bims-ovdlit 2025-11-23 papers

bims-ovdlit

Biomed News

on Ovarian cancer: early diagnosis, liquid biopsy and therapy

Issue of 2025–11–23
fifteen papers selected by
Lara Paracchini, Humanitas Research

Human fallopian tube epithelial organoids with TP53 mutation recapitulate features of serous tubal intraepithelial carcinoma (STIC).
Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.
Liquid biopsy epigenetics: establishing a molecular profile based on cell-free DNA.
Cross-dataset pan-cancer detection by correlating cell-free DNA fragment coverage with open chromatin sites across cell types.
Age, lifestyle, and disease affect ciliary transport in the human fallopian tube.
ASSOCIATION BETWEEN TYPE AND LOCATION OF GERMLINE BRCA1/2 PATHOGENIC OR LIKELY PATHOGENIC VARIANTS WITH PHENOTYPE AND PROGNOSIS IN YOUNG PATIENTS WITH BREAST CANCER: RESULTS FROM AN INTERNATIONAL COHORT STUDY.
PARPi and myeloid neoplasms; the Italian MITO-MaNGO experience based on a multicentric survey.
Circulating tumor DNA monitoring in ovarian cancer patients receiving PARPi maintenance therapy: Can we further personalize treatment?
Multi-Omics Meets Premalignancy: Paving the Way for Early Prevention of Cancer.
Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer.
Genome doubling as a dynamic driver of ovarian cancer evolution: insights from single-cell sequencing.
RECAP-seq: restriction enzyme-based CpG-methylated fragment amplification for early cancer detection.
Clinical and genomic features of Lynch syndrome differ by tumor site and disease spectrum.
Identifying high-risk relapse in early-stage I to II ovarian cancer using the CA125 ELIMination rate constant K (KELIM) score: a Gynecologic Cancer InterGroup individual patient-data meta-analysis.
Adenine DNA methylation associated with transcriptionally permissive chromatin is widespread across eukaryotes.

Gynecol Oncol. 2025 Nov 20. pii: S0090-8258(25)01076-5. [Epub ahead of print]203 198-208

Human fallopian tube epithelial organoids with TP53 mutation recapitulate features of serous tubal intraepithelial carcinoma (STIC).

Judith Kraiczy, Bo Yu.

   OBJECTIVE: Serous tubal intraepithelial carcinoma (STIC) is the immediate precursor lesion for high-grade serous ovarian carcinoma (HGSOC) and harbors universal TP53 mutations. The lack of an appropriate in vitro model for STIC presents a major challenge in studying its pathogenesis. We aimed to develop a human in vitro model that mimics STIC lesions.
METHODS: Using CRISPR-Cas9 gene editing, we generated human fallopian tube epithelial organoids with TP53 loss-of-function mutations (TP53-/- FTOs). We characterized TP53-/- FTOs on a cellular and molecular level using immunofluorescence confocal imaging, copy number variation (CNV) analysis, and RNA sequencing.
RESULTS: TP53-/- FTOs recapitulated key features of STIC lesions. They exhibited increased proliferation and nuclear abnormalities, including nuclear enlargement and atypical mitotic figures. Copy number variation analysis revealed aneuploidy in some TP53-/- FTOs. Compared to unedited controls, TP53-/- FTOs demonstrated significant transcriptomic changes, including the downregulation of DNA repair genes and upregulation of epithelial-mesenchymal transition (EMT) pathways. Similar to STIC lesions, TP53-/- FTOs showed a marked reduction in ciliated cells and ciliogenesis-associated gene expression.
CONCLUSIONS: These findings suggest that p53 loss in FTOs promotes a proliferative and genomically unstable state that is conducive to carcinogenesis. The TP53-/- FTO model we have generated provides a valuable tool for studying early events in ovarian carcinogenesis and for developing new strategies for the early detection and prevention of ovarian cancer.

Keywords:  Aneuploidy; Human fallopian tube epithelial organoids; Ovarian cancer; Ovarian carcinogenesis; Serous tubal intraepithelial carcinoma (STIC); TP53 mutations

DOI:  https://doi.org/10.1016/j.ygyno.2025.10.038
Res Sq. 2025 Oct 03. pii: rs.3.rs-7572112. [Epub ahead of print]

Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.

