bims-tumhet Biomed News
on Tumor heterogeneity
Issue of 2025–08–17
eight papers selected by
Sergio Marchini, Humanitas Research
  1. Methylation Data Analysis and Interpretation.
  2. Circulating tumor DNA methylation in colorectal cancer: a meta-analysis.
  3. Tracing the evolution of sequencing into the era of genomic medicine.
  4. The National Health Service-Galleri multi-cancer screening trial: explanation and justification of unique and important design issues.
  5. Improvement of the sensitivity of circulating tumor DNA-based liquid biopsy: current approaches and future perspectives.
  6. Estimating the Opportunity for Early Detection of Ovarian Cancer Using Individual-Patient Data from a Large Randomized Controlled Trial.
  7. Dissecting Tumor Heterogeneity by Liquid Biopsy-A Comparative Analysis of Post-Mortem Tissue and Pre-Mortem Liquid Biopsies in Solid Neoplasias.
  8. Preliminary evaluation of ShallowHRD performance compared to HRDetect in familial breast cancer tumors.
  1. Annu Rev Biomed Data Sci. 2025 Aug;8(1): 605-632
    Methylation Data Analysis and Interpretation.
    Yuehua Zhu, Weiguang Mao, Rezwan Hosseini, Maria Chikina.
      DNA methylation, a covalent modification, fundamentally shapes mammalian gene regulation and cellular identity. This review examines methylation's biochemical underpinnings, genomic distribution patterns, and analytical approaches. We highlight three distinctive aspects that separate methylation from other epigenetic marks: its remarkable stability as a silencing mechanism, its capacity to maintain distinct states independently of DNA sequence, and its effectiveness as a quantitative trait linking genotype to disease risk. We also explore the phenomenon of methylation clocks and their biological significance. The review addresses technical considerations across major assay types-both array-based technologies and sequencing approaches-with emphasis on data normalization, quality control, cell proportion inference, and the specialized statistical models required for next-generation sequencing analysis.
    Keywords:  RRBS; WGBS; differential methylation; methylation; methylation array; methylation clocks
    DOI:  https://doi.org/10.1146/annurev-biodatasci-120924-091033
  2. Clin Chim Acta. 2025 Aug 08. pii: S0009-8981(25)00422-X. [Epub ahead of print]578 120543
    Circulating tumor DNA methylation in colorectal cancer: a meta-analysis.
    Zhipeng Pan, Guoqing Li, Hanqing Wu, Faming Pan.
       OBJECTIVES: To synthetically evaluate the diagnostic performance of circulating tumor DNA (ctDNA) methylation for colorectal cancer (CRC).
    METHODS: Relevant articles published before March 4, 2025 were searched. The pooled sensitivity, specificity, positive and negative likelihood ratio, diagnostic odds ratio (DOR), and the areas under the summary receiver operating characteristic curve (AUC) were calculated. Subgroup analysis and meta-regression were used to evaluate potential sources of heterogeneity.
    RESULTS: Totally, 147 articles containing 15,133 CRC patients were included in this meta-analysis. The pooled sensitivity, specificity and DOR of ctDNA methylation were 0.655, 0.902 and 20.662, respectively, yielding an AUC of 0.8851. Meanwhile, the combination of ctDNA methylation and carcinoembryonic antigen (CEA) achieved an AUC of 0.9269, with a sensitivity of 0.804, with a specificity of 0.904. Subgroup and meta-regression analyses indicated that the diagnostic value of multiple genes (AUC = 0.9059) and digital PCR assay (AUC = 0.8907) was higher than that of single gene and other assays. Gene dosage and detection method might be the sources of heterogeneity. There was no publication bias among these articles.
    CONCLUSION: The overall performance of ctDNA methylation had great diagnostic accuracy for the early screening and diagnosis of CRC, especially after combining with CEA, but many open questions remain before clinical application.
