bims-tumhet 2025-11-23 papers

bims-tumhet

Biomed News

on Tumor heterogeneity

Issue of 2025–11–23
twelve papers selected by
Sergio Marchini, Humanitas Research

Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.
Genome doubling as a dynamic driver of ovarian cancer evolution: insights from single-cell sequencing.
Human fallopian tube epithelial organoids with TP53 mutation recapitulate features of serous tubal intraepithelial carcinoma (STIC).
Liquid biopsy epigenetics: establishing a molecular profile based on cell-free DNA.
Unraveling the interplay of DNA methylation and chromosome organization.
Circulating tumor DNA monitoring in ovarian cancer patients receiving PARPi maintenance therapy: Can we further personalize treatment?
From concept to clinic: a roadmap for DNA methylation biomarkers in liquid biopsies.
RECAP-seq: restriction enzyme-based CpG-methylated fragment amplification for early cancer detection.
Whole-exome ctDNA sequencing reveals intratumoral heterogeneity and drivers of relapse in locally advanced head and neck cancer.
CNAScope: pan-cancer copy number aberration database with functional annotation and interactive visualization.
Endometrial cancer therapy in 2026.
Turning genes into medicines.

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
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
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
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
Biochem Soc Trans. 2025 Nov 10. pii: BST20253094. [Epub ahead of print]

Unraveling the interplay of DNA methylation and chromosome organization.

Yuhe Pei, Guoqiang Li.

  Eukaryotic DNA has been covalently modified by DNA methylation and folded into a three-dimensional conformation in the nucleus. While the functions of DNA methylation and chromosome organization have been widely discussed, respectively, the interplay between DNA methylation and chromosome organization remains less clear and needs to be further explained. In this review, we first discuss the cross-talk between DNA methylation and chromosome conformation, highlighting the complexity and importance of DNA methylation on chromosome organization. We also summarize the current methodologies that capture DNA methylation and chromosome organization individually or simultaneously in bulk and single cells. These mechanistic and methodological advancements facilitate broad interest in unveiling the interplay between DNA methylation and chromosome organization.

Keywords:  DNA methylation; chromosome organization; multi-omics method

DOI:  https://doi.org/10.1042/BST20253094
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
Oncogene. 2025 Nov 20.

From concept to clinic: a roadmap for DNA methylation biomarkers in liquid biopsies.

Heidi Pharo, Hege Marie Vedeld, Ingrid Vikan Sjurgard, Rita Pinto, Guro Elisabeth Lind.

Global cancer incidence continues to rise, emphasizing the urgent need for improved diagnostics and management strategies. DNA methylation biomarkers in liquid biopsies offer a promising, minimally invasive solution. Despite their potential, only a few tests have successfully transitioned from research to clinical practice. This review addresses key aspects influencing successful biomarker development and clinical implementation-including liquid biopsy source selection, biomarker discovery workflow and targeted validation in clinical sample series-and provide strategies to improve accuracy, reproducibility and clinical utility. Altogether, these considerations could aid in bridging the translational gap from research to clinical application, and to increase the number of clinically implemented liquid biopsy tests.

DOI: https://doi.org/10.1038/s41388-025-03624-5
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
ESMO Open. 2025 Nov 19. pii: S2059-7029(25)01773-9. [Epub ahead of print]10(12): 105904

Whole-exome ctDNA sequencing reveals intratumoral heterogeneity and drivers of relapse in locally advanced head and neck cancer.

G Bruixola, J Martín-Arana, F Gimeno-Valiente, J A Carbonell-Asins, B García-Micó, B Martínez-Castedo, D González-Camblor, N Grimalt, M García-Bartolomé, C Alfaro-Cervelló, V Escorihuela, M E Iglesias, M Maroñas, D Dualde, A Cervantes, N Tarazona.

