bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2026–02–15
eleven papers selected by
Lara Paracchini, Humanitas Research
  1. Comparing approaches to designing and accelerating evaluation of multicancer early detection tests.
  2. High-Grade Serous Ovarian Carcinoma in the Genomics Era: Current Applications, Challenges and Future Directions.
  3. Clinical validation of a tissue-agnostic genome-wide methylome enrichment assay to monitor response to pembrolizumab.
  4. Holistic determination of ends of cfDNA molecules.
  5. Hereditary Endometrial Cancer: Lynch Syndrome, Mismatch Repair Deficiency, and Emerging Genetic Predispositions-A Comprehensive Review with Clinical and Laboratory Guidelines.
  6. Inherited resilience.
  7. Circulating tumor DNA dynamics and clinical outcomes in patients with advanced Colorectal Cancer treated with cetuximab-based induction and maintenance treatment.
  8. Sequencing DNA methylation and hydroxymethylation at co-occurring chromatin features.
  9. Comprehensive repertoire of the chromosomal alteration and mutational signatures across 16 cancer types.
  10. Clonal hematopoiesis boosts response to immune checkpoint therapy.
  11. Pan-cancer inference and validation of hypermorphic, hypomorphic and neomorphic mutations.
  1. J Natl Cancer Inst. 2026 Feb 09. pii: djaf282. [Epub ahead of print]
    Comparing approaches to designing and accelerating evaluation of multicancer early detection tests.
    Hormuzd A Katki.
      
    DOI:  https://doi.org/10.1093/jnci/djaf282
  2. Int J Mol Sci. 2026 Feb 06. pii: 1617. [Epub ahead of print]27(3):
    High-Grade Serous Ovarian Carcinoma in the Genomics Era: Current Applications, Challenges and Future Directions.
    Molly Elizabeth Lewis, Chiara Caricato, Hannah Leigh Roberts, Subhasheenee Ganesan, Nadia Amel Seksaf, Eleni Maniati, Michail Sideris.
      High-grade serous ovarian carcinoma (HGSOC) is characterised by profound genomic instability and limited durable responses to standard therapy, leading to poor prognosis. The use of next-generation sequencing technologies has improved understanding of its molecular landscape, revealing consistent Tumour Protein p53 (TP53) mutations, homologous recombination defects, pathway alterations, and epigenetic dysregulation. Such genomic profiling now underpins the classification criteria between the ovarian cancer subtypes described by the Cancer Genome Atlas. Widespread chromosomal instability and pathogenic variants in multiple genes distinguish HGSOC from other subtypes of ovarian cancer and, further, from low-grade serous ovarian cancer. Importantly, the new-found understanding of the genomic landscape of HGSOC guides the use of platinum-based chemotherapies and Poly(ADP-ribose) Polymerase (PARP) inhibitors, with homologous recombination deficiency emerging as a cancer vulnerability that enhances treatment response. A combined multi-omics approach integrates transcriptomics, proteomics, metabolomics, and epigenomics to further the understanding of the characteristics, therapeutic targets and treatment resistance within HGSOC. Despite these advances, major challenges persist, including intratumoural heterogeneity and the poor diversity of genomic datasets. Artificial Intelligence (AI) technology, Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing, neoantigen-guided immunotherapy and ovarian cancer vaccination indicate a promising future for genomics-guided interventions and support the integration of genomics within multi-omic approaches to improve HGSOC outcomes.
    Keywords:  BRCA; TP53; genomics; high-grade serous ovarian carcinoma; homologous recombination
    DOI:  https://doi.org/10.3390/ijms27031617
  3. NPJ Precis Oncol. 2026 Feb 13.
    Clinical validation of a tissue-agnostic genome-wide methylome enrichment assay to monitor response to pembrolizumab.
    Eric Y Stutheit-Zhao, Yongqi Zhong, Collin A Melton, Elizabeth D Lightbody, Michael A Hinterberg, Yarong Wang, Owen Hall, Eduardo V Sosa, Jeremy B Provance, Junjun Zhang, Abel Licon, Zhihui Amy Liu, Albiruni R Abdul Razak, Anna Spreafico, Philippe L Bedard, Aaron R Hansen, Stephanie Lheureux, Pamela S Ohashi, Alan Williams, Scott V Bratman, Brian A Allen, Jing Zhang, Daniel D De Carvalho, Anne-Renee Hartman, Lillian L Siu, Enrique Sanz-Garcia.
