bims-tumhet 2025-08-03 papers

bims-tumhet

Biomed News

on Tumor heterogeneity

Issue of 2025–08–03
twenty papers selected by
Sergio Marchini, Humanitas Research

Decoding the Genomic and Functional Landscape of Emerging Subtypes in Ovarian Cancer.
Surgical and blood-based minimal residual disease in patients with ovarian cancer after frontline therapy: Clinical outcomes and translational opportunities.
DNA methylation in esophageal cancer: technological advances and early detection clinical applications.
Opportunistic salpingectomy for prevention of ovarian cancer among the general population.
Advancements in DNA methylation technologies and their application in cancer diagnosis.
Decrypting cancer's spatial code: from single cells to tissue niches.
Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer.
ESGO-ESTRO-ESP guidelines for the management of patients with endometrial carcinoma: update 2025.
ctDNA methylation profiling reveals NBL1 as a promising biomarker for early ovarian cancer screening.
Modeling and targeting general and chromosome-specific aneuploidy in cancer.
A Narrative Review of the Role of Non-Viral Circulating Tumor DNA Profiling in Predicting the Treatment Response and Recurrence in Head and Neck Squamous Cell Carcinoma.
Methylation-based ctDNA tumor fraction changes predict long-term clinical benefit from immune checkpoint inhibitors in RADIOHEAD, a real-world pan-cancer study.
The Cancer Genome in the Long Reads Era.
B cells are major players in cancer immunity.
Comparison of Comprehensive Genomic Profiling Testing "Ion Torrent Genexus Sequencer" With FoundationOne.
The Prognostic Role of Tertiary Lymphoid Structures and Immune Microenvironment Signatures in Early-Stage EGFR-Mutant Lung Adenocarcinoma.
Analytical validation and sequencing coverage studies suggest that performance of a liquid biopsy assay is tumor agnostic (DNA-is-DNA).
Immune memory shapes ovarian cancer recurrence.
Chemoresistance Evolution in Ovarian Cancer Delineated by Single-Cell RNA Sequencing.
The multi-dimensional role of cancer epidemiology in cancer prevention: discovery science and beyond.

Cancer Discov. 2025 Jul 31.

Decoding the Genomic and Functional Landscape of Emerging Subtypes in Ovarian Cancer.

Giulia Micoli, Kari Lavikka, Yilin Li, Anna Pirttikoski, Daria Afenteva, Wojciech Senkowski, Giovanni Marchi, Anna Vaharautio, Taru A Muranen, Titta Joutsiniemi, Sakari Hietanen, Anni Virtanen, Krister Wennerberg, Johanna Hynninen, Jaana Oikkonen, Sampsa Hautaniemi.

Ovarian high-grade serous carcinoma (HGSC) is characterized by pervasive genomic instability and high inter- and intra-tumor heterogeneity. Approximately half of HGSC tumors harbor homologous recombination deficiency (HRD), rendering them vulnerable to PARP inhibitors and platinum-based chemotherapy. In contrast, patients lacking HRD (HR-proficient, HRP) generally respond poorly to the current therapies. To overcome heterogeneity and identify relevant HGSC subtypes, we characterized the genomic landscape of 640 tumors from 243 patients using whole-genome sequencing. Our chromosomal instability (CIN) signature-based analysis characterized the structural variation landscape and revealed five HGSC subtypes, validated in an independent dataset. Two HRD subtypes, associated with BRCA1- or BRCA2-driven alterations, demonstrated favorable treatment responses. Strikingly, three HRP subtypes emerged, marked by unique structural alterations and gene expression patterns, tumor microenvironment interactions, and different chemotherapy responses. Finally, organoid experiments showed subtype-specific sensitivity to CHK1 inhibition, suggesting prexasertib as a potential targeted treatment for most currently untreatable HRP patients.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0652
Clin Cancer Res. 2025 Aug 01.

Surgical and blood-based minimal residual disease in patients with ovarian cancer after frontline therapy: Clinical outcomes and translational opportunities.

Anne Knisely, Yibo Dai, Graham L Barlow, Sanghoon Lee, Barrett Lawson, Helen Clark, Bryan Fellman, Ying Yuan, Wei Lu, Idania Carolina Lubo Julio, Rossana N Lazcano, Manoj Chelvanambi, Brenda Melendez, Bharat Singh, Bhavana Singh, Khalida Wani, Jianfeng Chen, Chih-Chen Yeh, Jianjun Gao, Sean Barnes, Ou Shi, Khaja B Khan, Alejandra G Serrano, Lorena I Gomez-Bolanos, Carly Bess Scalise, Samantha K Cheung, Punashi Dutta, Sharlene Velichko, Adam C ElNaggar, Minetta C Liu, Roni N Wilke, Jeffrey How, Lois M Ramondetta, David M Boruta, Gwyn Richardson, Aaron Shafer, Shannon N Westin, Travis Sims, Anil K Sood, Pedro T Ramirez, Alexander J Lazar, Pamela T Soliman, Karen Lu, Cara L Haymaker, Luisa M Solis Soto, Jennifer A Wargo, Rachel Grisham, Kai W Wucherpfennig, Linghua Wang, Amir A Jazaeri.