    Keywords:  Circulating tumor DNA; Colorectal cancer; Diagnosis; Meta-analysis; Methylation
    DOI:  https://doi.org/10.1016/j.cca.2025.120543
  3. Nat Rev Genet. 2025 Aug 15.
    Tracing the evolution of sequencing into the era of genomic medicine.
    Elaine R Mardis, Richard K Wilson.
      Accelerated discovery in biomedical science is typically punctuated by technological advances, and the past decade has been exemplary regarding breakthroughs in our genomic understanding of human biology in health and disease. This phenomenon was facilitated by the availability of a human genome reference sequence and the development and continuous improvement of next-generation and single-molecule sequencing technologies, accompanied by advances in computational analytics. These fundamental tools have driven the emergence of innovative methods that capture different aspects of human cell biology, with exquisite detail genome wide, in a sequence-based readout. The resulting expansion of knowledge has poised these approaches for clinical adoption, fulfilling the original intention of decoding the human genome and ushering in the era of genomic medicine.
    DOI:  https://doi.org/10.1038/s41576-025-00884-5
  4. J Natl Cancer Inst. 2025 Aug 09. pii: djaf218. [Epub ahead of print]
    The National Health Service-Galleri multi-cancer screening trial: explanation and justification of unique and important design issues.
    Peter Sasieni, Charles Swanton, Richard D Neal.
      Despite there being a plethora of multi-cancer early-detection tests, NHS-Galleri (ISRCTN91431511) is the only randomized controlled trial (RCT) of a multi-cancer liquid biopsy in a screening setting thus far. The NHS-Galleri trial has generated much debate, and it has been criticized in the medical press. Some of these criticisms stem from differing opinions over the choice of primary endpoint, others from poor reporting in statements to journalists from those not directly involved in the trial. Some of the debate is positive, and relates to the speed of enrolment, and the equity in participation, which have shown what is possible in large population-based RCTs. Here we explain our reasoning for undertaking the trial and designing it in the way we did. We focus on the reason to consider multi-cancer screening and why we felt that the results from non-randomized clinical studies of GRAIL's Galleri test justified a large RCT. We also consider the very slow progress in adopting effective cancer screening historically and in reducing cancer mortality through early detection. There is a need to plan now for future research and implementation depending on the results of the trial. NHS-Galleri is the first double-blind cancer screening RCT. It also, unusually, uses late-stage cancer incidence (rather than cancer mortality) as its primary outcome.
    Keywords:  Advanced stage; cell-free DNA; circulating tumor DNA; health inequalities; late-stage; multi-cancer early detection; nested analyses; pilot implementation; randomized controlled trial; sensitivity; surrogate endpoint; trial design
    DOI:  https://doi.org/10.1093/jnci/djaf218
  5. Explor Target Antitumor Ther. 2025 ;6 1002333
    Improvement of the sensitivity of circulating tumor DNA-based liquid biopsy: current approaches and future perspectives.
    Ekaterina S Kuligina, Grigoriy A Yanus, Evgeny N Imyanitov.
      Liquid biopsy (LB) is a complex of procedures aimed at the detection of tumor-derived fragments (nucleic acids, proteins, cells, etc.) persisting in the blood or other body fluids. It can be utilized for early cancer diagnosis, analysis of biomarkers of tumor drug sensitivity and prognosis, monitoring of minimal residual disease (MRD), etc. Circulating tumor DNA (ctDNA) is an accessible and reliable LB analyte as it may contain tumor-specific mutations and is amenable to efficient detection by next-generation sequencing (NGS) or droplet digital PCR (ddPCR). High level of ctDNA is typically associated with increased tumor burden and poor prognosis, whereas treatment-related ctDNA clearance increases the probability of a favorable disease outcome. Major efforts have been invested in enhancing the analytical performance of ctDNA detection. Stimulation of apoptosis of tumor cells by irradiation of cancer lumps has been shown to result in a transient but modest increase in ctDNA concentration. There are several sophisticated modifications of ultra-deep NGS protocols, which discriminate between "true" low-copy mutation-specific signals and sequencing artifacts. Slowing physiological ctDNA decay by interfering with liver macrophages and circulating nucleases has shown promise in animal experiments. Reproducibility of ctDNA-based LB assays remains insufficient for samples with ultra-low content of ctDNA; hence, interlaboratory harmonization of ctDNA testing procedures is of paramount importance.