      Immunotherapy has significantly improved the treatment of metastatic solid tumors; however, detecting early signs of response to enable timely intervention for resistant tumors remains challenging. A blood-only circulating tumor DNA (ctDNA) test may provide a rapid assessment of tumor response without reliance on matched tumor tissue. We applied a tissue-agnostic, genome-wide methylation enrichment assay, based on cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq), to plasma samples from patients in a phase 2 trial evaluating pembrolizumab across multiple solid tumors (NCT02644369). A decrease in ctDNA from baseline to pre-cycle 3 was significantly associated with higher objective response and clinical benefit rates and longer progression-free and overall survival in univariate analyses, with these associations remaining significant in multivariable models except for overall survival. These results validate a commercial-grade, tissue-agnostic plasma cfDNA methylation platform for immunotherapy response monitoring, which may facilitate earlier, more informed treatment decisions and improve patient outcomes.
    DOI:  https://doi.org/10.1038/s41698-026-01327-y
  4. Cell Genom. 2026 Feb 06. pii: S2666-979X(26)00004-2. [Epub ahead of print] 101142
    Holistic determination of ends of cfDNA molecules.
    Peiyong Jiang, Mary-Jane L Ma, Rong Qiao, Yuwei Shi, Jing Liu, Qing Zhou, Wenlei Peng, W K Jacky Lam, Jinyue Bai, L Y Lois Choy, W H Adrian Tsui, Yasine Malki, Guannan Kang, Stephanie C Y Yu, Dongyan Xiong, Grace L H Wong, Landon L Chan, John Wong, Stephen L Chan, Vincent W S Wong, K C Allen Chan, Y M Dennis Lo.
      Cell-free DNA (cfDNA) end motifs serve as fragmentomics biomarkers for cancer. Prior studies primarily focused on 5' ends, whereas 3' ends were overlooked due to artifactual modification in existing sequencing protocols. We utilized single-stranded library preparation ("2-end sequencing") to assess the native 5' and 3' end motifs (EM5 and EM3, respectively). Additionally, we demonstrated diagnostic power from the nucleotide motifs located immediately upstream and downstream of 5' and 3' ends, named pre-end motifs (PREMs) and post-end motifs (POEMs). These fragmentomics markers collectively achieved an area under the curve (AUC) of 0.95 for hepatocellular carcinoma (HCC) detection. Fragmentomics-based methylation analysis of 3' ends (3' FRAGMA) improved detection of HCC (AUC: 0.97). We further developed "4-end sequencing" to interrogate both ends of both strands of a double-stranded cfDNA molecule, enhancing fragmentomics-based cancer detection. Holistic end profiling adds to the armamentarium of liquid biopsy and sheds light on the biology of cfDNA fragmentation.
    Keywords:  cancer detection; end motifs; fragmentomics; noninvasive
    DOI:  https://doi.org/10.1016/j.xgen.2026.101142
  5. Int J Mol Sci. 2026 Jan 28. pii: 1304. [Epub ahead of print]27(3):
    Hereditary Endometrial Cancer: Lynch Syndrome, Mismatch Repair Deficiency, and Emerging Genetic Predispositions-A Comprehensive Review with Clinical and Laboratory Guidelines.
    Andrzej Kluk, Hanna Gryczka, Małgorzata Braszka, Rafał Ałtyn, Hanna Markiewicz, Jan K Ślężak, Ewa Dwojak, Joanna Czerniak, Paweł Zieliński, Bartosz J Płachno, Paula Dobosz.