PURPOSE: Minimal residual disease (MRD) after frontline treatment of advanced stage ovarian cancer remains a longstanding barrier to cure. We investigated the prognostic and translational value of MRD detection by second look laparoscopy (SLL) and circulating tumor DNA (ctDNA) at the completion of frontline therapy.
EXPERIMENTAL DESIGN: Patients with high-grade epithelial ovarian cancer with complete clinical response to frontline therapy who underwent SLL and plasma collection for ctDNA were included. Progression-free survival (PFS) and overall survival (OS) were estimated based on MRD and clinicopathologic status. Spatial transcriptomics (GeoMx and Visium) and proteomics (CODEX) profiling were performed on serial samples from select patients.
RESULTS: Forty of 95 (42.1%) patients had surgically detected MRD, which was associated with worse PFS (median PFS 7.4 vs 23.8 months; p<0.001) and OS (median OS 33.9 vs not reached; p<0.001). SLL positivity was an independent negative prognostic factor for OS (HR 4.40, 95% CI 1.37-14.21, p=0.013) in multivariable analysis. Among 44 patients who underwent SLL and had ctDNA testing, 34% (15/44) were ctDNA-positive, which was associated with worse PFS (6.4 vs 28.1 months; p<0.001) and OS (32.4 months vs not reached; p=0.008). We demonstrated the feasibility of spatial multi-omics in studying MRD, and their ability to provide hypothesis-generating observations, implicating the upregulation of the hypoxia signaling pathway, expression of multiple druggable targets (CDK6, GLS, MSLN, ERBB2, etc.), and immune exclusion, in MRD lesions.
CONCLUSIONS: Approximately half of patients in clinical remission after frontline therapy have assessable MRD which can inform prognosis, therapeutic target discovery, and clinical trials.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0512
Front Oncol. 2025 ;15 1543190

DNA methylation in esophageal cancer: technological advances and early detection clinical applications.

Jiyu Tang, Xiaoming Shi, Chao Song, Wenjing Zhang, Yan Yan, Linchao Dai, Di Wu, Jie Qiu, Jiahuan Liu, Tao Wang, Zuhong Lu.

  Esophageal cancer (EC) is a malignant tumor with high mortality rates, where early screening and diagnosis are critical for improving patient outcomes. DNA methylation, a key epigenetic modification, has emerged as a significant biomarker for early detection of EC. The advancement in DNA methylation sequencing technologies, including first-generation and next-generation sequencing (NGS), has revolutionized the way we identify and analyze these biomarkers. First-generation sequencing, has been instrumental in identifying specific methylation sites. However, its limited throughput renders it impractical for large-scale screening of multiple samples. In contrast, NGS offers high-throughput capabilities, allowing for the simultaneous analysis of thousands of DNA fragments. NGS significantly enhances the efficiency and accuracy of DNA methylation profiling, permitting genome-wide identification of multiple methylation markers. This approach offers a promising avenue for the enhanced early detection of EC by providing a comprehensive view of the methylation landscape. The integration of NGS into clinical practice is capable of transforming EC screening by offering heightened sensitive and specific approach to identifying patients at risk. As our comprehension of the role of DNA methylation in cancer progression deepens, the development of targeted therapies based on methylation profiles may also become a reality. In conclusion, the evolution of DNA methylation sequencing technologies has unlocked new avenues for the early EC detection. While first-generation sequencing has laid the groundwork for characterizing specific methylation events, NGS has expanded the scope of screening, offering a more robust and scalable solution for identifying early-stage EC.

Keywords:  DNA methylation biomarkers; clinical application; early detection; esophageal cancer; technology of methylation

DOI:  https://doi.org/10.3389/fonc.2025.1543190
Curr Opin Obstet Gynecol. 2025 Jul 22.

Opportunistic salpingectomy for prevention of ovarian cancer among the general population.

Kirstie McLoughlin, Melissa A Merritt.

   PURPOSE OF REVIEW: Ovarian cancer remains the most lethal gynaecological cancer. Early detection and treatment options are limited, so prevention is key. This article reviews the current opinion on opportunistic salpingectomy for ovarian cancer prevention within the general population.
RECENT FINDINGS: Salpingectomy (the removal of the fimbriated ends of the fallopian tubes) reduces ovarian cancer risk without inducing early menopause or depleting ovarian reserves. The International Federation of Gynecology and Obstetrics firmly supports the use of salpingectomy opportunistically (in addition to planned abdominal surgery) for ovarian cancer risk reduction. When salpingectomy should be provided as an elective surgery, and what nongynecological surgeries can be used as opportunities for salpingectomy, is an ongoing discussion.
SUMMARY: As understanding of the safety and efficacy of opportunistic salpingectomy has solidified into guidelines, its use for ovarian cancer risk reduction has increased. However, the uptake of opportunistic salpingectomy has varied between geographic regions and across institutions. In the US, roughly a third of women undergo a hysterectomy during their lifetime, each of these women should have a chance to consider opportunistic salpingectomy for ovarian cancer prevention. Education about the benefits and harms of opportunistic salpingectomy is both necessary and effective in reducing inequities in access to this risk-reducing surgery.

