Cancers

22 pages, 1303 KB

Open AccessArticle

In-Treatment Kinetics of Peripheral Blood Immune Markers in PD-L1 High Non-Small Cell Lung Cancer and Prognostic Relevance for Immunotherapy Outcomes

by Ioannis P. Trontzas, Ioanna-Evdokia Galani, Emmanouil Panagiotou, Efthymia Theofani, Anastasia Georganta, Konstantinos G. Kyriakoulis, Anastasia Palaiologou, Ioannis Vathiotis, Constantin Tamvakopoulos, Evangelos Andreakos and Konstantinos N. Syrigos

Cancers 2026, 18(10), 1623; https://doi.org/10.3390/cancers18101623 (registering DOI) - 17 May 2026

Abstract

Background: A substantial proportion of patients with non-small cell lung cancer (NSCLC) derive limited clinical benefit from immunotherapy. Monitoring of peripheral blood immune markers (PBIMs) may emerge as a useful tool to predict treatment outcomes with immune checkpoint inhibitors (ICIs). Patients/Methods: We prospectively [...] Read more.

Background: A substantial proportion of patients with non-small cell lung cancer (NSCLC) derive limited clinical benefit from immunotherapy. Monitoring of peripheral blood immune markers (PBIMs) may emerge as a useful tool to predict treatment outcomes with immune checkpoint inhibitors (ICIs). Patients/Methods: We prospectively measured several PBIMs in a PD-L1 high (TPS ≥ 50%) NSCLC cohort of patients treated with first-line pembrolizumab monotherapy. Kinetics over the first year of treatment were assessed at baseline (T0) and at 21 days (T1), 3 months (T2), 6 months (T3) and at 1 year (T4) post-treatment initiation. Associations with clinical outcomes were explored after a 2-year follow-up period. Results: In total, 31 patients with PD-L1 high locally advanced or metastatic NSCLC were prospectively enrolled. Over the first year of treatment, levels of CRP, IL-17α, IL-6, and IL-8 were significantly decreased. Early kinetics analysis showed significant decrease in total leukocytes, neutrophils, CRP, and MIP-3α/CCL20, as well as significant transient elevation of ITAC/CXCL11, IL-1β, IL-7, and TNFα, during the first 3 months of treatment. Early percent changes (Δ% at T1 and at T2) of ‘low’ vs. ‘high’ pretreatment levels showed significant differences for LDH, ITAC/CXCL11, GM-CSF, MIP-1α/CCL3, IL-2, IL-4, IL-5, and sPD-L1. Longitudinal analysis, stratified per responders and for pre-progression fluctuations, did not reveal significant findings. Among markers with acceptable discriminative performance, higher baseline CRP, complement C4, and IL-6 levels were associated with poorer clinical outcomes. In multivariable analysis, only C4 retained independent prognostic significance; however, integration of these PBIMs into composite indices improved prognostic performance. Conclusions: In this prospective study, longitudinal monitoring of PBIMs provided descriptive insights into immune and inflammatory dynamics during pembrolizumab treatment; however, no significant associations were observed between in-treatment biomarker kinetics and clinical outcomes. In exploratory analyses, baseline CRP, complement C4, and IL-6 levels were associated with clinical outcomes, and their integration into composite indices improved prognostic performance. These findings suggest that specific baseline PBIMs may carry prognostic relevance, while the role of in-treatment monitoring remains to be further clarified in larger prospective studies. Full article

(This article belongs to the Special Issue The Future of Cancer Immunotherapy: Biomarkers, Tumor Microenvironment, and Precision Medicine)

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17 pages, 1935 KB

Open AccessArticle

Twelve-Month Metastatic State as a Landmark-Based Prognostic Stratifier in Metastatic Sarcoma

by Theodoros Loupasis, Janet Ruthenberg, Bettina Vogel, Markus Schärer, Georg Schelling, Philip Heesen, Gabriela Studer, Bruno Fuchs and on behalf of the Swiss Sarcoma Network

Cancers 2026, 18(10), 1622; https://doi.org/10.3390/cancers18101622 (registering DOI) - 17 May 2026

Abstract

Background: Prognostic assessment in metastatic sarcoma remains challenging, and baseline variables may not adequately reflect outcome after metastatic onset. We investigated whether the 12-month landmark provides clinically relevant prognostic stratification for post-metastasis survival, while institution was examined as a contextual and adjustment variable [...] Read more.