    Keywords:  Liquid biopsy; analytical performance; cancer therapy; circulating tumor DNA; circulating tumor DNA assays; next-generation sequencing; reproducibility
    DOI:  https://doi.org/10.37349/etat.2025.1002333
  6. Cancer Epidemiol Biomarkers Prev. 2025 Aug 14.
    Estimating the Opportunity for Early Detection of Ovarian Cancer Using Individual-Patient Data from a Large Randomized Controlled Trial.
    Marc D Ryser, Shannon T Holloway, Raphaël Morsomme, Andy Ryan, Sophia Apostolidou, Aleksandra Gentry-Maharaj, Kemal Caglar Gogebakan, Jane Lange, Jason Xu, Usha Menon, Ruth Etzioni.
       BACKGROUND: The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) did not detect a reduction in ovarian cancer (OC) mortality with either multimodal screening (MMS) or transvaginal ultrasound screening (USS) compared to no screening. The trial data provide an invaluable resource to quantify the opportunity for interception in OC.
    METHODS: We used Bayesian inference to estimate OC natural history based on individual screening and cancer diagnosis records from UKCTOCS, a randomized controlled OC screening trial conducted in England, Wales, and Northern Ireland. The trial included 202,638 women aged 50 to 74 years with no family history of OC, randomized in a 1:1:2 ratio to annual MMS (serum CA125 interpreted using the Risk of Ovarian Cancer Algorithm), annual USS, or no screening. The current analysis included 199,499 women, with 674,806 screens and 2,025 cancer diagnoses.
    RESULTS: Among high-grade serous cancers (HGSCs), the estimated preclinical detectable phase (PCDP) was 1.7 years (95% credible interval [CI], 1.3-2.2), compared with 7.8 years (95% CI, 5.7-10.6) for non-HGSCs. The PCDP depended on screening modality: for HGSCs, it was longer in the MMS arm (2.2 years) compared with the USS arm (0.8 years), whereas for non-HGSCs, it was shorter in the MMS arm (2.7 years) compared with the USS arm (8.2 years).
    CONCLUSIONS: The interception opportunity for OC strongly depends on histological subtype and screening modality.
    IMPACT: Achieving a clinically significant benefit of OC early detection will require prolonging the interception window through judicious combination of first- and second-line tests.
    DOI:  https://doi.org/10.1158/1055-9965.EPI-25-0498
  7. Int J Mol Sci. 2025 Aug 06. pii: 7614. [Epub ahead of print]26(15):
    Dissecting Tumor Heterogeneity by Liquid Biopsy-A Comparative Analysis of Post-Mortem Tissue and Pre-Mortem Liquid Biopsies in Solid Neoplasias.
    Tatiana Mögele, Kathrin Hildebrand, Aziz Sultan, Sebastian Sommer, Lukas Rentschler, Maria Kling, Irmengard Sax, Matthias Schlesner, Bruno Märkl, Martin Trepel, Maximilian Schmutz, Rainer Claus.