Keywords:  guidelines; ovarian cancer; prevention; risk-reducing surgery; salpingectomy

DOI:  https://doi.org/10.1097/GCO.0000000000001051
Epigenetics. 2025 Dec;20(1): 2539995

Advancements in DNA methylation technologies and their application in cancer diagnosis.

Yang Yang, Xiaosha Wen, Li Wang.

  DNA methylation is a common epigenetic modification that maintains the integrity of the DNA sequence while profoundly influencing gene expression and phenotypic variation. Aberrant DNA methylation has been associated with the onset and progression of diseases, including cancer, metabolic disorders, and neurodevelopmental disorders. Recent advancements in detection technology led to a gradual increase in the exploration of DNA methylation as a valuable biomarker for cancer diagnosis and therapy. Single-base resolution has been achieved for whole-genome methylation analyses through second-generation sequencing technology, significantly enhancing detection efficiency. Additionally, PCR-based methods offer simple and feasible solutions for methylation analysis. In this review, we discuss various methods for detecting DNA methylation, focusing on bisulfite conversion-based techniques, methylation-sensitive restriction enzyme methods, enzyme conversion-based methods, third-generation sequencing approaches, and artificial intelligence. Furthermore, we briefly summarize the methylation biomarkers used for tumor diagnosis and the corresponding sample types employed. We believe that this information provides valuable insights for selecting and optimizing DNA methylation analysis tools.

Keywords:  DNA methylation biomarkers; DNA methylation technology; cancer diagnosis

DOI:  https://doi.org/10.1080/15592294.2025.2539995
Mol Oncol. 2025 Jul 25.

Decrypting cancer's spatial code: from single cells to tissue niches.

Cenk Celik, Shi Pan, Eloise Withnell, Hou Wang Lam, Maria Secrier.

  Spatial transcriptomics (ST) has emerged as a powerful tool to map gene expression patterns to the local tissue structure in cancer, enabling unprecedented insights into cellular heterogeneity and tumour microenvironments. As the technology matures, developing new, spatially informed analytical frameworks will be essential to fully leverage its potential to elucidate the complex organisation and emerging properties of cancer tissues. Here, we highlight key challenges in cancer spatial transcriptomics, focusing on three emerging topics: (a) defining cell states, (b) delineating cellular niches and (c) integrating spatial data with other modalities that can pave the way towards clinical translation. We discuss multiple analytical approaches that are currently implemented or could be adapted in the future in order to tackle these challenges, including classical biostatistics methods as well as methods inherited from geospatial analytics or artificial intelligence. In the rapidly expanding landscape of ST, such methodologies lay the foundation for biological discoveries that conceptualise cancer as an evolving system of interconnected niches.

Keywords:  AI; cancer; cell state; cellular niche; digital pathology; geospatial statistics; spatial transcriptomics

DOI:  https://doi.org/10.1002/1878-0261.70100
Cancer Cell. 2025 Jul 22. pii: S1535-6108(25)00276-4. [Epub ahead of print]

Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer.

Eleonora Ghisoni, Fabrizio Benedetti, Aspram Minasyan, Mathieu Desbuisson, Paula Cunnea, Alizée J Grimm, Noémie Fahr, Charlotte Capt, Nicolas Rayroux, Flavia De Carlo, Doga C Gulhan, Julien Dagher, David Barras, Matteo Morotti, Juan A Marín-Jiménez, Bovannak Stewen Chap, Tania Santoro, Giulia Spagnol, Mapi Fleury, Katerina Fortis, Julien Dorier, Mary K Townsend, Stephanie Tissot, Sylvie Rusakiewicz, Humberto J Ferreira, Anne I Kraemer, Michal Bassani-Stenberg, Elizabeth M Swisher, Lana A Kandalaft, Spyridon A Mastroyannis, Kathleen T Montone, Daniel J Powell, Susana Banerjee, Kathryn L Terry, Shelley S Tworoger, Mikaël J Pittet, Janos L Tanyi, George Coukos, Melissa A Merritt, Christina Fotopoulou, Jose R Conejo-Garcia, Denarda Dangaj Laniti.

  Immunotherapy has shown limited success in recurrent ovarian cancer (OC), with prognostic insights largely derived from treatment-naive tumors. We analyzed 697 tumor samples (566 primary and 131 recurrent) from 595 OC patients across five independent cohorts, capturing tumor-infiltrating lymphocytes (TILs) heterogeneity and identifying four immune phenotypes linked to prognosis and TIL:myeloid networks driving malignant progression. We found that in preclinical mouse models, mirroring inflamed human OCs, the recurrent Brca1mut tumors maintained activated TILs:dendritic cells (DCs) niches but evaded immune control through upregulation of COX/PGE2 signaling. Conversely, recurrent Brca1wt tumors displayed loss of TILs:DCs niches and accumulated immunosuppressive tumor microenvironment (TME) networks featuring Trem2/ApoEhigh tumor associated macrophages (TAMs) and Nduf4l2high/Galectin3high malignant states. Recurrent tumors recapitulate the immunogenic landscapes of original cancers. Our findings reveal BRCA-dependent TIL:myeloid crosstalk as key to persistent immunogenicity in recurrent OC and propose new targets to enhance chemotherapy efficacy.

