bims-ovdlit 2026-03-22 papers

Issue of 2026–03–22
three papers selected by
Lara Paracchini, Humanitas Research

EMBO Mol Med. 2026 Mar 19.

ctDNA monitoring using tumor-informed copy number analysis.

Ze Zhou, Ros Cutts, Sarah Hrebien, Christina X Zhang, Isaac Garcia-Murillas, Woody Z Zhang, Alexander M Frankell, Wendy N Cooper, Amit Roshan, Nicholas C Turner, Tommy Kaplan, Nitzan Rosenfeld, Hui Zhao.

Methods to detect circulating tumor DNA (ctDNA) enable minimally invasive responsive monitoring of cancer dynamics. However, sensitive and cost-effective methods are still lacking. Current methods for detecting cancer signals in shallow whole-genome sequencing (sWGS) data from cell-free DNA (cfDNA) via copy number aberration (CNA) analysis typically have a limit of detection of approximately 3% tumor fraction (TF). We developed informCNA, a bioinformatics method that leverages CNA information from sWGS of tumor or pre-treatment plasma samples with high TF as references, enabling ctDNA detection down to 0.2% TF across multiple cancer types. In 177 serial plasma samples from 18 patients with ovarian cancer, informCNA showed high concordance with the standard serum protein marker CA-125 and identified recurrence a median of 3.7 months earlier than CA-125 test. These results demonstrate the potential of personalized CNA analysis through sWGS for estimating ctDNA burden, enabling precise and cost-effective disease monitoring and early detection of relapse.

Keywords: Copy Number Aberration (CNA); Liquid Biopsy; Tumor-informed; cfDNA; ctDNA

DOI: https://doi.org/10.1038/s44321-026-00399-4

Nat Commun. 2026 Mar 15.

Both genome instability and replicative senescence stem from the shortest telomere in telomerase-negative cells.

Prisca Berardi, Veronica Martinez-Fernandez, Anaïs Rat, Fernando R Rosas Bringas, Pascale Jolivet, Rachel Langston, Stefano Mattarocci, Alexandre Maes, Théo Aspert, Bechara Zeinoun, Karine Casier, Hinke G Kazemier, Gilles Charvin, Marie Doumic, Michael Chang, Maria Teresa Teixeira.

In the absence of telomerase, telomere shortening triggers replicative senescence, a tumor suppressor mechanism that is also associated with oncogenic genomic instability. Yet, the precise mechanism that connects these seemingly opposing forces remains poorly understood. To directly study the complex interplay between senescence, telomere dynamics, and genomic instability, we develop a system in Saccharomyces cerevisiae to generate and track telomeres of precise length in the absence of telomerase. Using single-telomere and single-cell analyses combined with mathematical modeling, we identify a threshold length at which telomeres switch into dysfunction. A single shortest telomere below the threshold length is necessary and sufficient to trigger the onset of replicative senescence in a majority of cells. At population level, fluctuation assays establish that rare genomic instability arises predominantly in cis to the shortest telomere as Pol32-dependent non-reciprocal translocations that result in re-elongation of the shortest telomere and likely transient escape from senescence. The switch of the shortest telomere into dysfunction and subsequent processing in telomerase-negative cells thus serves as the mechanistic link between replicative senescence onset, genomic instability and the initiation of post-senescence survival.

DOI: https://doi.org/10.1038/s41467-026-70352-z

Oncoscience. 2026 ;13 44-54

Tumor-informed liquid biopsy detection of structural variants in high grade serous ovarian cancer.

Jian Li, Shiro Takamatsu, Allison L Brodsky, Thomas Welte, Katherine Calzoncinth, Veena K Vuttaradhi, Joseph Celestino, Barrett Lawson, R Tyler Hillman.

BACKGROUND: High grade serous ovarian cancer (HGSOC) recurs frequently and commercial tests have emerged for tumor-informed, cell-free DNA (cfDNA)-based detection of minimal residual disease. These tests are based on somatic single nucleotide variants prevalent in many cancers and thus are not well matched to HGSOC, which is dominated by structural genomic rearrangements. The purpose of this study was to evaluate the feasibility of a structural-variant (SV)-informed, cfDNA-based method for detecting clonal and subclonal HGSOC disease burden.
METHODS: A method was developed for detecting patient-specific SV breakpoints using digital droplet PCR (ddPCR) with custom tumor-informed primer/probe pairs. Test parameters were first estimated using synthetic cfDNA generated by ultrasonication of genomic DNA from ovarian cancer cell lines. The optimized workflow was implemented in which whole genome sequencing of multisite pre-treatment HGSOC biopsies performed and high confidence SVs were called by multiple published SV callers. Real-time PCR and ddPCR were used for assay development.
RESULTS: Following the optimized workflow, tumor-specific SV breakpoint-spanning primers/probe sets of four HGSOC patients' multisite biopsies were designed and validated by real-time PCR and ddPCR. Together with four HGSOCs, a total of 29 SVs breakpoints-spanning tumor-informed primers/probe sets were designed and validated in multisite biopsies. 15 validated tumor-specific SVs were selected for quantification in their corresponding liquid biopsies using the validated ddPCR, and 9 had measurements in liquid biopsies.
CONCLUSIONS: Our result shows the detection of SVs from pre-treatment cfDNA using tumor-informed breakpoints-spanning ddPCR is feasible and may enable a novel and sensitive method for monitoring on-treatment disease burden.

Keywords: biomarker; ctDNA; liquid biopsy; ovarian cancer; structural variant

DOI: https://doi.org/10.18632/oncoscience.645