Dale Garsed, Tibor Zwimpfer, Sian Fereday, Ahwan Pandey, Dinuka Ariyaratne, Madawa Jayawardana, Laura Twomey, Céline Laumont, Catherine Kennedy, Adelyn Bolithon, Nicola Meagher, Katy Milne, Phineas Hamilton, Jennifer Alsop, Antonis Antoniou, George Au-Yeung, Matthias Beckmann, Amy Berrington de Gonzalez, Christiani Bisinotto, Freya Blome, Clara Bodelon, Jessica Boros, Alison Brand, Michael Carney, Alicia Cazorla-Jimenez, Derek Chiu, Elizabeth Christie, Anita Chudecka-Glaz, Penny Coulson, Kara Cushing-Haugen, Cezary Cybulski, Kathleen Darcy, Cath David, Trent Davidson, Arif Ekici, Esther Elishaev, Julius Emons, Tobias Engler, Rhonda Farrell, Anna Fischer, Montserrat Garcia-Closas, Aleksandra Gentry-Maharaj, Prafull Ghatage, Rosalind Glasspool, Philipp Harter, Andreas Hartkopf, Arndt Hartmann, Sebastian Heikaus, Brenda Hernandez, Anusha Hettiaratchi, Sabine Heublein, David Huntsman, Mercedes Jimenez-Linan, Michael Jones, Eunjoung Kang, Ewa Kaznowska, Tomasz Kluz, Felix Kommoss, Gottfried E Konecny, Rutgerus Kruitwagen, Jessica Kwon, Diether Lambrechts, Cheng-Han Lee, Jenny Lester, Samuel Leung, Yee Leung, Anna Linder, Jolanta Lissowska, Liselore Loverix, Jan Lubiński, Constantina Mateoiu, Iain McNeish, Malak Moubarak, Gregg Nelson, Nikilyn Nevins, Alexander Olawaiye, Siel Olbrecht, Sandra Orsulic, Ana Osorio, Carmel Quinn, Ganendra Raj Mohan, Isabelle Ray-Coquard, Cristina Rodriguez-Antona, Patricia Roxburgh, Matthias Rübner, Stuart Salfinger, Spinder Samra, Minouk Schoemaker, Hans-Peter Sinn, Gabe Sonke, Linda Steele, Colin Stewart, Aline Talhouk, Adeline Tan, Christopher Tarney, Sarah Taylor, Koen Van de Vijver, Maaike Avan der Aa, Toon Van Gorp, Els Van Nieuwenhuysen, Lilian van Wagensveld, Andrea Wahner-Hendrickson, Christina Walter, Chen Wang, Julia Welz, Nicolas Wentzensen, Lynne Wilkens, Stacey Winham, Boris Winterhoff, Michael Anglesio, Andrew Berchuck, Francisco Candido do Reis, Paul Cohen, Thomas Conrads, Philip Crowe, Jennifer Doherty, Peter Fasching, Renée Fortner, Maria Garcia, Simon Gayther, Marc Goodman, Jacek Gronwald, Holly Harris, Florian Heitz, Hugo Horlings, Beth Karlan, Linda Kelemen, George Maxwell, Usha Menon, Francesmary Modugno, Susan Neuhausen, Joellen Schildkraut, Annette Staebler, Karin Sundfeldt, Anthony Swedlow, Ignace Vergote, Anna Wu, James Brenton, Paul Pharoah, Celeste Pearce, Malcolm Pike, Ellen Goode, Susan Ramus, Martin Köbel, Brad Nelson, Anna DeFazio, Michael Friedlander, David Bowtell.

BRCA -associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA -deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA -deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA -deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1 -deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2 -deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2 -deficient HGSC with exceptionally short survival. BRCA1 -deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (g BRCA pv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in g BRCA pv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA -deficient HGSC.

DOI: https://doi.org/10.21203/rs.3.rs-7572112/v1
Mol Oncol. 2025 Nov 21.

Liquid biopsy epigenetics: establishing a molecular profile based on cell-free DNA.

Christoffer Trier Maansson, Anders Lade Nielsen, Boe Sandahl Sorensen.

  Liquid biopsies containing circulating tumor DNA (ctDNA) are important biomarkers across several forms of cancer. The detection of mutations in cell-free DNA (cfDNA) indicates the presence of ctDNA. However, unsatisfactory ctDNA mutation sensitivities, issues with sequencing errors, and clonal hematopoiesis variants have limited the clinical utility of mutation-based ctDNA assays. Recently, a new avenue of cfDNA assays has been developed, focusing on cfDNA epigenetics. Here, we outline the recent advancements in cfDNA epigenetics, focusing on cfDNA methylation, fragmentomics, and post-translational modifications (PTMs) of circulating nucleosomes. We present various methylation strategies concerning ctDNA detection and tissue of origin (TOO) analyses. cfDNA fragmentomics focuses on cfDNA fragment lengths, fragment end motifs, and nucleosome positioning to infer gene expression and estimate the ctDNA fraction. Lastly, we discuss the development of cell-free chromatin immunoprecipitation of circulating nucleosomes with PTMs. This method has been implemented to detect tumor gene expression, TOO, and treatment resistance. Combining the epigenetic features of cfDNA will expand the utility of liquid biopsies to give a more comprehensive insight into tumor biology, treatment response, and resistance.