Keywords:  PGE(2) signaling; TREM2; immune phenotype; myeloid-T cell networks; ovarian cancer; recurrence; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2025.07.005
Lancet Oncol. 2025 Aug;pii: S1470-2045(25)00167-6. [Epub ahead of print]26(8): e423-e435

ESGO-ESTRO-ESP guidelines for the management of patients with endometrial carcinoma: update 2025.

Nicole Concin, Xavier Matias-Guiu, David Cibula, Nicoletta Colombo, Carien L Creutzberg, Jonathan Ledermann, Mansoor Raza Mirza, Ignace Vergote, Nadeem R Abu-Rustum, Tjalling Bosse, Cyrus Chargari, Sophie Espenel, Anna Fagotti, Christina Fotopoulou, Sonia Gatius, Antonio González-Martin, Sigurd Lax, Bar Levy, Domenica Lorusso, Gabriella Macchia, Christian Marth, Philippe Morice, Ana Oaknin, Maria Rosaria Raspollini, Richard Schwameis, Jalid Sehouli, Alina Sturdza, Alexandra Taylor, Anneke Westermann, Pauline Wimberger, François Planchamp, Remi A Nout.

In 2023, based on advances in the understanding of the pathological and molecular features of endometrial carcinoma, an updated International Federation of Gynaecology and Obstetrics (FIGO) staging system was published, aiming to better define prognostic groups and identify relevant treatment subgroups by including factors reflecting tumour biology (histological subtypes, lymphovascular space invasion, and molecular classification) alongside refinements of anatomical factors (peritoneal carcinomatosis and lymph node metastasis). As part of its mission to improve the quality of care for people with gynaecological cancers, the European Society of Gynaecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) updated the ESGO-ESTRO-ESP evidence-based guidelines published in 2021 by incorporating this revised FIGO staging and the large body of new evidence addressing the management of endometrial carcinoma. The development process of these guidelines was based on a systematic literature review and critical appraisal process involving an international multidisciplinary development group consisting of 30 experts from relevant disciplines (gynaecological oncology, radiation oncology, medical oncology, and pathology). A patient representative was also included. Before publication, the guidelines were reviewed by 225 independent international practitioners in cancer care delivery and three patient representatives from Asia, Europe, North Africa, North America, the Middle East, and South America to ensure a global perspective. These guidelines comprehensively cover diagnosis, management, follow-up, and patient education. Management includes surgical and adjuvant therapy according to the stage of the disease, and metastatic and recurrent disease. The management algorithms and the principles of radiotherapy and pathological evaluation are also defined.

DOI: https://doi.org/10.1016/S1470-2045(25)00167-6
World J Surg Oncol. 2025 Jul 28. 23(1): 305

ctDNA methylation profiling reveals NBL1 as a promising biomarker for early ovarian cancer screening.

Shunxian Zhou, Huan Yin, Lei Yan, Nian Xie, Chun Fu.

   BACKGROUND: Early detection of epithelial ovarian cancer (EOC) is crucial for improving patient survival. Current screening methods have limitations, highlighting the need for novel biomarkers. Circulating tumor DNA (ctDNA) methylation analysis offers a promising approach.
METHODS: This study included 10 patients with EOC and 10 patients with benign pelvic masses. We collected plasma samples from these patients and isolated ctDNA. We then conducted whole-genome methylation sequencing using the TAPS (TET-assisted pyridine borane sequencing) method, which allows for single-base resolution detection of 5-methylcytosine and 5-hydroxymethylcytosine. Bioinformatics analysis was performed to identify differentially methylated genes and regions. We further validated candidate biomarkers using bisulfite sequencing, qRT-PCR, and IHC. TCGA methylation data were analyzed for external validation.
RESULTS: We identified 35 differentially methylated genes, with NBL1 and CASZ1 as potential candidates. NBL1 gene hypermethylation in EOC patients was significantly associated with reduced mRNA expression, suggesting its role as a tumor suppressor gene. CASZ1 methylation patterns were inconsistent between blood and tissue, indicating limited utility as a diagnostic biomarker. We also observed widespread hypo-methylation across the genome and hyper-methylation in specific regions of differential methylation. GO and KEGG pathway enrichment analyses revealed that the differentially methylated genes were involved in various biological processes and pathways relevant to cancer pathogenesis. There is a significant negative correlation between the methylation level and the mRNA level of the NBL1 gene, suggesting that hypermethylation of the NBL1 gene may be associated with a reduction in its expression. Furthermore, immunohistochemical analysis indicates a downregulation of NBL1 expression in ovarian cancer tissues, which contrasts with the strong positive expression observed in benign tissues.
CONCLUSION: Our study demonstrates the potential of ctDNA methylation analysis for early EOC detection. we propose that NBL1 gene hold potential as screening biomarkers for ovarian cancer.

Keywords:  CtDNA methylation; Early detection; Epithelial ovarian cancer; NBL1

DOI:  https://doi.org/10.1186/s12957-025-03957-1
Genes Dev. 2025 Jul 28.

Modeling and targeting general and chromosome-specific aneuploidy in cancer.

Aleah Goldberg, Maria Trifas, Teresa Davoli.