      Endometrial cancer is the most common gynaecologic malignancy in high-income countries, with a rising incidence largely driven by reproductive factors, obesity, and prolonged exposure to unopposed oestrogens. Although most cases are sporadic, approximately 2-5% are associated with hereditary cancer syndromes, of which Lynch syndrome represents the most important contributor. Lynch syndrome results from germline mutations in DNA mismatch repair (MMR) genes and is associated with a substantially increased lifetime risk of endometrial cancer, reaching up to 71% in carriers of MutS homologue 6 (MSH6) mutations. Hereditary cancer predisposition typically follows an autosomal dominant inheritance pattern and may be suspected based on clinical warning signs such as early disease onset, multiple primary malignancies, a strong family history, or the presence of microsatellite instability in tumour tissue. In addition to Lynch syndrome, rarer genetic conditions-including Cowden syndrome (PTEN), Li-Fraumeni syndrome (TP53), polymerase proofreading-associated polyposis (POLE/POLD1), and hereditary breast and ovarian cancer syndromes (BRCA1/2)-also contribute to hereditary endometrial cancer risk. Recognition of these genetic backgrounds is essential for accurate diagnosis, personalised surveillance, and the implementation of targeted preventive and therapeutic strategies. Despite major advances in molecular diagnostics, hereditary endometrial cancer remains frequently underdiagnosed, leading to missed opportunities for cancer prevention among affected individuals and their families. This comprehensive review summarises current evidence on hereditary predispositions to endometrial cancer, with a particular emphasis on Lynch syndrome, and discusses underlying genetic mechanisms, inheritance patterns, diagnostic strategies, and clinical implications for screening, genetic counselling, and treatment optimisation.
    Keywords:  Lynch syndrome; endometrial cancer; genetic predisposition; hereditary cancer syndromes; mismatch repair deficiency
    DOI:  https://doi.org/10.3390/ijms27031304
  6. Nat Rev Cancer. 2026 Feb 10.
    Inherited resilience.
    Daniela Senft.
      
    DOI:  https://doi.org/10.1038/s41568-026-00914-2
  7. Clin Cancer Res. 2026 Feb 11.
    Circulating tumor DNA dynamics and clinical outcomes in patients with advanced Colorectal Cancer treated with cetuximab-based induction and maintenance treatment.
    Valérie Boige, Olivier Bouché, Claire Mulot, Ludovic Evesque, Meher Ben Abdelghani, Jean-Marc Phelip, Laurent Mineur, Marie-Pierre Galais, Anne-Laure Villing, Vincent Hautefeuille, Christelle De La Fouchardière, Dominique Genet, Slim Lassoued, Aurélien Carnot, Emmanuel Mitry, Stéphane Jacquot, Delphine Serazin, Camille Bourreau, Justine Abdelli, Emilie Brument, Pierre Laurent-Puig, Lise Roca, Hélène Blons.
       PURPOSE: We investigated whether circulating tumor DNA (ctDNA) changes may be useful to assess clinical outcomes in metastatic colorectal cancer (mCRC) patients randomized in the TIME-PRODIGE28 trial comparing bi-weekly maintenance with cetuximab alone to observation after 4-month FOLFIRI plus cetuximab induction chemotherapy.
    EXPERIMENTAL DESIGN: ctDNA samples were collected at four time points from baseline until disease progression during the first chemotherapy-free interval, and analyzed using next generation sequencing and methylation markers approaches. Progression-free (PFS) and overall (OS) survival from randomization were analyzed according to ctDNA kinetics and EGFR-MAPK pathway alterations.
    RESULTS: Among 139 randomized patients, 104 (74.8%) had paired samples available. Patients with negative baseline ctDNA remaining negative after 4-month induction chemotherapy had significantly longer PFS from randomization (9.6 months) as compared to patients with ctDNA decrease of ≥ 80% (3.4 months) or ctDNA decrease of < 80% (2.1 months, p=0.013). Patients with EGFR-MAPK pathway alterations identified either in tissue or baseline ctDNA had worse PFS and OS from randomization. Acquired alterations found in 17/63 (26.9%) patients at disease progression during the first chemotherapy-free interval were associated with worse OS from reintroduction of the full induction chemotherapy (14.9 vs 19.4 months, p=0.025).
    CONCLUSIONS: Our findings show the prognostic impact of both ctDNA kinetics and EGFR-MAPK pathway alterations dynamics following induction chemotherapy with FOLFIRI-cetuximab in mCRC patients. Prospective studies evaluating ctDNA-guided treatment strategies are needed to validate the clinical utility of ctDNA monitoring to improve patient selection for first-line treatment de-escalation and anti-EGFR-based maintenance regimens, including treatment adaptation over time. TRIAL REGISTRATION clinicaltrials.gov identifier NCT02404935.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-3555
  8. Nat Commun. 2026 Feb 10.
    Sequencing DNA methylation and hydroxymethylation at co-occurring chromatin features.