Keywords:  cell‐free ChIP; cell‐free DNA; epigenetics; fragmentomics; liquid biopsy; methylation

DOI:  https://doi.org/10.1002/1878-0261.70145
Nat Commun. 2025 Nov 21.

Cross-dataset pan-cancer detection by correlating cell-free DNA fragment coverage with open chromatin sites across cell types.

Ludvig Renbo Olsen, Denis Odinokov, Jakob Qvortrup Holsting, Karoline Kondrup, Laura Iisager, Maria Rusan, Simon Buus, Britt Elmedal Laursen, Michael Borre, Mads Ryø Jochumsen, Kirsten Bouchelouche, Amanda Frydendahl, Mads Heilskov Rasmussen, Tenna Vesterman Henriksen, Marijana Nesic, Christina Demuth, Sia Viborg Lindskrog, Iver Nordentoft, Philippe Lamy, Christina Therkildsen, Lars Dyrskjøt, Karina Dalsgaard Sørensen, Claus Lindbjerg Andersen, Anders Jakobsen Skanderup, Søren Besenbacher.

The fragmentation patterns of whole genome sequenced cell-free DNA are promising features for tumor-agnostic cancer detection. However, systematic biases challenge their cross-cohort generalization. We introduce LIONHEART, an open source cancer detection method specifically optimized to generalize across datasets. The method correlates bias-corrected cfDNA fragment coverage across the genome with the locations of accessible chromatin regions from 898 cell and tissue type features. We use these correlations to detect changes in the cell-free DNA cell type composition caused by cancer. We test LIONHEART on nine datasets and fourteen cancer types (1106 non-cancer controls, 1449 cancers) obtained from different studies and show that it can distinguish cancer samples from non-cancer controls across cohorts with ROC AUC scores ranging from 0.62-0.95 (mean = 0.83, std = 0.12). We further validate the method on an external dataset, achieving a ROC AUC of 0.917.

DOI: https://doi.org/10.1038/s41467-025-66503-3
Sci Rep. 2025 Nov 18. 15(1): 40594

Age, lifestyle, and disease affect ciliary transport in the human fallopian tube.

Caoimhe Neville, Sven Reese, Barbara Hughes, Kate Glennon, Ann Treacy, Donal J Brennan, Sabine Kölle.

  The synchronized beating of ciliated cells within the human fallopian tube is crucial for the transport of the oocyte and the early embryo. To date, the precise effects of age, lifestyle, and disease on ciliary beating in the human fallopian tube are still unknown. Therefore, we set out to evaluate the effects of cycle stage, age, BMI, smoking, and alcohol, as well as the impact of ovarian cysts, uterine fibroids (myomas), cervical cancer, and endometrial cancer on human tubal ciliary beat frequency (CBF). Samples were obtained from control patients undergoing risk reduction surgery as well as from patients with ovarian cysts, benign myomas, as well as from patients with cervical cancer and endometrial cancer. Tubal samples were obtained during hysterectomy with salpingo-oophorectomy and examined using quantitative digital live cell imaging under near in vivo conditions and in real-time. Our results showed that tubal CBF was independent of cycle stage and anatomical location in the oviduct. There was a significant relationship between patient age and CBF (< 45 years Spearman's rho=-0.708, p = < 0.001 and > 45 years Spearman's rho=-0.752, p = < 0.001). Smoking caused a significant increase in CBF (generalised linear model, p = 0.025), whereas regular alcohol consumption had no effect. Increased BMI was associated with significantly decreased CBF (Spearman's rho=-0.543, p = 0.024). CBF was also significantly decreased in cycling patients affected by ovarian cysts (generalised linear model for repeated measurements, p = 0.004), in patients with uterine myomas (generalised linear model, p = 0.027), as well as in patients with cervical cancer (cycling patients, generalised linear model, p = 0.002) and endometrial cancer (menopausal patients, generalised linear model, p = 0.003). Overall, our results show that tubal ciliary function is impaired by obesity and smoking, as well as by benign myomas and malignant gynaecological cancer. Altered CBF impairs proper embryo transport speed, decreasing the chance of successful pregnancy. Thus, modulating early embryo transport might be a valuable tool for optimizing the success rates of assisted reproductive technologies (ART) both in infertile healthy patients as well as in young cervical cancer patients.

Keywords:  Ciliary beating; Disease; Fallopian tube; Lifestyle; Oviduct

DOI:  https://doi.org/10.1038/s41598-025-24285-0
Ann Oncol. 2025 Nov 17. pii: S0923-7534(25)06262-3. [Epub ahead of print]

ASSOCIATION BETWEEN TYPE AND LOCATION OF GERMLINE BRCA1/2 PATHOGENIC OR LIKELY PATHOGENIC VARIANTS WITH PHENOTYPE AND PROGNOSIS IN YOUNG PATIENTS WITH BREAST CANCER: RESULTS FROM AN INTERNATIONAL COHORT STUDY.