  Throughout the last century, aneuploidy has been cemented as a hallmark of cancer. Although the association of aneuploidy with tumorigenesis has been well established, the role of these genetic imbalances in tumor formation has only recently begun to be elucidated. Advancements in genomics have revealed the complexity and context dependence of the effect of aneuploidy on cancer growth, while developments in genetic editing have allowed for proper modeling of specific aneuploidies. In this review, we discuss the key factors to consider when studying the role of aneuploidy in cancer and the tools that are available to do so. We then highlight recent studies that establish phenotypic contributions of aneuploidy to tumorigenicity. In particular, we highlight how general aneuploidy and chromosomal instability affect the tumor microenvironment and how specific chromosomal alterations, including the loss of chromosome 9p and the gain of chromosomes 8q and 1q, influence tumor behavior and therapeutic responses. Finally, we emphasize the potential of targeting aneuploidy-induced vulnerabilities to improve cancer treatment outcomes.

Keywords:  aneuploidy; cancer genomics; cell biology; chromosome; genome instability

DOI:  https://doi.org/10.1101/gad.352766.125
Cancers (Basel). 2025 Jul 09. pii: 2279. [Epub ahead of print]17(14):

A Narrative Review of the Role of Non-Viral Circulating Tumor DNA Profiling in Predicting the Treatment Response and Recurrence in Head and Neck Squamous Cell Carcinoma.

Ugur Gezer, Rasim Meral, Emre Özgür, Ebru E Yörüker, Abel Bronkhorst, Stefan Holdenrieder.

  Head and neck squamous cell carcinomas (HNSCCs) that develop from the mucosal epithelium in the oral cavity, pharynx, and larynx are a heterogeneous group of malignant tumors. A lack of appropriate screening and diagnostic methods leads to late diagnoses, with the majority of patients having locally advanced disease, which is associated with a high risk of local recurrence and a poor prognosis and is usually treated with combination therapies. Biomarkers for predicting the therapy response and risk of recurrence in HNSCC patients are urgently needed. Liquid biopsy, e.g., the profiling of circulating biomarkers in bodily fluids, is a promising approach with increasing utility in the early detection and diagnosis of cancer, monitoring cancer progression, patient stratification and treatment selection, detecting minimal residual disease (MRD), and predicting recurrence across different cancer types, including HNSCC. Among liquid biomarkers, circulating tumor DNA (ctDNA), which is based on detecting tumor-specific mutations, insertions/deletions, copy number alterations, and methylation, is the most promising transformative tool in cancer management and personalized cancer treatment. In this review, we provide an update of recent data on the role of non-viral ctDNA in the management of HNSCC patients. Accumulating data suggests the enormous potential of ctDNA profiling by serial sampling during and after definitive therapy in detecting MRD and predicting recurrence in HNSSC patients treated with a single treatment modality (surgery or radiotherapy) or with combination therapies, including immune-checkpoint-inhibitor-based immunotherapy. By incorporating the latest immunotherapy trials and organizing the data by the treatment modality, this review offers a novel perspective not found in previous surveys.

Keywords:  chemoradiation; ctDNA; head and neck squamous cell carcinoma; immunotherapy; radiotherapy; treatment

DOI:  https://doi.org/10.3390/cancers17142279
Cancer Res Commun. 2025 Jul 29.

Methylation-based ctDNA tumor fraction changes predict long-term clinical benefit from immune checkpoint inhibitors in RADIOHEAD, a real-world pan-cancer study.

Samantha I Liang, Zoe Quandt, Sara Wienke, Jing Wang, Sean Gordon, Reagan M Barnett, Jude Masannat, Kyle Chang, Carin R Espenschied, Katie J Quinn, Kimberly C Banks, Enjun Yang, John E Connolly.

Current response evaluation methods have accuracy limitations. Monitoring with a circulating tumor DNA (ctDNA) methylation-based tumor fraction (TF) may provide a more accurate assessment of tumor burden across solid tumors. In this study, we evaluate a tissue-free, methylation-based TF and explore the association with treatment outcomes in RADIOHEAD, a cohort of 1,070 patients with solid tumors receiving standard of care (SoC) ICI regimens, with blood samples collected prospectively for retrospective analysis. 1,997 baseline and serial on-treatment plasma samples from 627 patients with stage IV cancer were analyzed with an analytically validated next-generation sequencing (NGS) methylation-based ctDNA assay (Guardant Reveal). The primary outcome measure was real-world progression-free survival (rwPFS). Secondary outcomes included real-world overall survival (rwOS) and the lead time between non-molecular response (nMR) to rwPFS event. Patients with any decrease in TF while receiving ICI had superior outcomes. Patients with >80% decrease in TF at two timepoints or TF below the limit of quantification (LOQ) had longer rwPFS and rwOS than those with <80% decrease (nMR) (rwPFS HR 0.24 [95% CI 0.19, 0.32] p<0.005; rwOS HR 0.28 [95% CI 0.21, 0.38] p<0.005). nMR was detected prior to clinical progression in 209 patients with a median lead time of 3.03 months. Among 627 stage IV cancer patients receiving SoC ICI, monitoring with methylation-based TF identified patients who have significantly longer rwPFS and rwOS. Changes in TF on ICI can provide additional response data earlier than imaging alone and support the potential of serial monitoring to inform treatment decisions.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0151
Methods Mol Biol. 2025 ;2955 317-359

The Cancer Genome in the Long Reads Era.

