bims-ovdlit 2025-12-14 papers

Issue of 2025–12–14
seven papers selected by
Lara Paracchini, Humanitas Research

Nat Med. 2025 Dec 10.

Liquid biopsies across the cancer care continuum.

Blair V Landon, Akshaya V Annapragada, Noushin Niknafs, Victor E Velculescu, Valsamo Anagnostou.

Liquid biopsies have the potential to transform precision oncology by enabling the sensitive and timely detection of cancer across various clinical settings. Minimally invasive analyses of circulating cell-free DNA (cfDNA) have emerged as cutting-edge approaches for cancer detection, characterization and monitoring. Early efforts focused on mutation-based targeted sequencing, whereas newer methods use whole-genome and epigenome sequencing combined with artificial intelligence to broaden the range of alterations that can be assessed in cfDNA. Despite these advances, substantial technical and clinical challenges prevent widespread adoption. Key areas for improvement include achieving clinically meaningful detection sensitivities, enhancing assay accessibility and prospectively evaluating the clinical sensitivity of circulating tumor DNA burden in early and metastatic settings, to support the integration of liquid biopsies into therapeutic decision-making. Here we discuss technologies and analytical methodologies in cfDNA detection, together with their clinical validity and utility. We highlight opportunities to address key challenges and to support the implementation of liquid biopsies throughout the cancer care continuum.

DOI: https://doi.org/10.1038/s41591-025-04093-9

Nat Commun. 2025 Dec 09. 16(1): 9945

Circulating tumor DNA refines risk stratification of neoadjuvant therapy-resistant breast tumors.

Early-stage breast cancers resistant to neoadjuvant therapy (NAT), characterized by high residual cancer burden (RCB) after treatment, have an increased risk of metastatic recurrence. Here, we show that circulating tumor DNA (ctDNA) detected using a tumor-informed test (1) can improve risk stratification of patients with NAT-resistant tumors (RCB-II/RCB-III) and (2) predict response to NAT. Stratification using ctDNA status at pretreatment or post-NAT and ctDNA dynamics identified NAT-resistant tumors with a significantly decreased risk of metastatic recurrence. ctDNA clearance as early as week 3 across receptor subtypes predicted favorable responses to NAT, including immunotherapies. Interestingly, less than a fifth of patients with NAT-resistant tumors were ctDNA-positive post-NAT. Serial mutation profiling of NAT-resistant tumors revealed that patient-specific ctDNA assay variants remained detectable over time, including in tumors of patients ctDNA-negative post-NAT. Refining risk stratification for NAT-resistant tumors using ctDNA and understanding ctDNA shedding in these tumors could guide treatment decisions to prevent or delay metastatic recurrence.

DOI: https://doi.org/10.1038/s41467-025-65432-5

Nature. 2025 Dec 10.

Somatic evolution following cancer treatment in normal tissue.

PEACE Consortium

The extent to which exogenous sources, including cancer treatment, contribute to somatic evolution in normal tissue remains unclear. Here we used high-depth duplex sequencing1 (more than 30,000× coverage) to analyse 168 cancer-free samples representing 16 organs from 22 patients with metastatic cancer enroled in the PEACE research autopsy study. In every sample, we identified somatic mutations (range 305-2,854 mutations) at low variant allele frequencies (median 0.0000323). We extracted 16 distinct single-base substitution mutational signatures, reflecting processes that have moulded the genomes of normal cells. We identified alcohol-induced mutation acquisition in liver, smoking-induced mutagenesis in lung and cardiac tissue, and multiple treatment-induced processes, which correlated with therapy type and duration. Exogenous sources, including treatment, underpinned, on average, more than 40% of mutations in liver but less than 10% of mutations in brain samples. Finally, we observed tissue-specific selection, with positive selection in tissues such as lung (PTEN and PIK3CA), liver (NF2L2) and spleen (BRAF and NOTCH2), and limited selection in others, such as brain and cardiac tissue. More than 25% of driver mutations in normal tissue exposed to systemic anti-cancer therapy, including in TP53, could be attributed to treatment. Immunotherapy, although not associated with increased mutagenesis, was linked to driver mutations in PPM1D and TP53, illustrating how non-mutagenic treatment can sculpt somatic evolution. Our study reveals the rich tapestry of mutational processes and driver mutations in normal tissue, and the profound effect of lifetime exposures, including cancer treatment, on somatic evolution.