A Toss, E Blondeaux, E Tenedini, L Bonamici, R Graffeo, L Livraghi, C Villarreal-Garza, R Bernstein Molho, A Kwong, J Balmana, H Wildiers, E Agostinetto, K A Phillips, K Pogoda, T Renaud, C Rousset-Jablonski, A Ferrari, H C F Moore, F A Peccatori, S Paluch-Shimon, R Fruscio, C Micheri, S M Wong, W Cui, C Vernieri, M Lee, L De Marchis, F J Couch, L Del Mastro, F Puglisi, P A Meireles, Z Kemp, A Matikas, J Plichta, M Del Pilar Estevez-Diz, A Di Meglio, N Cichowska-Cwalinska, C Gianni, R Yerushalmi, R Sanchez-Bayona, B Mrinakova, L Matos, G Bianchini, M Caleffi, A Krivokuca, Y Abdou, M Mariño-Mariño, A Parokonnaya, M Okano, N Antone, C Saavedra, A Sonnenblick, R Duchnowska, H L Pais, N Harbeck, L Cortesi, V Delucchi, C De Angelis, M Lambertini.

   BACKGROUND: Clinical implications of specific pathogenic and likely pathogenic variant (LP/PV) types and locations in the BRCA1 or BRCA2 tumor-suppressor genes remain to be elucidated.
PATIENTS AND METHODS: The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study that included BRCA mutation carriers diagnosed with invasive breast cancer at the age of ≤40 years between January 2000 and December 2020. In this analysis, only patients with detailed available information on LP/PVs in the BRCA genes were included. Clinicopathologic features and survival outcomes (disease-free survival [DFS] and overall survival [OS]) were investigated according to LP/PV type (insertion-deletion mutations [INDEL] vs single nucleotide variants [SNV] vs copy number variations [CNV]; truncating vs non-truncating LP/PVs; frameshift vs nonsense vs splicing vs missense LP/PVs) and location (exon involved and protein domain).
RESULTS: Out of 5660 patients from 109 centers worldwide, 3294 were eligible for the present analysis (2080 BRCA1 and 1214 BRCA2). The distribution of LP/PV types showed no meaningful associations with baseline clinicopathologic features. BRCA1 protein truncating variants were associated with worse OS compared to non-truncating variants (HR 2.00 [1.17-3.41]). A similar, though non-significant, trend was observed for BRCA2. Missense variants were linked to better OS for both BRCA1 (HR 0.48 [0.28-0.84]) and BRCA2 mutation carriers (HR 0.17 [0.03-0.96]). Regarding variant location, BRCA1 LP/PVs outside exons 2, 10, and 19 were associated with improved OS. In BRCA2, LP/PVs located in exons 15-26 and other regions were linked to worse DFS compared to those in exon 10, with no significant differences in OS.
CONCLUSIONS: This study advances our understanding of the influence of specific types of BRCA LP/PVs on breast cancer characteristics and outcomes. A deeper understanding of these mutation-specific features will drive future research and support the development of tailored clinical strategies based on individual BRCA variant.

Keywords:  BRCA1; BRCA2; Hereditary breast cancer; overall survival; protein-truncating variant; variant type

DOI:  https://doi.org/10.1016/j.annonc.2025.11.004
ESMO Open. 2025 Nov 18. pii: S2059-7029(25)01772-7. [Epub ahead of print]10(12): 105903

PARPi and myeloid neoplasms; the Italian MITO-MaNGO experience based on a multicentric survey.

M Turinetto, C Marchetti, G Scandurra, N Colombo, G Cormio, S Cecere, D Pellegrini, C De Angelis, C Abeni, M C Petrella, A Ferrero, C Camnasio, F Villa, S Mammoliti, M Giordano, G Valabrega, M DeStefanis, G Cirigliano, S Boccia, M Distefano, P Chiusolo, M T Perri, V Lombardo, G Caruso, V Loizzi, E Coppola, V Barberi, M R Lamia, A Fagotti, S Pignata.