Luca Ermini.

  Cancer genomics, driven by advancements in sequencing technologies, is rapidly transforming our understanding of tumor biology. The advent of high-throughput short-read sequencing technologies has enabled a paradigm shift in cancer genomics, providing unprecedented resolution of mutations that drive tumorigenesis. Initially, short-read sequencing dominated the field, revealing the repertoire of mutational signatures and the complexities of tumor heterogeneity. However, the inherent limitations of short-read sequencing, particularly in resolving complex structural variations and repetitive regions, underscored the need for alternative approaches. This chapter delves into the transformative potential of long-read sequencing in overcoming these limitations, ushering in a new era for cancer genomics. By spanning larger genomic regions, long-reads offer a more comprehensive view of structural variations, phasing information, and complex rearrangements, crucial for deciphering the evolutionary trajectories of cancer. Furthermore, the chapter examines the dynamics of somatic evolution, comparing Darwinian and non-Darwinian frameworks, and discusses how these models inform our understanding of cancer progression which have implications for cancer therapies. Finally, a bioinformatics workflow, leveraging long-read sequencing data, is outlined to enable the identification of cancer-associated mutations. Integrating cutting-edge sequencing technologies with advanced computational approaches is essential for accelerating oncological research and improving cancer therapies. Long-read sequencing is poised to unveil the complex genomic architecture of cancers, potentially leading to more precise and effective treatments.

Keywords:  Bioinformatics; Cancer evolution; Cancer genome; Genomics; Next and third generation sequencing

DOI:  https://doi.org/10.1007/978-1-0716-4702-8_15
Immunol Lett. 2025 Jul 30. pii: S0165-2478(25)00097-5. [Epub ahead of print] 107064

B cells are major players in cancer immunity.

Théo Bouloudani, Guilhem Pupier, Catherine Sautès-Fridman, Wolf Herman Fridman.

  The discovery of Tertiary Lymphoid Structures (TLS) within tumors has reshaped our understanding of cancer immunity. Unlike the classical view that immune responses are solely initiated in lymph nodes, TLS, ectopic lymphoid aggregates resembling secondary lymphoid organs, can form in the tumor microenvironment (TME). These structures contain T cells, B cells, dendritic cells (DC) presenting antigenic peptides to T cells in the T cell zone of TLS, and follicular dendritic cells (FDC) which are stromal cells involved in the formation of germinal centers (GCs) and presenting antigens, under the form of immune complexes, to B cells. Mature TLS with GCs support B cell differentiation into antibody-producing plasma cells (PCs). Clinical studies reveal that TLS presence correlates with improved survival and response to immunotherapy across multiple cancers, including melanoma, NSCLC, and renal cell carcinoma. Notably, B cells within TLS undergo clonal expansion, somatic hypermutation, and isotype switching, generating tumor-reactive antibodies (IgG, IgA). IgG-opsonized tumor cells can be eliminated by macrophages or NK cells via antibody-dependent cell mediated cytotoxicity or apoptosis by macrophages via antibody-dependent phagocytosis whereas IgA may have dual roles, sometimes promoting immunosuppression. Additionally, B cells enhance antigen presentation to T cells, amplifying anti-tumor responses. Emerging strategies aim to induce TLS formation (e.g., via CXCL13, lymphotoxins…) or harness B cells for adoptive therapies. Future research should clarify tumor-specific antibody targets and optimize TLS induction to enhance immunotherapy. In summary, TLS and B cells are pivotal in shaping anti-tumor immunity, offering novel biomarkers and therapeutic avenues for cancer treatment.

Keywords:  B cells; Tertiary lymphoid structures; cancers; checkpoint blockade; immunotherapy; response

DOI:  https://doi.org/10.1016/j.imlet.2025.107064
Anticancer Res. 2025 Aug;45(8): 3479-3486

Comparison of Comprehensive Genomic Profiling Testing "Ion Torrent Genexus Sequencer" With FoundationOne.

Kenji Fujiyoshi, Rie Sugihara, Naoki Miyamoto, Yoriko Watanabe, Tomoya Sudo, Sanae Numata, Jun Akiba, Hideyuki Abe, Yuka Ichinose, Kenji Inoue, Shuichi Ozono, Takeharu Ono, Kentaro Orioka, Masaki Kashihara, Ryousuke Kajiwara, Hiroyuki Kawano, Akihiko Kawahara, Ryuta Takase, Uhi Toh, Kazuaki Hashimoto, Toru Hisaka, Shingo Hirai, Masahiro Mitsuoka, Daiki Miyazaki, Fumi Yoshitomi, Ken Yamamoto, Hirohito Umeno, Masahisa Nomura, Yoshiki Naito.