DOI: https://doi.org/10.1038/s41586-025-09792-4

Int J Mol Sci. 2025 Dec 03. pii: 11708. [Epub ahead of print]26(23):

Minimal Residual Disease Detection: Bridging Molecular and Clinical Strategies for Recurrence Prevention in Gynecologic Cancers.

Andi Darma Putra, Naufal Syafiq Darmawan, Aldi Tamara Rahman, Lasmini Syariatin.

Gynecologic cancers remain a major global health burden, particularly in low- and middle-income countries, with high incidence and mortality rates around 45-50%. The detection of minimal residual disease (MRD) is transforming the management of recurrence risk in gynecologic cancers through highly sensitive molecular technologies. MRD encompasses small populations of residual cancer cells or post-treatment molecular traces but remain undetectable by conventional methods. Its detection relies on circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and advanced next-generation sequencing (NGS), with ctDNA-based MRD assays having sensitivity levels between 85% and over 99%. Other technologies, such as liquid biopsies and digital PCR, are also in development. MRD status has demonstrated high predictors of recurrence and survival with positive MRD strongly associated with poor outcomes and negative MRD indicates sustained remission. However, MRD detection faces significant limitations, such as tumor heterogeneity, inconstant ctDNA levels, technical issues of false-negative results, and limited clinical accessibility. Therefore, this review presents current evidence regarding the molecular detection of MRD in gynecologic malignancies and assesses its prognostic and predictive relevance. Ultimately, MRD continuous integration into clinical practice offers a promising modality to enable early relapse detection, more precise therapeutic decision-making, and the improvement of personalized medicine access to gynecologic cancers worldwide.

Keywords: cancer detection; cancer recurrence; circulating tumor DNA; circulating tumor cells; gynecologic cancer; minimal residual disease

DOI: https://doi.org/10.3390/ijms262311708

Science. 2025 Dec 11. 390(6778): 1102-1103

Chromosome shattering in cancer.

Stanley Clarke, Marcin Imieliński.

A protein that cuts double-stranded DNA contributes to chromosome scrambling in human cancer cells.

DOI: https://doi.org/10.1126/science.aed1825

Nat Commun. 2025 Dec 11.

H3K36 Methylation as a Guardian of Epigenome Integrity.

Reinnier Padilla, Gerry A Shipman, Cynthia Horth, Michel Gravel, Eric Bareke, Jacek Majewski.

H3K36 methylation is a key epigenetic mark with critical roles in development and disease. Here, we systematically dissect its functions using CRISPR-engineered mouse mesenchymal stem cells lacking combinations of the five H3K36 methyltransferases, culminating in quintuple knockout cells devoid of H3K36me2/3. We show that H3K36me2 influences enhancer activity, supports the expression of their target genes, and safeguards active genes from encroachment of the repressive marks, H3K27me2/3. In addition, we find that the loss of H3K36me triggers redistribution of large heterochromatic H3K9me3 domains into euchromatin, in part mediated by SUV39H1, leading to global epigenomic remodelling, constitutive heterochromatin erosion, and a collapse of 3D genome organization. Parallel analyses in human HNSCC cells overexpressing the H3K36M oncohistone reveal conserved disruptions to the epigenome and chromatin architecture. Together, these results establish H3K36 methylation as a pivotal regulator of chromatin state and genomic structure.

DOI: https://doi.org/10.1038/s41467-025-66365-9