Background: Prognostic assessment in metastatic sarcoma remains challenging, and baseline variables may not adequately reflect outcome after metastatic onset. We investigated whether the 12-month landmark provides clinically relevant prognostic stratification for post-metastasis survival, while institution was examined as a contextual and adjustment variable rather than as the primary analytic focus. Methods: This retrospective observational study was based on prospectively collected real-world-time clinical data from two sarcoma centers. Overall survival (OS) and post-metastasis survival (PMS) were first analyzed descriptively across the two contributing centers using Kaplan–Meier methods. The principal analysis was a landmark-based prognostic stratification of PMS from 12 months after first metastatic documentation, with patients classified at the landmark as oligometastatic or polymetastatic. Univariable and multivariable Cox regression models were used to assess prognostic associations. Results: A total of 236 patients were included (135 at Institution A and 101 at Institution B). Crude OS was broadly comparable between institutions, whereas PMS showed a numerical separation. In the landmark analysis, metastatic state at 12 months clearly stratified subsequent PMS, with persistent oligometastatic disease associated with more favorable outcome than polymetastatic disease. In the reduced multivariable landmark model, polymetastatic state at 12 months remained the strongest independent predictor of inferior PMS (HR 3.09, 95% CI 1.87–5.09; p = 0.00001). High histologic grade also retained independent adverse prognostic significance (G3 vs. G1: HR 5.16, 95% CI 1.59–16.79; p = 0.006), whereas institution showed only a non-significant trend after adjustment (HR 0.67, 95% CI 0.42–1.07; p = 0.094). Conclusions: In metastatic sarcoma, realized metastatic state at 12 months provides stronger landmark-based prognostic stratification for post-metastasis survival than crude institutional comparison. These findings support a longitudinal state-based prognostic framework in which survival after metastatic onset is more informatively stratified by disease state at the 12-month landmark than by crude center attribution. Full article

(This article belongs to the Section Cancer Metastasis)

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18 pages, 1272 KB

Open AccessReview

The Immunologic Paradox of BTK Inhibitors in Chronic Lymphocytic Leukemia: Selectivity, Hypogammaglobulinemia, and Infection Risk

by Mihaela Andreescu, Sorin Ioan Tudorache, Cosmin Alec Moldovan, Adina-Diana Moldovan, Daniel Cochior, Viola Popov, Bogdan Andreescu, Diana Ionescu and Monica-Daniela Padurariu-Covit

Cancers 2026, 18(10), 1621; https://doi.org/10.3390/cancers18101621 (registering DOI) - 17 May 2026

Abstract

Bruton’s tyrosine kinase (BTK) inhibitors have revolutionized B-cell malignancy treatment but paradoxically increase infection susceptibility. Covalent BTK inhibitors (Ibrutinib, Acalabrutinib, Zanubrutinib) induce sustained BTK blockade but disrupt immune homeostasis through off-target effects on T-cell and myeloid signaling, contributing to hypogammaglobulinemia and increased risk [...] Read more.