   INTRODUCTION: The introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer has raised increasing concerns about PARPi-related myeloid neoplasms (PrMN). Therapy-related neoplasms, including myelodysplastic syndromes and acute myeloid leukemia, account for 10%-20% of cases. Expanding PARPi indications, longer survival, and aging populations may contribute to rising PrMN incidence. Randomized clinical trials and real-world analyses show a significant risk increase, but data on individual PARPi, treatment lines, and prior therapies are limited.
METHODS: We evaluated PrMN incidence across 17 Italian centers using a 71-item survey distributed to MITO (Multicenter Italian Trials on Ovarian cancer) and MaNGO (Mario Negri Gynecologic Oncology) centers, focusing on patients treated with PARPi outside clinical trials.
RESULTS: Of 2320 patients (1254 BRCA-mutated), 56 (2.55%) developed MN: 35 myelodysplastic syndromes and 21 acute myeloid leukemia (2 patients had both, counted once). Among them, 31 had BRCA mutations (2.5%). Incidence by drug was: olaparib 2.5%, niraparib 2%, and rucaparib 3.4%. An unclear correlation emerged between treatment duration and PrMN risk, with a median onset of 18.9 months. Risk increased with additional therapy lines: 0.52% (first), 4.2% (second), 1.8% (third), 10.8% (fourth), and 12.2% (>fourth lines). Among PrMN cases, 4 achieved remission, 4 had partial responses, 8 progressed, and 37 died.
CONCLUSIONS: While this survey is meant as hypotheses-generating, PrMN represent a rare but clinically relevant complication, particularly uncommon when PARPi are administered as first-line therapy. Their occurrence does not appear to be associated with the specific PARPi used or with BRCA mutation status. Early detection, monitoring, and identification of predictive factors are crucial as ovarian cancer outcomes improve and treatment exposure increases.

Keywords:  PARPi; ovarian cancer; therapy-related myeloid neoplasms

DOI:  https://doi.org/10.1016/j.esmoop.2025.105903
Gynecol Oncol. 2025 Nov 17. pii: S0090-8258(25)01083-2. [Epub ahead of print]204 37-43

Circulating tumor DNA monitoring in ovarian cancer patients receiving PARPi maintenance therapy: Can we further personalize treatment?

Michael D Toboni, Elizabeth T Evans, Carly Bess Scalise, Melissa Hardesty, Tara Berman, Kaitlyn Dinkins, Fibiana Oladipo, Nicole Hook, Jenifer Ferguson, Punashi Dutta, Jennah Moore, Bailee Oliver, Minetta C Liu, Adam C ElNaggar, Charles A Leath, Rebecca C Arend.

   OBJECTIVES: Recommendations for the length of maintenance therapy with poly (ADP-ribose) polymerase inhibitors (PARPi) in patients with ovarian cancer (OC) are derived from clinical trials with various durations of therapy. Here, we evaluated whether circulating tumor DNA (ctDNA) predicted recurrence/progression in OC patients receiving PARPi maintenance.
METHODS: This was a multi-center retrospective cohort study of real-world data from commercial ctDNA testing (Signatera™, Natera, Inc.) in patients with OC on PARPi maintenance following response to penultimate platinum-based therapy. Clinical data were collected on stage, setting, pathologic subtype, and biomarker status.
RESULTS: Fifty-three patients with OC were analyzed, with samples collected: i) prior to starting PARPi (pre-PARPi; N = 12), ii) during the first 12 months on PARPi (early; N = 34), and iii) beyond 12 months of PARPi therapy (late; N = 26). ctDNA was detected prior to PARPi initiation in 58 % (7/12) of patients, and none experienced sustained ctDNA clearance on PARPi therapy. Notably, none of the ctDNA-negative patients recurred at the last known clinical follow-up. Persistent/conversion to ctDNA positivity within the first 3 months of therapy was associated with significantly shorter progression-free survival (PFS) (p = 0.01). Patients who were serially ctDNA-negative/cleared ctDNA within 6 months on therapy had significantly improved PFS compared to those who were persistently positive/converted to positive (p = 0.003). Correlation with CA-125 and BRCA/HR status was not significant.
CONCLUSIONS: ctDNA status on-PARPi was a stronger predictor of disease progression compared to CA-125 or BRCA/HR status. While additional analyses are warranted, our data suggest that ctDNA is a promising biomarker for therapeutic decision-making.

Keywords:  Circulating tumor DNA; Ovarian cancer; PARPi; Tumor biomarkers; ctDNA

DOI:  https://doi.org/10.1016/j.ygyno.2025.11.005
Research (Wash D C). 2025 ;8 0930

Multi-Omics Meets Premalignancy: Paving the Way for Early Prevention of Cancer.

Feiran Zhang, Ziyi Zhou, Peng Zhang, Shao Li.

Comprehensive understanding of premalignant lesions (PMLs) represents a pivotal opportunity for cancer early detection and interception. Recently, advances in multi-omics technologies and artificial intelligence (AI) methods have provided unprecedented insights into PML-induced tumorigenesis. In this paper, we firstly catalog clinically recognized PMLs across 15 cancer types, emphasizing their epidemiological profiles and malignant transformation potentials. Then, we summarize recent intriguing discoveries and remaining challenges from bulk, single-cell, and spatial omics studies, highlighting how these omics technologies reveal the dynamic molecular, cellular, and spatial evolution from precancerous states to invasive malignancies. We further discuss network-based computational strategies for multi-omics integration and tumorigenesis trajectory inference, with applications of recent deep learning-based AI approaches. Finally, we highlight translational implications for PMLs, including developing high-precision early-diagnosis biomarkers and targeted pharmacological preventive strategies. Collectively, this paper underscores how the convergence of high-resolution multi-omics with sophisticated AI is poised to redefine PML research, enabling pan-cancer exceedingly-early risk stratification and pharmacological prevention.