    Rafael de Cesaris Araujo Tavares, Somdutta Dhir, Xuan He, Jack Monahan, Minna Taipale, Paula Golder, Aldo Ciau-Uitz, Walraj Gosal, David Tannahill, Shankar Balasubramanian.
      Epigenetic modifications govern chromatin dynamics and cell state. However, current methods cannot simultaneously resolve the presence of multiple DNA modifications at co-occurring chromatin-associated features. It is thus not clear how these features are physically coupled and how their combinations regulate genome function. To address this key question, we report 6-base-CUT&Tag, a method for simultaneous 6-base DNA sequencing at target chromatin features. Using 6-base-CUT&Tag to profile 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) at co-occurring histone modifications in mouse embryonic stem cells (mESCs), we identify feature-dependent 5mC/5hmC signatures previously unresolvable with untargeted or bisulfite-based workflows. We show that DNA methylation and hydroxymethylation are specifically coupled with the H3K4me1 mark in mESC enhancers and that H3K4me1-derived signatures robustly distinguish different enhancer functional states.
    DOI:  https://doi.org/10.1038/s41467-026-69429-6
  9. Nat Genet. 2026 Feb 13.
    Comprehensive repertoire of the chromosomal alteration and mutational signatures across 16 cancer types.
    Andrew Everall, Avraam Tapinos, Aliah Hawari, Alex J Cornish, Amit Sud, Daniel Chubb, Ben Kinnersley, Anna Frangou, Miguel Barquin, Josephine Jung, David N Church, Ludmil B Alexandrov, Richard S Houlston, Andreas J Gruber, David C Wedge.
      Whole-genome sequencing (WGS) enables exploration of the full spectrum of oncogenic processes that generate characteristic patterns of mutations. Mutational signatures provide clues to tumor etiology and highlight potentially targetable pathway defects. Here alongside single-base substitution, doublet-base substitution, small insertion and deletion and copy number aberration signatures previously covered by the Catalogue of Somatic Mutations in Cancer (COSMIC), we report signatures from an additional mutation type, structural variations (SVs), extracted de novo from WGS in 10,983 patients across 16 tumor types recruited to the 100,000 Genomes Project. Across the five mutation classes, we report 134 signatures, 26 of which are new to COSMIC, including an SV signature reference set. By relating signatures to genomic features and clinical phenotypes, we provide further insights into mutagenic processes and the application of signature analysis to precision oncology.
    DOI:  https://doi.org/10.1038/s41588-025-02474-x
  10. Nat Aging. 2026 Feb 12.
    Clonal hematopoiesis boosts response to immune checkpoint therapy.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-026-01082-6
  11. Nat Genet. 2026 Feb;58(2): 329-340
    Pan-cancer inference and validation of hypermorphic, hypomorphic and neomorphic mutations.
    Somnath Tagore, Samuel Tsang, Carla Tangermann, Lucas ZhongMing Hu, Sven Diederichs, Gordon B Mills, Andrea Califano.
      Although the functional effects of many recurrent cancer mutations have been characterized, The Cancer Genome Atlas contains more than 10 million functionally uncharacterized, nonrecurrent events. It is proposed that the context-specific activity of transcription factors assessed through the expression of their transcriptional targets serves as a sensitive and accurate reporter assay for evaluating the functional roles of oncogene mutations. Analysis of transcription factor activity in samples with mutations of unknown significance, compared to established gain-of-function (hypermorph) or loss-of-function (hypomorph) mutations in the same gene, enabled functional characterization of 583,089 individual mutational events across TCGA. This approach facilitated the identification of neomorphic mutations (gain of new function) or mutations that phenocopy mutations in other genes (mutational mimicry). Validation using exogenous mutation expression assays confirmed the majority of predicted loss-of-function, gain-of-function, neomorphic and neutral (no predicted functional effect) mutations in PIK3CA and FGFR2. These findings may inform targeted therapy decisions for patients with mutations of unknown significance in established oncogenes.
    DOI:  https://doi.org/10.1038/s41588-025-02482-x
This page is being maintained by Thomas Krichel. It was last updated on 2026‒02‒15 at 22:02.