   BACKGROUND/AIM: Comprehensive genomic profiling (CGP) with tissue- and blood-based next-generation sequencing (NGS) is integral to the delivery of personalized medicine for targeted cancer therapy. This study aimed to evaluate the variant concordance for somatic variants using two clinical NGS systems for conducting both tissue- and blood-based analyses: Genexus-OCA v3 (OCA) vs. FoundationOne CDx (F1) for tissues and Genexus OPA (OPA) vs. FoundationOne CDx Liquid (F1L) for blood.
PATIENTS AND METHODS: The concordance of genomic alterations between the two NGS analyses was compared in six patients with breast, head, and neck cancers using tissue and circulating tumor DNA biopsies.
RESULTS: A total of 130 genes were common between F1 and OCA, and 41 between F1L and OPA. When comparing FoundationOne to Genexus for common genes, the sensitivity and specificity of OCA and OPA were 55% and 99%, respectively. Nine single-nucleotide variants (SNVs), one copy number alteration (CNA), and one fusion were detected by both Genexus and FoundationOne. However, one SNV (MAP2K1 F53V), two CNAs (AKT3 and MYC), and one fusion (ESR-CCDC170) were detected only in Genexus, whereas two SNVs (TP53 Q331* and KRAS G12V) were detected only in FoundationOne.
CONCLUSION: The two cancer genome panels were equivalent but not perfect in terms of the detection of variants using tissue and blood, indicating that different assays and analytical methods may have influenced the results. When performing CGPs, it is important to consider the characteristics of each NGS-based CGP test and the genetic variants associated with each disease.

Keywords:  CGP; ctDNA; liquid biopsy; precision medicine

DOI:  https://doi.org/10.21873/anticanres.17709
Cancers (Basel). 2025 Jul 17. pii: 2379. [Epub ahead of print]17(14):

The Prognostic Role of Tertiary Lymphoid Structures and Immune Microenvironment Signatures in Early-Stage EGFR-Mutant Lung Adenocarcinoma.

Wei-Hsun Hsu, Chia-Chi Hsu, Min-Shu Hsieh, James Chih-Hsin Yang.

   BACKGROUND/OBJECTIVES: The role of tertiary lymphoid structures (TLSs) in cancer prognosis is well established, yet their significance in early-stage EGFR-mutant lung adenocarcinoma remains unclear. While outcomes for early-stage lung cancer are generally better than those of late-stage disease, recurrence remains a significant challenge. This study investigates the prognostic value of TLSs and their molecular characteristics in early-stage EGFR-mutant lung adenocarcinoma.
METHODS: TLSs were identified in tumor samples using multiplex immunohistochemistry (IHC), and their density was quantified. The PD-L1 tumor proportion score (TPS) and TLS density were analyzed for associations with disease-free survival (DFS). Gene expression profiling was performed to compare tumor microenvironment signatures between high- and low-TLS-density groups.
RESULTS: High TLS density correlated with significantly longer DFS (43 vs. 20.5 months, p = 0.0082). No relationship was found between TLS density and PD-L1 TPS or EGFR mutation subtype. Transcriptomic analysis revealed upregulated immune response genes in the high-TLS-density group, including those involved in T and B cell activation. Low-TLS-density tumors exhibited gene signatures promoting tumor growth, such as cell cycle and WNT pathway activation.
CONCLUSIONS: In summary, TLS density is a potential prognostic biomarker for DFS in early-stage EGFR-mutant lung adenocarcinoma, independent of PD-L1 TPS or EGFR mutation subtype. Enhanced immune activation in high-TLS-density tumors highlights TLSs as a potential target for improving outcomes in these patients.

Keywords:  EGFR-mutant lung adenocarcinoma; disease-free survival; tertiary lymphoid structure; tumor immune microenvironment

DOI:  https://doi.org/10.3390/cancers17142379
PLoS One. 2025 ;20(8): e0329392

Analytical validation and sequencing coverage studies suggest that performance of a liquid biopsy assay is tumor agnostic (DNA-is-DNA).

Wei Meng, Russell Petry, Norberto Pantoja Galicia, Allison van den Hout, Jessie Yu, Siliang Gong, Dhara Shah, Daokun Sun, Cui Guo, Shannon Bailey, Daniela Munafo, Ryan Woodhouse, Elizabeth Mansfield, Varun Pattani, Steven Perrault, Jun Zhou, Christine Vietz, Meijuan Li, Richard S P Huang.

Per regulatory and standard requirements (e.g., Clinical & Laboratory Standards Institute (CLSI) guidelines, United States Food and Drug Administration (FDA) correspondence), analytical validation (AV) for each companion diagnostic (CDx) biomarker should be repeated using a clinical sample set for each cancer type listed as an indication in labelling for a CDx. Using data from AV studies and Foundation Medicine (FMI)'s clinical database, we evaluated the hypothesis that analytical performance of the FoundationOne®Liquid CDx (F1LCDx) assay is not impacted by cancer type and that large sets of clinical, tumor-specific samples might not be necessary for analytical validation of specific CDx biomarkers. We retrospectively evaluated all liquid biopsy samples from F1LCDx assay AV studies that were executed between April 2019 and November 2021 and clinical samples processed by F1LCDx between September 2020 and October 2021. For the samples from AV studies, we evaluated the precision and concordance performance by F1LCDx between tumor types; and for the clinical samples, we performed analyses comparing the distribution of coverage between tumor types. A total of 31,247 F1LCDx clinical samples and 579 samples from F1LCDx AV studies with a total of 335 disease ontologies (DOs) were included in this study. For precision: the median absolute pairwise difference of mean reproducibility between any pairs of two tumor types is 0.94% [0.01%-2.63%] and the median absolute pairwise difference of mean repeatability between any pairs of two tumor types is 0.91% [0.03%-2.98%]. For concordance: the median absolute [Formula: see text] between any pairs of two tumor types is 1.39% [0.1%-4.1%] and the median absolute [Formula: see text] between any pairs of two tumor types is 0.05% [0%-1%]. For coverage, a similar distribution was observed between tumor types using F1LCDx clinical samples. Herein, the results based on the extensive cohort of 31,826 liquid biopsy samples sequenced by the F1LCDx assay demonstrated that both analytical assessment of precision and concordance and coverage are comparable among tumor types (i.e., deoxyribonucleic acid (DNA) is DNA). The tumor type that circulating tumor DNA (ctDNA) was derived from is therefore not a vital consideration for AV studies for F1LCDx assay.

