bims-ovdlit 2026-04-12 papers

Genome Med. 2026 Apr 09.

Longitudinal cell-free DNA methylome and fragmentome profiles in health uncover signatures of cell type and demographic origin.

Mio Aerden, Tatjana Jatsenko, Kaat Leroy, Kobe De Ridder, Anna Nootens, Valentina Piatti, Koen Devriendt, Joris Robert Vermeesch, Huiwen Che, Bernard Thienpont.

Keywords: Cell-free DNA; Deconvolution; Epigenetics; Fragmentomics; Liquid biopsy

DOI: https://doi.org/10.1186/s13073-026-01618-w

ESMO Open. 2026 Apr 07. pii: S2059-7029(26)00842-2. [Epub ahead of print]11(4): 106900

BRCA1 and BRCA2 pathogenic variants increase the risk of four less common cancer types.

H Sasagawa, M Endo, Y Iwasaki, Y Usui, Y N Koyanagi, G Innella, J Hadler, M T Parsons, K Numakura, Y Kamatani, Y Murakami, K Matsuo, K Matsuda, A B Spurdle, T Habuchi, Y Momozawa.

BACKGROUND: Previous family-based and case-control studies have expanded the cancer risk profile associated with pathogenic variants in BRCA1 and BRCA2, providing the potential for expanding personalized medicine. Less common cancer types may benefit greatly from such expansion of genetic evidence because of their limited treatments and poor prognoses.
METHODS: We conducted a case-control analysis of 3489 patients with nine less common cancer types (bladder, bone, brain, head and neck, sarcoma, skin, testis, thyroid, or ureteral cancer) and 38 842 controls without cancer to estimate the risk associated with BRCA1 and BRCA2 pathogenic variants of nine less common cancer types.
RESULTS: We identified 105 pathogenic variants among 994 germline variants. We observed four significant associations: BRCA1 with thyroid cancer [odds ratio (OR) 5.25, 95% confidence interval (CI) 2.06-13.38]; BRCA2 with bladder (OR 4.67, 95% CI 2.57-8.47), head and neck (OR 3.89, 95% CI 2.01-7.53), and skin cancers (OR 6.13, 95% CI 2.47-15.24). For bladder cancer, the impact of BRCA2 pathogenic variants was greater in females than in males (Pheterogeneity = 2.15 × 10-4; I2 = 92.70%).
CONCLUSIONS: These results provide evidence to inform more precise personalized medical options for individuals with BRCA1 or BRCA2 pathogenic variants.

Keywords: BRCA1/2; case-control study; germline pathogenic variant; less common cancer type; personalized medicine; sex difference

DOI: https://doi.org/10.1016/j.esmoop.2026.106900

Cancer. 2026 Apr 15. 132(8): e70380

Preclinical circulating tumor DNA shedding duration and prognostic implications of modeling 3669 patients with cancer in the American Cancer Society Cancer Prevention Study-3 and Circulating Cell-Free Genome Atlas Substudy 3.

Earl Hubbell, Alpa V Patel, Christina A Clarke, Emily L Deubler, Eric T Fung, Rong Jiang, Allison W Kurian, Cari Lichtman, Lauren R Teras, Oliver Venn, Nan Zhang, Charles Swanton.

INTRODUCTION: Previous studies have estimated the mean sojourn and dwell times within stages for commonly screened cancer types. However, little is known about the preclinical detection window of circulating tumor DNA (ctDNA) (ie, ctDNA positivity), which is important for understanding multicancer early detection.
METHODS: The duration of preclinical detectability and prognostic value of ctDNA detection was estimated from patients with cancer in two biobank studies: CPS-3, where cancer was diagnosed (n = 1064) within 3 years of a prior blood draw (2006-2013), and CCGA3 (NCT02889978), with a blood draw (2016-2019) concurrent with clinical diagnosis (n = 2604). To infer these quantities, Bayesian models were used for detection rates as a function of time, as well as to infer prognostic effects.
RESULTS: Median [credible interval] sojourn times were 0.75 [0.47, 1.30], 0.89 [0.61, 1.33], 1.2 [0.84, 1.67] years for cancers diagnosed at local, regional, and distant stage, respectively, and ranged by type from pancreas, 0.49 [0.26, 0.88] to lymphoma, 2.45 [1.14, 4.87]. The extrapolated effect of ctDNA positivity at clinical diagnosis versus negative in CPS-3 cancer cases was a relative hazard ratio of 1.98 [1.08-4.22] for mortality.
CONCLUSIONS: These results provide estimates for average ctDNA detectable sojourn time in tumors across multiple cancer sites and stages and can inform the design of future screening studies for multicancer early detection.

Keywords: cancer screening; circulating tumor DNA (ctDNA); multicancer early detection (MCED); preclinical; sojourn time

DOI: https://doi.org/10.1002/cncr.70380

bioRxiv. 2026 Mar 30. pii: 2026.03.26.714557. [Epub ahead of print]

Comparative single-cell atlases reveal injury-driven tubal epithelial regeneration as a window for ovarian carcinoma initiation.

Coulter Q Ralston, Andrea Flesken-Nikitin, Dah-Jiun Fu, Christopher S Ashe, Blaine A Harlan, Md Mozammal Hossain, Derek K Wang, Anna Yemelyanova, Elisa Schmoeckel, Andrew K Godwin, Doris Mayr, Benjamin D Cosgrove, Alexander Yu Nikitin.