Bruton’s tyrosine kinase (BTK) inhibitors have revolutionized B-cell malignancy treatment but paradoxically increase infection susceptibility. Covalent BTK inhibitors (Ibrutinib, Acalabrutinib, Zanubrutinib) induce sustained BTK blockade but disrupt immune homeostasis through off-target effects on T-cell and myeloid signaling, contributing to hypogammaglobulinemia and increased risk of bacterial, viral, and opportunistic fungal infections. Non-covalent inhibitors (Pirtobrutinib) and emerging BTK degraders offer more selective inhibition, preserving T-cell function and potentially mitigating infection risk, though their long-term immunological impact requires further study. Infection susceptibility varies across BTK inhibitor generations, reflecting differences in kinase selectivity, modulation of humoral and cellular immunity, and disease-intrinsic immune dysfunction in chronic lymphocytic leukemia. This review examines the mechanistic basis of BTK inhibitor-associated immune dysfunction, compares generational differences in selectivity and safety profiles, and provides evidence-based recommendations for infection risk mitigation in clinical practice. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: From Genetics to Therapy)

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22 pages, 13715 KB

Open AccessReview

Understanding the Interplay Between Obesity and Cancer: From Mechanisms to Therapeutic Opportunities

by Sunsook Hwang, Byungjoo Kim, Seungyeon Yang and Seung Min Jeong

Cancers 2026, 18(10), 1620; https://doi.org/10.3390/cancers18101620 (registering DOI) - 17 May 2026

Abstract

Obesity has risen to the forefront of global public health challenges, particularly due to its association with several chronic diseases. Its association with cancer has attracted significant research interest. The relationship between obesity and cancer is complex and profoundly influences tumorigenesis, cancer progression, [...] Read more.

Obesity has risen to the forefront of global public health challenges, particularly due to its association with several chronic diseases. Its association with cancer has attracted significant research interest. The relationship between obesity and cancer is complex and profoundly influences tumorigenesis, cancer progression, metastasis, and therapeutic efficacy. This review provides the molecular basis of these interactions, elucidating how obesity triggers changes in the tumor microenvironment, disrupts metabolic pathways, and promotes inflammation. These factors facilitate cancer development and reduce the efficacy of treatments. By unraveling these mechanisms, we aim to identify therapeutic strategies that could mitigate obesity’s detrimental effects on cancer outcomes and contribute to the development of more effective strategies for managing obesity-related cancers. Full article

(This article belongs to the Section Molecular Cancer Biology)

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29 pages, 4598 KB

Open AccessArticle

Therapeutically Engineering Exosomes to Target CD206+ M2 Macrophages to Prevent the Development of Primary Tumors and Distal Metastases in Breast Cancers

by Mahrima Parvin, Ahmet Alptekin, Sawaiz Kashif, Fowzia A. Selina, Mst Anika Bushra, Mohammad Syam, Mohammad H. Rashid, Alicia Arnold, Yutao Liu, Santhakumar Manicassamy, Hasan Korkaya and Ali S. Arbab

Cancers 2026, 18(10), 1619; https://doi.org/10.3390/cancers18101619 (registering DOI) - 16 May 2026

Abstract

Background/objective: Approximately 90% of breast cancer-related deaths result from recurrence and metastasis. Emerging evidence indicates that tumor recurrence, invasion, and metastatic spread are strongly influenced by both the tumor microenvironment (TME) and the metastatic niche. M2 macrophages promote immune suppression, inhibit inflammation, [...] Read more.

