumor purity (TP) and tumor microenvironment (TME) prognostic risk model. Proteomic analysis validated the TP-TME-related signatures. Joint analysis of scRNA-seq and ST-seq revealed characteristic clusters associated with TP high-risk subtypes, and immunohistochemistry confirmed the expression of key genes. We conducted functional enrichment analysis, transcription factor activity inference, cell-cell interaction, drug efficacy analysis, and mutation information analysis to identify a novel subtype of HCC.

RESULTS: Our analyses constructed a robust HCC prognostic risk prediction model. The patients with TP-TME high-risk subtypes predominantly exhibit hypoxia and activation of the Wnt/beta-catenin, Notch, and TGF-beta signaling pathways. Furthermore, we identified a novel subtype, XPO1+Epithelial. This subtype expresses signatures of the TP risk subtype and aligns with the biological behavior of high-risk patients. Additional analyses revealed that XPO1+Epithelial is influenced primarily by fibroblasts via ligand-receptor interactions, such as FN1-(ITGAV+ITGB1), and constitute a significant component of the TP-TME subtype. Moreover, XPO1+Epithelial interact with monocytes/macrophages, T/NK cells, and endothelial cells through ligand-receptor pairs, including MIF-(CD74+CXCR4), MIF-(CD74+CD44), and VEGFA-VEGFR1R2, respectively, thereby promoting the recruitment of immune-suppressive cells and angiogenesis. The ST-seq cohort treated with Tyrosine Kinase Inhibitors (TKIs) and Programmed Cell Death Protein 1 (PD-1) presented elevated levels of TP and TME risk subtype signature genes, as well as XPO1+Epithelial, T-cell, and endothelial cell infiltration in the treatment response group. Drug sensitivity analyses indicated that TP-TME high-risk subtypes, including sorafenib and pembrolizumab, were associated with sensitivity to multiple drugs. Further exploratory analyses revealed that CTLA4, PDCD1, and the cancer antigens MSLN, MUC1, EPCAM, and PROM1 presented significantly increase expression levels in the high-risk subtype group.

CONCLUSIONS: This study constructed a robust prognostic model for HCC and identified novel subgroups at the single-cell level, potentially assisting in the assessment of prognostic risk for HCC patients and facilitating personalized drug therapy.

PMID:39712016 | PMC:PMC11659151 | DOI:10.3389/fimmu.2024.1517312

MedComm (2020). 2024 Dec 20;6(1):e70020. doi: 10.1002/mco2.70020. eCollection 2025 Jan.

ABSTRACT

Metastatic brain tumors, also called brain metastasis (BM), represent a challenging complication of advanced tumors. Tumors that commonly metastasize to the brain include lung cancer and breast cancer. In recent years, the prognosis for BM patients has improved, and significant advancements have been made in both clinical and preclinical research. This review focuses on BM originating from lung cancer and breast cancer. We briefly overview the history and epidemiology of BM, as well as the current diagnostic and treatment paradigms. Additionally, we summarize multiomics evidence on the mechanisms of tumor occurrence and development in the era of artificial intelligence and discuss the role of the tumor microenvironment. Preclinically, we introduce the establishment of BM models, detailed molecular mechanisms, and cutting-edge treatment methods. BM is primarily treated with a comprehensive approach, including local treatments such as surgery and radiotherapy. For lung cancer, targeted therapy and immunotherapy have shown efficacy, while in breast cancer, monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates are effective in BM. Multiomics approaches assist in clinical diagnosis and treatment, revealing the complex mechanisms of BM. Moreover, preclinical agents often need to cross the blood-brain barrier to achieve high intracranial concentrations, including small-molecule inhibitors, nanoparticles, and peptide drugs. Addressing BM is imperative.

PMID:39712454 | PMC:PMC11661909 | DOI:10.1002/mco2.70020