DOI: https://doi.org/10.34133/research.0930
NPJ Genom Med. 2025 Nov 20. 10(1): 73

Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer.

Daniel R Barnes, Jonathan P Tyrer, Joe Dennis, Goska Leslie, Manjeet K Bolla, Michael Lush, Amber M Aeilts, Kristiina Aittomäki, Nadine Andrieu, Irene L Andrulis, Hoda Anton-Culver, Adalgeir Arason, Banu K Arun, Judith Balmaña, Elisa V Bandera, Rosa B Barkardottir, Lieke P V Berger, Amy Berrington de Gonzalez, Pascaline Berthet, Katarzyna Białkowska, Line Bjørge, Amie M Blanco, Marinus J Blok, Kristie A Bobolis, Natalia V Bogdanova, James D Brenton, Henriett Butz, Saundra S Buys, Maria A Caligo, Ian Campbell, Carmen Castillo, Kathleen B M Claes, Sarah V Colonna, Linda S Cook, Mary B Daly, Agnieszka Dansonka-Mieszkowska, Miguel de la Hoya, Anna deFazio, Allison DePersia, Yuan Chun Ding, Jennifer A Doherty, Susan M Domchek, Thilo Dörk, Zakaria Einbeigi, Christoph Engel, D Gareth Evans, Lenka Foretova, Renée T Fortner, Florentia Fostira, Maria Cristina Foti, Eitan Friedman, Megan N Frone, Patricia A Ganz, Aleksandra Gentry-Maharaj, Gord Glendon, Andrew K Godwin, Anna González-Neira, Mark H Greene, Jacek Gronwald, Aliana Guerrieri-Gonzaga, Ute Hamann, Thomas V O Hansen, Holly R Harris, Jan Hauke, Florian Heitz, Frans B L Hogervorst, Maartje J Hooning, John L Hopper, Chad D Huff, David G Huntsman, Evgeny N Imyanitov, Louise Izatt, Anna Jakubowska, Paul A James, Ramunas Janavicius, Esther M John, Siddhartha Kar, Beth Y Karlan, Catherine J Kennedy, Lambertus A L M Kiemeney, Irene Konstantopoulou, Jolanta Kupryjanczyk, Yael Laitman, Ofer Lavie, Kate Lawrenson, Jenny Lester, Fabienne Lesueur, Carlos Lopez-Pleguezuelos, Phuong L Mai, Siranoush Manoukian, Taymaa May, Iain A McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Jennifer M Mongiovi, Marco Montagna, Kirsten B Moysich, Susan L Neuhausen, Finn C Nielsen, Catherine Noguès, Edit Oláh, Olufunmilayo I Olopade, Ana Osorio, Laura Papi, Harsh Pathak, Celeste L Pearce, Inge S Pedersen, Ana Peixoto, Tanja Pejovic, Pei-Chen Peng, Beth N Peshkin, Paolo Peterlongo, C Bethan Powell, Darya Prokofyeva, Miquel Angel Pujana, Paolo Radice, Muhammad U Rashid, Gad Rennert, George Richenberg, Dale P Sandler, Naoko Sasamoto, Veronica W Setiawan, Priyanka Sharma, Weiva Sieh, Christian F Singer, Katie Snape, Anna P Sokolenko, Penny Soucy, Melissa C Southey, Dominique Stoppa-Lyonnet, Rebecca Sutphen, Christian Sutter, Yen Y Tan, Manuel R Teixeira, Kathryn L Terry, Liv Cecilie V Thomsen, Marc Tischkowitz, Amanda E Toland, Toon Van Gorp, Ana Vega, Digna R Velez Edwards, Penelope M Webb, Jeffrey N Weitzel, Nicolas Wentzensen, Alice S Whittemore, Stacey J Winham, Anna H Wu, Siddhartha Yadav, Yao Yu, Argyrios Ziogas, Andrew Berchuck, Fergus J Couch, Ellen L Goode, Marc T Goodman, Alvaro N Monteiro, Kenneth Offit, Susan J Ramus, Harvey A Risch, Joellen M Schildkraut, Mads Thomassen, Jacques Simard, Douglas F Easton, Michelle R Jones, Georgia Chenevix-Trench, Simon A Gayther, Antonis C Antoniou, Paul D P Pharoah.

Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We meta-analyzed >22 million variants for 398,238 women from the Ovarian Cancer Association Consortium (OCAC), UK Biobank (UKBB) and Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) to identify novel HGSOC susceptibility loci. Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was TP53 3'-UTR SNP rs78378222-T's association with HGSOC (per-T-allele relative risk (RR) = 1.44, 95% CI:1.28-1.62, P = 1.76 × 10-9). Polygenic scores (PGS) were developed using OCAC and CIMBA data and trained on FinnGen data. The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95% CI:1.37-1.54) per standard deviation when validated in the UKBB. This study represents the largest HGSOC GWAS to date - demonstrating that improvements in imputation reference panels and increased sample sizes help to identify HGSOC associated variants that previously went undetected, ultimately improving PGS which can improve personalized HGSOC risk prediction.

DOI: https://doi.org/10.1038/s41525-025-00529-w
J Ovarian Res. 2025 Nov 19. 18(1): 274

Genome doubling as a dynamic driver of ovarian cancer evolution: insights from single-cell sequencing.

Tianjiao Zhao, Tianshi Zhao, Dengyu Dong, Dengyue Dong.

  Whole-genome doubling (WGD) is a macro-evolutionary event that is both prevalent and prognostically significant in human cancers, particularly in high-grade serous ovarian carcinoma (HGSOC). Historically, WGD has been viewed as a consequence of widespread genomic instability, but recent advancements in single-cell sequencing (sc-seq) have reframed its role as a central, dynamic driver of tumor evolution. This review summarizes cutting-edge findings, demonstrating how WGD acts as a catalyst for a distinct evolutionary trajectory characterized by the rapid accumulation of chromosomal losses and the selection of highly adaptable clones. A key finding is the resolution of a biological paradox: WGD-driven chromosomal instability, which should provoke an immune response, is instead correlated with a profoundly immunosuppressive phenotype via the repression of key innate immune pathways. Finally, this review discusses the clinical implications of these discoveries, highlighting WGD's potential as a predictive biomarker and a source of unique therapeutic vulnerabilities, paving the way for targeted strategies in advanced HGSOC.

Keywords:  Chromosomal instability; High-grade serous ovarian carcinoma; Immunosuppression; Tumor evolution; Whole-genome doubling

DOI:  https://doi.org/10.1186/s13048-025-01860-7
Sci Rep. 2025 Nov 19. 15(1): 40892

RECAP-seq: restriction enzyme-based CpG-methylated fragment amplification for early cancer detection.

Dongju Shin, Taehoon Kim, Jaywon Lee, Hwang-Phill Kim, Tae-You Kim, Duhee Bang.

  Aberrant DNA methylation drives cancer development, yet current screening methods require substantial resources for targeted enrichment across multiple CpG-rich regions. Early cancer detection in cell-free DNA (cfDNA) presents additional challenges due to low circulating tumor DNA fractions (0.01-10%) that dilute cancer-specific signals. To address these limitations, we developed Restriction Enzyme-based CpG-methylated fragment AmPlification sequencing (RECAP-seq) to selectively enrich hypermethylated fragments from existing Enzymatic Methyl-seq (EM-seq) libraries. RECAP-seq combines EM-seq library preparation with BstUI restriction enzyme digestion to target CGCG motifs, achieving preferential enrichment of CpG islands. With spike-in experiments using cell line mixtures, RECAP-seq successfully distinguished samples as low as 0.001%. The method identified 7,091 hypermethylated markers, including ALX4 which showed progressive increases with colorectal cancer stage. Clinical validation using cfDNA from 35 healthy donors and 47 colorectal cancer patients demonstrated robust detection with an area under the curve (AUC) of 0.932, achieving 78.7% sensitivity at 95% specificity.

Keywords:  Cell-free DNA; Colorectal cancer; DNA methylation; DNA restriction enzymes; Detection; Enrichment

DOI:  https://doi.org/10.1038/s41598-025-24708-y
Nat Commun. 2025 Nov 19. 16(1): 10179

Clinical and genomic features of Lynch syndrome differ by tumor site and disease spectrum.

Shisen Li, Ningning Luo, Gaoxin Jin, Tiantian Han, Xiangyu Yin, Didi Guo, Xing Zhang, Zhaobang Tan.

Lynch Syndrome (LS) carriers occasionally develop central nervous system (CNS) malignancies or tumors in organs not traditionally linked to the syndrome. These tumors are poorly characterized in the literature, and there is no sufficient consensus on guidelines and management recommendations for these tumors. Here we study LS from the tumor perspective and profile 238 pan-cancer specimens from 228 genetically confirmed LS carriers. Tumors are stratified into CNS LS-related, non-CNS LS-related, and non-CNS LS-unrelated groups according to anatomic site and established LS tumor spectrum. Comparative analyses against TCGA reveal significant alterations in LS incidence within endometrial and hepatic cancers. Across the three groups, we reveal marked heterogeneity in germline pathogenic-variant distribution, age at diagnosis, somatic mutation landscapes, tumor mutational burden, and microsatellite-instability status. This site- and spectrum-based stratification of a large, pan-cancer LS cohort underscores the heterogeneity of the LS and provides a data-driven foundation for refining future disease management strategies.

