bims-tumhet 2025-03-30 papers

Nat Commun. 2025 Mar 26. 16(1): 2981

Impact of BRCA mutations, age, surgical indication, and hormone status on the molecular phenotype of the human Fallopian tube.

The human Fallopian tube (FT) is an important organ in the female reproductive system and has been implicated as a site of origin for pelvic serous cancers, including high-grade serous tubo-ovarian carcinoma (HGSC). We have generated comprehensive whole-genome bisulfite sequencing, RNA-seq, and proteomic data of over 100 human FTs, with detailed clinical covariate annotations. Our results challenge existing paradigms that extensive epigenetic, transcriptomic and proteomic alterations exist in the FTs from women carrying heterozygous germline BRCA1/2 pathogenic variants. We find minimal differences between BRCA1/2 carriers and non-carriers prior to loss of heterozygosity. Covariates such as age and surgical indication can confound BRCA1/2-related differences reported in the literature, mainly through their impact on cell composition. We systematically document and highlight the degree of variations across normal human FT, defining five groups capturing major cellular and molecular changes across various reproductive stages, pregnancy, and aging. We are able to associate gene, protein, and epigenetic changes with these and other clinical covariates, but not heterozygous BRCA1/2 mutation status. This sheds new light into prevention and early detection of tumorigenesis in populations at high-risk for ovarian cancer.

DOI: https://doi.org/10.1038/s41467-025-58145-2

Future Oncol. 2025 Mar 25. 1-12

Cost-effective shallow genome-wide sequencing for profiling plasma cfDNA signatures to enhance lung cancer detection.

BACKGROUND: Lung cancer (LC) screening via low-dose computed tomography (LDCT) faces challenges including high false-positive rates and low patient compliance. Circulating tumor DNA (ctDNA)-based tests offer a minimally invasive alternative but are limited by high costs and low sensitivity, particularly in early-stage detection. This study introduces a cost-effective, shallow genome-wide sequencing approach for LC detection by profiling multiple cell-free DNA (cfDNA) signatures.
METHODS: We developed a multimodal cfDNA assay with shallow sequencing coverage (0.5×) that integrates fragmentomic, nucleosome, end-motif, and copy number alteration analyses. A machine-learning model trained on a discovery cohort (99 LC patients, 168 healthy controls) and validated on an independent cohort (58 LC patients, 71 controls) demonstrated robust performance.
RESULTS: The ensemble model exhibited outstanding performance, achieving an AUC of 0.97 and a specificity of 92% in both the discovery and validation cohorts, with sensitivities of 94% and 90%, respectively. Notably, it outperformed hotspot mutation-based assays and the multi-cancer SPOT-MAS assay in sensitivity across all LC stages.
CONCLUSIONS: This assay provides a cost-effective, accurate, and minimally invasive method for LC detection, addressing the limitations of current screening methods. It represents a promising complementary tool to improve early detection and patient outcomes in LC.

Keywords: Lung cancer; cfDNA; copy number alteration; end-motif; fragmentomic; nucleosome; shallow genome-wide sequencing

DOI: https://doi.org/10.1080/14796694.2025.2483154

ESMO Open. 2025 Mar 21. pii: S2059-7029(25)00164-4. [Epub ahead of print]10(4): 104296

Detection of minimal residual disease and prediction of recurrence in breast cancer using a plasma-only circulating tumor DNA assay.

W Janni, B Rack, T W P Friedl, A D Hartkopf, L Wiesmüller, K Pfister, F Mergel, A Fink, T Braun, F Mehmeti, N Uhl, A De Gregorio, J Huober, T Fehm, V Müller, T A Rich, D J Dustin, S Zhang, S T Huesmann.

BACKGROUND: Detection of minimal residual disease (MRD) in early breast cancer (EBC) after curative-intent treatment may identify patients at risk for recurrence. Most circulating tumor DNA (ctDNA)-based MRD assays require knowledge of genomic alterations from tumor tissue. However, tissue availability may be limited in some patients. Here, we evaluated sensitivity and specificity for recurrence detection, using a plasma-only ctDNA MRD assay.
MATERIALS AND METHODS: For this pilot study, 47 plasma samples from 38 EBC patients were collected at 12 or 36 months post-diagnosis or at clinical recurrence. ctDNA presence was determined by a custom bioinformatics classifier that identifies tumor-derived somatic variants and methylation profiles specific to individual cancer types using a 5-Mb next-generation sequencing panel.
RESULTS: ctDNA was detected at or before distant recurrence in 11/14 (79%) patients [sensitivity was 85% (11/13) among samples collected within 2 years from recurrence]. Lead time was evaluable in 4/6 (67%) samples collected before distant recurrence with detectable ctDNA and ranged from 3.4 to 18.5 months. ctDNA was not detected in samples from patients without recurrence (n = 13).
CONCLUSIONS: This study demonstrates the feasibility of MRD detection in EBC using a plasma-only multiomic ctDNA-based approach. Larger studies are ongoing to further validate the clinical performance of the assay and demonstrate its applications.

Keywords: MRD; breast cancer recurrence; circulating tumor DNA; ctDNA; early breast cancer; minimal residual disease

DOI: https://doi.org/10.1016/j.esmoop.2025.104296