bims-tumhet 2025-04-27 papers

Nucleic Acids Res. 2025 Apr 22. pii: gkaf313. [Epub ahead of print]53(8):

DirectHRD enables sensitive scar-based classification of homologous recombination deficiency.

Ruolin Liu, Eugenia Roberts, Heather A Parsons, Elizabeth H Stover, Atish D Choudhury, Justin Rhoades, Timothy Blewett, David D Yang, Joyce F Liu, Erica L Mayer, Viktor A Adalsteinsson.

Homologous recombination deficiency (HRD) is a predictive biomarker for efficacy of PARP (poly ADP-ribose polymerase) inhibition and platinum chemotherapy for cancer patients but remains challenging to detect. The discovery of patients without pathogenic mutations in known HR genes but exhibiting genomic scars indicative of HRD led to the FDA approval of the first scar-based HRD test. Despite advancements in whole genome sequencing (WGS) and integration of large training datasets with machine learning models, current methods lack the sensitivity required for detecting HRD scars in low tumor purity samples, especially in liquid biopsies. Here, we describe DirectHRD, a genomic scar-based HRD classifier based on WGS. Compared to other WGS-based methods, DirectHRD exclusively utilizes a highly specific type of HRD scar-small deletions with microhomology-and its associated signatures in a probabilistic framework. We applied DirectHRD to 501 tumor and 90 cell-free DNA (cfDNA) samples from 4 cancer types: breast, ovarian, prostate, and pancreas. Among all 501 tumor biopsies, DirectHRD achieved 100% detection of HRD with high specificity (>90%). Across all 90 cfDNA samples, the method achieved an area under the curve of 0.87 and demonstrated the ability to detect HRD at tumor fractions as low as 1%, making it 10 times more sensitive than state-of-the-art methods.

DOI: https://doi.org/10.1093/nar/gkaf313

Clin Cancer Res. 2025 Apr 24.

CHIP'ing Signal from Noise in Liquid Biopsy.

Elsa Bernard, Jean-Baptiste Micol.

The presence of clonal hematopoiesis (CH) in cell-free DNA (cfDNA) analysis can distort the interpretation of results and impact cancer treatment decisions. This CCR Translations discusses the importance of distinguishing the origin of cfDNA variants as tumoral or hematopoietic and its potential clinical implications.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0569

Head Neck. 2025 Apr 21.

Accurate and Efficient Detection of Nasopharyngeal Carcinoma Using Multi-Dimensional Features of Plasma Cell-Free DNA.

Song Zhang, Jiahui Tang, Pin Cui, Weihuang He, Xiaohui Lin, Shubing Wang, Yuanxian Liu, Xiaohua Tan, Shu Xu, Mingji Feng, Hanming Lai.

BACKGROUND: The incidence of Nasopharyngeal carcinoma (NPC) is rising in recent years, especially in some non-developed parts of the world. Hence, cost-efficient means for sensitive detection of NPC are vital.
METHODS: We recruited 646 participants, including healthy individuals, patients with benign nasopharyngeal diseases, and NPC patients for plasma cell-free DNA(cfDNA), which underwent low-depth whole-genome sequencing (WGS) to extract multi-dimensional molecular features, including fragmentation pattern, end motif, copy number variation(CNV), and transcription factors(TF). Based on these features, we employed a machine learning algorithm to build prediction models for NPC detection.
RESULTS: We achieved a sensitivity of 95.8% and a specificity of 99.4% to discriminate NPC patients from healthy individuals.
CONCLUSIONS: This study can be a proof-of-concept for these multi-dimensional molecular features to be implemented as a noninvasive approach for the detection and even early detection of NPC.

Keywords: cell‐free DNA; copy number variations (CNV); machine learning; nasopharyngeal carcinoma; whole genome sequencing (WGS)

DOI: https://doi.org/10.1002/hed.28154

Commun Med (Lond). 2025 Apr 24. 5(1): 137

Clinical utility and future perspectives of liquid biopsy in colorectal cancer.

Giorgio Patelli, Luca Lazzari, Giovanni Crisafulli, Andrea Sartore-Bianchi, Alberto Bardelli, Salvatore Siena, Silvia Marsoni.

DOI: https://doi.org/10.1038/s43856-025-00852-4

J Liq Biopsy. 2025 Jun;8 100293

The growing field of liquid biopsy and its Snowball effect on reshaping cancer management.

Roberto Borea, Carolina Reduzzi.

Liquid biopsy (LB) has emerged as a transformative tool in oncology, providing a minimally invasive approach for tumor detection, molecular characterization, and real-time treatment monitoring. By analyzing circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), extracellular vesicles (EVs), and microRNA (miRNA), LB enables comprehensive tumor profiling without the need for traditional tissue biopsies. Over the past decade, research in this field has expanded exponentially, leading to the integration of LB into clinical practice for specific cancer types, including lung and breast cancer. In 2024, the Journal of Liquid Biopsy (JLB) published innovative studies exploring the latest advancements in LB technologies, biomarkers, and their applications for cancer detection, minimal residual disease (MRD) monitoring, and therapy response assessment. This review synthesizes recent findings on the role of LB in cancer treatment and monitoring across different biomarkers, with a particular focus on newly published studies and their context within translational research. Additionally, it highlights emerging techniques such as fragmentomics, artificial intelligence, and multiomics, paving the way for more precise, personalized treatment decisions. Despite these advancements, challenges remain in standardizing methodologies, optimizing clinical validation, and integrating LB into routine oncological workflows. This mini-review highlights the evolving landscape of LB research and its potential to revolutionize cancer diagnosis, treatment monitoring, and therapeutic decision-making, ushering in a new era of precision oncology.

Keywords: Circulating tumor DNA/ctDNA; Circulating tumor cells/CTCs; Liquid biopsy; MicroRNA/miRNA; Solid tumors

DOI: https://doi.org/10.1016/j.jlb.2025.100293

N Engl J Med. 2025 Apr 24. 392(16): 1594-1608

Tumor-Infiltrating Clonal Hematopoiesis.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear.
METHODS: We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors.
RESULTS: Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth.
CONCLUSIONS: TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).

DOI: https://doi.org/10.1056/NEJMoa2413361

Cancer Discov. 2025 Apr 24.

Intrinsic properties of the lymph node render it immunologically susceptible to metastasis.

Benjamin M Kahn, Raymond W S Ng, Il-Kyu Kim, Cody Eskandarian, Chelsey O Chen, Bing Huang, Alfredo Lucas, Lequn Li, Ivan Maillard, Ben Z Stanger.

Lymph nodes (LNs) are the staging grounds for anti-tumor immunity, therefore their high susceptibility to metastatic colonization is a paradox. Previous studies have suggested that extrinsic tumor-derived factors precondition the draining LN to enable tumor cell survival by promoting a state of immune suppression. Here, we investigate whether properties of the LN itself may impede its ability to clear metastasizing tumor cells. Using multiple immunocompetent transplant models, we show that LNs possess intrinsic features, independent of preconditioning, which make them an advantageous site for tumor cells to evade T cell control. Tumor growth in the LN is facilitated by regulatory T cells, which locally suppress the cytolytic capacity of tumor-specific CD8 T cells by restricting IL-2. These findings identify an intrinsic mechanism that contributes to the high rate of LN metastasis in solid tumors.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1847