      Tumor heterogeneity encompasses genetic, epigenetic, and phenotypic diversity, impacting treatment response and resistance. Spatial heterogeneity occurs both inter- and intra-lesionally, while temporal heterogeneity results from clonal evolution. High-throughput technologies like next-generation sequencing (NGS) enhance tumor characterization, but conventional biopsies still do not adequately capture genetic heterogeneity. Liquid biopsy (LBx), analyzing circulating tumor DNA (ctDNA), provides a minimally invasive alternative, offering real-time tumor evolution insights and identifying resistance mutations overlooked by tissue biopsies. This study evaluates the capability of LBx to capture tumor heterogeneity by comparing genetic profiles from multiple metastatic lesions and LBx samples. Eight patients from the Augsburger Longitudinal Plasma Study with various types of cancer provided 56 postmortem tissue samples, which were compared against pre-mortem LBx-derived circulating-free DNA sequenced by NGS. Tissue analyses revealed significant mutational diversity (4-12 mutations per patient, VAFs: 1.5-71.4%), with distinct intra- and inter-lesional heterogeneity. LBx identified 51 variants (4-17 per patient, VAFs: 0.2-31.1%), which overlapped with mutations from the tissue samples by 33-92%. Notably, 22 tissue variants were absent in LBx, whereas 18 LBx-exclusive variants were detected (VAFs: 0.2-2.8%). LBx effectively captures tumor heterogeneity, but should be used in conjunction with tissue biopsies for comprehensive genetic profiling.
    Keywords:  NGS; clonal evolution; liquid biopsy; mutational landscape and molecular pathology; tumor heterogeneity
    DOI:  https://doi.org/10.3390/ijms26157614
  8. Sci Rep. 2025 Aug 11. 15(1): 29442
    Preliminary evaluation of ShallowHRD performance compared to HRDetect in familial breast cancer tumors.
    Louise Adel Jensen, Caroline Hey Baekgaard, Mie Bohnensack Larsen, Susanne Eriksen Boonen, Anne Marie Bak Jylling, Zainab Hikmat, Qin Hao, Thomas van Overeem Hansen, Inge Søkilde Pedersen, Martin Jakob Larsen, Mads Thomassen.
      Determining the Homologous Recombination Deficiency (HRD)-status of a malignant tumor is central in predicting patient response to specific treatments. Therefore, precise and cost-effective tools are needed for clinical implementation. HRDetect is widely regarded as a golden standard for determining HRD-status. In contrast, ShallowHRD is a simpler algorithm. However, it offers a more economical alternative optimized for Formalin-Fixed, Paraffin-Embedded tissue (FFPE) and potentially useful for most breast cancer patients. Data from shallow whole-genome sequencing (1-5X) on FFPE tissue and whole-genome sequencing (50X, and additionally downscaled to 5X) on fresh frozen tissue from 19 patients were analyzed using ShallowHRD and compared to the HRD-status attained by HRDetect using Receiver Operating Characteristic (ROC) curve analysis. Further, Spearman rank correlation was calculated to estimate the correlation between ShallowHRD and HRDetect scores, as well as between the three ShallowHRD datasets. The comparison of ShallowHRD to HRDetect displayed a significant specificity (85.7-100%) and sensitivity (80%) in all data groups. The ROC curve analyses illustrated that ShallowHRD displayed an area under the curve statistically similar to what was previously reported for HRDetect in all three data sets. The Spearman correlation also indicated significant correlation between ShallowHRD and HRDetect scores for the three datasets (HRDetect vs. FFPE (1-5X) (ρ = 0.68, p = 0.0013), Fresh Frozen (5X) (ρ = 0.58, p = 0.0086), and Fresh Frozen (50X) (ρ = 0.50, p = 0.029)). The ShallowHRD analysis was of good quality in all data groups, and the ShallowHRD scores were similar across data groups. One sample was incorrectly labeled as HRD-negative by ShallowHRD, but it contained one variant of unknown significance (VUS) in RAD51D, requiring further investigation. HRD-status from ShallowHRD correlated well with HRDetect output in this preliminary study, potentially making ShallowHRD an accurate, efficient, and more economical alternative for clinical use. However, further examination and validation in larger cohorts are required.
    Keywords:  Breast cancer; Cancer genomics; HRDetect; Homologous recombination deficiency (HRD); ShallowHRD; Whole genome sequencing (WGS)
    DOI:  https://doi.org/10.1038/s41598-025-14122-9
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