   BACKGROUND: The mechanisms underlying tumor evolution and treatment resistance in locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are not fully understood. This study used whole-exome sequencing (WES) of paired tumor tissue and circulating tumor DNA (ctDNA) to analyze intratumoral heterogeneity (ITH) and clonal dynamics at diagnosis and relapse.
PATIENTS AND METHODS: Between January 2017 and September 2022, we enrolled 152 patients with LA-HNSCC treated with radical chemoradiotherapy. Tumor tissue and plasma samples were collected at baseline and at relapse. WES was carried out on DNA extracted from tissue, plasma, and germline samples. Oncogenic variants were analyzed to evaluate tumor evolution and ITH. Concordance, pathway alterations, and associations with survival were examined.
RESULTS: Out of the 152 patients selected, 81 were excluded based on clinical criteria. Of the 71 remaining patients, 37 had the complete set of samples of adequate quality for analysis. The most frequent mutations involved TP53 (48%), KMT2D (34%), and NOTCH1 (34%) at diagnosis. Pathogenic germline variants, including actionable mutations in BRCA2, CHK2, and KIT, were identified in 13.5% of cases. Concordance between tissue and plasma was low (median 11.8% at baseline, 12.4% at relapse), with up to 67% of oncogenic variants found only in ctDNA. Longitudinal analysis revealed limited overlap (10.3%) between baseline and relapse ctDNA, with some emerging resistance-associated mutations in PI3K-mTORC2 and ATM-CHK2 pathways. Alterations in IL6-JAK-STAT3 and RHO GTPase pathways were enriched in locoregional relapses (adjusted P < 0.001). Mutations in MMP15 and PTPRE were linked to shorter locoregional progression-free survival, whereas PDE2A mutations were associated with prolonged progression-free survival.
CONCLUSIONS: WES of ctDNA uncovers extensive ITH and identifies molecular drivers of resistance not captured by tissue biopsies. These findings support the use of plasma ctDNA analysis to monitor tumor evolution and personalize follow-up in LA-HNSCC, especially given the anatomical complexity that often limits repeated tissue sampling.

Keywords:  LA-HNSCC; biomarkers; ctDNA; intratumor heterogeneity; precision medicine

DOI:  https://doi.org/10.1016/j.esmoop.2025.105904
Nucleic Acids Res. 2025 Nov 20. pii: gkaf1242. [Epub ahead of print]

CNAScope: pan-cancer copy number aberration database with functional annotation and interactive visualization.

Xikang Feng, Jieyi Zheng, Sisi Peng, Anna Jiang, Ka Ho Ng, Chengshang Lyu, Qiangguo Jin, Lingxi Chen.

Copy number aberrations (CNAs) are critical drivers of genomic diversity in oncology, where recurrent CNAs frequently underlie tumorigenesis. However, existing public resources are limited in their somatic CNA specificity, breadth across multiple data modalities, and support for recurrent CNAs with online functional annotation and interactive visualization. Here, we present CNAScope (https://cna.fengslab.com/), a database that curates and functionally annotates over 3 954 361 CNA profiles and 3 946 319 metadata from 810 datasets, 174 464 samples, 3 018 672 single cells, and 764 232 spatial cells/spots, spanning 77 cancer subtypes from eight data sources and 55 cancer initiatives and institutions. CNAScope offers downloadable CNA annotations and interactive visualizations at bin, gene, and pathway term levels, including phylogenetic inference, clustering, dimension reduction, and focal/consensus CNA detection. Users can explore data through interactive heatmaps, phylogenetic trees, embedding plots, CN charts, and focal/consensus plots, or upload and annotate their own CNAs in real time. In all, with its large curated data volume and rich annotation capabilities, CNAScope serves as a vital resource for accelerating cancer research.

DOI: https://doi.org/10.1093/nar/gkaf1242
Curr Opin Obstet Gynecol. 2025 Nov 20.

Endometrial cancer therapy in 2026.

Victoria E Rodriguez, Miles Morrow, Rajeshree Rajpara, Dana M Chase.

   PURPOSE OF REVIEW: Endometrial cancer is one of the few cancers that has continued to rise in incidence over the past decade, necessitating novel diagnostic and treatment approaches.
RECENT FINDINGS: A revised staging system for endometrial cancer has been implemented in the last 5 years as growing attention has also been directed toward identifying biomarkers and other factors that offer deeper insights into tumor biology and therapeutic responses. Fertility-preserving therapy can be an option for younger patients when certain criteria are met. The use of immunotherapy for advanced stages (III or IV) or recurrent endometrial cancer has been studied extensively over the last 5 years, with new treatment options including checkpoint inhibitors. Recurrent cases have a particularly poor prognosis, and there have been limited options for patients. New treatments have been approved by the United States Food and Drug Administration (FDA) for recurrent endometrial cancer, leading to improved outcomes for patients.
SUMMARY: There have been improvements in endometrial cancer therapy, leading to increased survival and improved outcomes; however, there are unmet needs that need to be addressed in 2026 and beyond.

Keywords:  endometrial cancer; therapeutic approaches; treatment advances

DOI:  https://doi.org/10.1097/GCO.0000000000001078
Nat Med. 2025 Nov 21.

Turning genes into medicines.

Katherine A High.

DOI: https://doi.org/10.1038/s41591-025-04069-9