DOI: https://doi.org/10.1038/s41467-025-65164-6
Int J Gynecol Cancer. 2025 Oct 10. pii: S1048-891X(25)01839-0. [Epub ahead of print]36(1): 102719

Identifying high-risk relapse in early-stage I to II ovarian cancer using the CA125 ELIMination rate constant K (KELIM) score: a Gynecologic Cancer InterGroup individual patient-data meta-analysis.

Pauline Corbaux, Benoit You, Tatsuo Kagimura, Rosalind M Glasspool, Iain McNeish, Adrian Cook, Mansoor R Mirza, Kristina Lindemann, Anna V Tinker, Stephen Welch, Isabelle L Ray-Coquard, Fabien Subtil, Olivier Colomban, Julien Péron, Eleni Karamouza, Caroline Kelly, Liz-Anne Lewsley, Xavier Paoletti, Nozomu Yanaihara.

   OBJECTIVE: Despite curative surgery and adjuvant chemotherapy, a significant number of early stage I to II ovarian cancers relapse. The CA125 ELIMination rate constant K (KELIM) is a pragmatic indicator of tumor intrinsic chemosensitivity in advanced epithelial ovarian cancer. We assessed the prognostic value of KELIM in patients with early-stage ovarian cancer, with respect to 5-year recurrence-free survival and overall survival, using the Meta-Analysis in Ovarian Cancer, which is the Gynecologic Cancer InterGroup individual patient-data meta-analysis of randomized trials evaluating different adjuvant chemotherapy regimens.
METHODS: Individual patient KELIM values were previously estimated in 5884 patients from the Meta-Analysis in Ovarian Cancer. The prognostic value of KELIM was assessed using univariable & multivariable analyses in patients with resected International Federation of Gynecology and Obstetrics stage I and II disease.
RESULTS: Overall, 1143 patients were identified, including clear cell (46.7%); serous (23.7%); endometrioid (12.4%); and mucinous carcinomas (3.9%). In multivariable analyses, a favorable KELIM score (≥1.0) was associated with higher 5-year recurrence-free survival (68.3% vs 55.9%; HR 0.61, 95% CI 0.48 to 0.77) and 5-year overall survival (80.7% vs 72.8%; HR 0.50, 95% CI 0.36 to 0.68), as was the histological sub-type. In exploratory analyses, KELIM score was a prognostic factor regarding 5-year recurrence-free survival and overall survival across all sub-types (especially clear cell carcinoma and serous, with HR ranging from 0.45 to 0.63) with baseline CA125 ≥15 IU/L, except for mucinous histology.
CONCLUSIONS: The pragmatic KELIM score is an independent prognostic factor in patients with a non-mucinous stage I to II ovarian cancer optimally resected and treated with adjuvant chemotherapy. KELIM may help identify the patients at higher risk of relapse and death requiring closer follow-up or treatment intensification.

Keywords:  CA125 KELIM; Early-Stage Ovarian Cancer; Epithelial Ovarian Cancer; Mathematical Modeling; Prognostic Biomarker

DOI:  https://doi.org/10.1016/j.ijgc.2025.102719
Nat Genet. 2025 Nov 18.

Adenine DNA methylation associated with transcriptionally permissive chromatin is widespread across eukaryotes.

Pedro Romero Charria, Cristina Navarrete, Vladimir Ovchinnikov, Lan Xu, Luke A Sarre, Victoria Shabardina, Ewa Ksiezopolska, Elena Casacuberta, David Lara-Astiaso, Arnau Sebé-Pedrós, Alex de Mendoza.

DNA methylation is a key regulator of eukaryotic genomes, most commonly through 5-methylcytosine (5mC). In contrast, the existence and function of N6-methyladenine (6mA) in eukaryotes have been controversial, with conflicting reports resulting from methodological artifacts. Nevertheless, some unicellular lineages, including ciliates, early-branching fungi and the alga Chlamydomonas, show robust 6mA signals, raising questions about their origin and evolutionary role. Here we apply Oxford Nanopore sequencing to profile 6mA at base-pair resolution across 18 unicellular eukaryotes representing all major supergroups. We find that robust 6mA patterns occur only in species that encode the adenine methyltransferase AMT1. Notably, 6mA consistently accumulates downstream of transcriptional start sites, positioned between H3K4me3-marked nucleosomes, indicating a conserved association with transcriptional activation. Our results support the idea that the last eukaryotic common ancestor had a dual methylation system, with transcription-linked 6mA and repressive 5mC, which has been repeatedly simplified in both multicellular and unicellular lineages through the loss of the AMT1 pathway.

DOI: https://doi.org/10.1038/s41588-025-02409-6