DOI: https://doi.org/10.1371/journal.pone.0329392
Cancer Cell. 2025 Jul 16. pii: S1535-6108(25)00174-6. [Epub ahead of print]

Immune memory shapes ovarian cancer recurrence.

Analisa DiFeo.

Despite current progress, many patients with ovarian cancer (OC) often relapse after therapy. In this issue of Cancer Cell, Ghisoni et al. integrate multiomic and functional analyses to provide a roadmap for biomarker-driven therapy in OC and suggest that immune phenotyping could be incorporated into clinical stratification.

DOI: https://doi.org/10.1016/j.ccell.2025.05.001
Int J Mol Sci. 2025 Jul 15. pii: 6760. [Epub ahead of print]26(14):

Chemoresistance Evolution in Ovarian Cancer Delineated by Single-Cell RNA Sequencing.

Yuanmei Wang, Zongfu Tang, Haoyu Li, Run Zhou, Hao Wu, Xiaoping Cen, Yi Zhang, Wei Dong, Huanming Yang.

  High-grade serous ovarian cancer (HGSOC) is an aggressive gynecological malignancy characterized by intraperitoneal spread and chemotherapy resistance. Chemotherapies have demonstrated limited effectiveness in HGSOC, underscoring the urgent need to evaluate how the tumor microenvironment (TME) was reshaped by chemotherapy in different sites of tumor foci. In this study, we performed single-cell transcriptomic analysis to explore the TME in samples obtained from various sites of tumor foci, with or without the history of Neoadjuvant chemotherapy (NACT). We discovered that chemotherapy reshaped the tumor immune microenvironment, evident through the reduction in human leukocyte antigen (HLA) diversity and the increase in PDCD1/CD274 in CD8_ANXA1, LAMP3+ dendritic cell (DC_LAMP3), and EREG+ monocytes (mono_EREG). Moreover, cancer.cell.2, cancer-associated C3+ fibroblasts (CAF_C3), and Fibrocyte_CD34, which are prone to accumulate in the metastatic site and post-NACT group, harbored poor clinical outcome, reflected in the immune exclusion and tumor progression signaling. Cell-cell communication identified a stronger interaction between cancer.cell.2 and CAF_C3, as well as Fibrocyte_CD34, in post-NACT samples, indicating that chemotherapy reshapes pre-existing cell clusters in a site-dependent manner. Our findings suggest that chemotherapy and sites of foci were critical for the transcriptional reprogramming of pre-existed cell clusters. Our study offers a single-cell phenotype data substrate from which to develop a personalized combination of chemotherapy and immunotherapy.

Keywords:  high-grade serous ovarian cancer; neoadjuvant chemotherapy; single-cell RNA sequence; transcriptome reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms26146760
J Natl Cancer Inst. 2025 Jul 30. pii: djaf200. [Epub ahead of print]

The multi-dimensional role of cancer epidemiology in cancer prevention: discovery science and beyond.

Amy Berrington De Gonzalez, Marc J Gunter, Mary K Schubauer-Beriganl, Montserrat Garcia-Closas.

The pivotal role of epidemiology in the identification of the causes of cancer is well recognised. However, after this identification the translation of those findings into cancer prevention typically requires further epidemiological research. The role of cancer epidemiology in these next steps and other aspects of cancer prevention, is perhaps, less well appreciated. Here we describe a framework for the multi-dimensional role of cancer epidemiology in cancer prevention including: 1) hazard identification 2) risk assessment 3) understanding natural history and 4) evaluating biological targets for prevention. The approaches required will vary depending on the type of prevention strategy. For example, primary prevention will usually require hazard identification and risk assessment and/or burden estimation, whereas secondary prevention will require studies of the natural history of disease. We describe the types of epidemiological study designs that are used to address these four dimensions and the role of novel methods in their success. We illustrate this with five examples: occupational radiation exposure, menopausal hormone therapy, per- and polyfluoroalkyl substances, obesity and lung CT screening. These examples show how the framework provides a systematic approach to define research questions and interpret results in the context of cancer prevention. This broader view of the field of cancer epidemiology also requires broader measures of success that go beyond the discovery of causes and estimates of population attributable fractions, through to reductions of harmful exposures and eventually lowering of cancer incidence and mortality in the affected populations.

DOI: https://doi.org/10.1093/jnci/djaf200