High-grade serous carcinoma (HGSC), the most lethal form of ovarian cancer, preferentially originates in the tubal epithelium (TE) of the distal uterine tube (also known as Fallopian tube or oviduct). Mouse models are widely used to study how HGSC initiates in humans; however, the extent to which mouse and human uterine tubes are comparable remains unclear. Here, we conduct cross-species single-cell transcriptomic comparative analyses and organoid assay validations to reveal conserved differentiation trajectories from bipotent progenitors to secretory or ciliated cell fates. Regional analyses of both datasets reveal enriched injury repair features in the distal human TE, where mice lack such a trend. Experimentally inducing mechanical injury to the mouse TE yields significant expansion of pre-ciliated cells compared to uninjured counterparts. Furthermore, inactivation of Trp53 and Rb1, whose pathways are commonly altered in HGSC, in regenerating pre-ciliated cells leads to rapid neoplastic transformation, implicating post-traumatic repair as a permissive window for malignant transformation. Together, our findings establish a comparative atlas of cell states between mice and humans, show that injury-associated regeneration may contribute to the known vulnerability of the fimbrial region, and raise potential concerns regarding procedures or conditions that mechanically perturb the tubal epithelium.

DOI: https://doi.org/10.64898/2026.03.26.714557

Nat Commun. 2026 Apr 09.

Combining multiplexed assays of variant effect for enhanced BRCA2 variant classification.

Chunling Hu, Sounak Sahu, Wenan Chen, Melissa Galloux, Marcy E Richardson, Megan F Bishop, Rachid Karam, Tina Pesaran, Jie Na, Huaizhi Huang, Jeffrey N Weitzel, Katherine N Nathanson, Siddhartha Yadav, Nicholas J Boddicker, Susan M Domchek, Alvaro N Monteiro, Edwin S Iversen, Shyam K Sharan, Fergus J Couch.

Determining the clinical relevance of BRCA2 variants of uncertain significance is critical for informed risk management. Recently, two saturation genome editing studies assessed the functional effects of all single nucleotide variants in the BRCA2 C-terminal DNA Binding Domain. To improve the accuracy of functional data used for ACMG/AMP variant classification, we combined results from these studies in four composite models and evaluated the performance of each model using variants with known classifications. Here, we show that an "Integrated VarCall Model", which combined raw functional data for 6383 variants from the original studies, yielded 98.8% accuracy and out-performed the original studies and other combined data models. Incorporation of the "Integrated VarCall Model" functional data with other sources of evidence according to ClinGen BRCA1/2 variant curation expert panel specifications resulted in classification of 5926 (92.8%) BRCA2 variants as pathogenic (n = 735) or benign (n = 5191) and provides valuable insights for individuals with BRCA2 variants.

DOI: https://doi.org/10.1038/s41467-026-71393-0

medRxiv. 2026 Mar 30. pii: 2026.03.24.26348354. [Epub ahead of print]

Genome-Wide Variations of End Motif in Cell-Free DNA Fragments Distinguish Immunotherapy Responders from Non-Responders in Head and Neck Cancer: A Multi-Institute Prospective Study.

Reliable, minimally invasive biomarkers for predicting immunotherapy response in head and neck squamous cell carcinoma (HNSCC) remain an unmet clinical need. Here, using patients from a prospective, multi-institutional phase II clinical trial ( NCT02641093 ), we performed whole-genome sequencing of 185 plasma cell-free DNA (cfDNA) samples collected longitudinally from 68 patients with locally advanced, surgically resectable HNSCC undergoing neoadjuvant and adjuvant pembrolizumab treatment. We developed the regional motif diversity score (rMDS), a novel fragmentomic metric quantifying the entropy of cfDNA 5' end motifs across genomic regions. Remarkably, unsupervised analysis revealed that rMDS robustly distinguished immunotherapy responders from non-responders, outperforming established cfDNA fragmentomic metrics and copy number alterations, while demonstrating independence from technical confounders. Longitudinal analysis revealed dynamic rMDS changes in genomic regions enriched for immune-, lectin-, and keratinization-related genes-hallmarks of squamous cell carcinoma-reflecting the interplay between tumor and peripheral immunity during the immunotherapy treatment. Interestingly, the regions with the most dynamic rMDS changes were highly enriched in telomere-proximal loci, suggesting a novel link between telomere biology and cfDNA fragmentation. A machine learning classifier based on rMDS achieved robust predictive performance across multiple validation settings (AUC 0.89-0.99), with the highest accuracy at post-treatment timepoints and superior to PD-L1 expression and tumor fraction in the same sample. Predicted responders demonstrated significant trends toward improved disease-free survival (log rank test p=0.035, hazard ratio: 2.67, 95% confidence interval: 1.03-6.92), underscoring the clinical utility of rMDS-based stratification. These findings position rMDS as a biologically meaningful and clinically actionable biomarker for immunotherapy response in HNSCC, supporting its integration into future risk assessment frameworks and broader cancer care.

DOI: https://doi.org/10.64898/2026.03.24.26348354

Sci Rep. 2026 Apr 06.

Distinct molecular profiles associated with early vs late genome instability in cancer.

Lucie Gourmet, James Lam, Adam Pennycuick, Luis Zapata, Parag Mallick, Simon Walker-Samuel.

DOI: https://doi.org/10.1038/s41598-026-44528-y