Background/objective: Approximately 90% of breast cancer-related deaths result from recurrence and metastasis. Emerging evidence indicates that tumor recurrence, invasion, and metastatic spread are strongly influenced by both the tumor microenvironment (TME) and the metastatic niche. M2 macrophages promote immune suppression, inhibit inflammation, and facilitate epithelial-to-mesenchymal transition, invasion, neovascularization, and tumor progression. These phenomena are particularly pronounced in triple-negative breast cancer (TNBC). The objectives of this study were to develop engineered exosomes to selectively deplete CD206+ M2 macrophages from the TME to delay the growth of primary tumors and distal metastasis and enhance overall survival. Methods: Engineered exosomes were developed using our invented platform to selectively target and deplete alternatively activated CD206+ M2 macrophages in primary and metastatic TMEs via antibody-dependent cell-mediated cytotoxicity (ADCC). The engineered exosomes were characterized for size, zeta potential, and successful incorporation of targeting peptides and proteins. Whole-body and tumor-specific biodistribution were assessed. In vitro and in vivo experiments were conducted to evaluate targeting specificity. Toxicity and immunogenicity were examined in immunocompetent animal models. Two treatment paradigms were employed. Results: Engineered exosomes containing M2 macrophage-targeting peptides and Fc-mIgG2b were successfully made, and no significant size difference was observed between the engineered and control exosomes. Both in vitro and in vivo studies confirmed the specificity of the engineered exosomes. Biodistribution studies showed no significant uptake or retention by the resident macrophages in the lung and liver. No significant immune activation, based on cytokine profiling, or organ-specific toxicity was observed in immunocompetent models. Flow cytometry studies using splenocytes showed significant depletion of M2 macrophages following treatments with engineered exosomes; however, no effect on the distribution of T cells was observed. M2-targeting engineered exosomes significantly delayed the post-resection recurrence and metastasis of tumors, and improved animal survival. Conclusions: These findings support the potential of precision exosome-based strategies for enhancing therapeutic outcomes in breast cancer. Full article

(This article belongs to the Topic Extracellular Vesicles: Isolation, Characterization, Function, Application and Utility)

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24 pages, 1614 KB

Open AccessArticle

Leveraging Ensemble Machine Learning Models for the Detection of Primary Myelofibrosis in Electronic Health Records

by Arkadiusz Sycz, Michal J. Dabrowski, Kinga Marciniak, Aleksandra Jurczuk, Anna Meryn, Michał Konopelko, Marek Dudziński, Mirosław Markiewicz, Wojciech Homenda, Marta Sobas, Łukasz Szukalski, Karolina Kaczorowska-Bilska, Agnieszka Gala-Błądzińska, Szymon Fornagiel, Jarosław Piszcz, Grzegorz Helbig, Patryk Węglarz, Sylwia Kot, Paweł Turczyn, Brygida Kwiatkowska, Marcin Rymko, Artur Przelaskowski, Grzegorz W. Basak and Karol Lis Show full author list Hide full author list

Cancers 2026, 18(10), 1618; https://doi.org/10.3390/cancers18101618 (registering DOI) - 16 May 2026

Abstract

Background and Objectives: Primary myelofibrosis (PMF) is a rare hematologic malignancy with non-specific symptoms, causing diagnostic delays and missed diagnoses. Automated screening in heterogeneous electronic health records (EHRs) is challenging due to class imbalance, data sparsity, and incomplete labeling. We investigated two [...] Read more.

Background and Objectives: Primary myelofibrosis (PMF) is a rare hematologic malignancy with non-specific symptoms, causing diagnostic delays and missed diagnoses. Automated screening in heterogeneous electronic health records (EHRs) is challenging due to class imbalance, data sparsity, and incomplete labeling. We investigated two complementary objectives: (1) developing a screening algorithm using routine EHR data to identify PMF-risk patients for hematology consultation, and (2) assessing the applicability of positive-unlabeled (PU) learning. Methods: Using EHR data from 10 Polish hospitals, we evaluated several ensemble models and found that LightGBM achieved the best performance. Results: LightGBM achieved AP 20.83% (95% CI: 19.18–24.35%), sensitivity 45.52% (95% CI: 39.48–52.72%), and precision 14.72% (95% CI: 13.80–17.01%)—substantially exceeding expected prevalence (over 340-fold enrichment). The model captured interactions among RDW and PLT parameters revealing high-risk unlabeled patients with confirmed diagnoses (n = 5) or clinical profiles resembling PMF cases (n = 31), confirming PU problem. Conclusions: Although PU methods enhanced sensitivity, they reduced precision to levels exceeding real-world healthcare capacity. Ensemble learning enables disease identification in clinical settings. Full article

(This article belongs to the Section Methods and Technologies Development)

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17 pages, 1804 KB

Open AccessArticle

Twenty Years of Cytoreductive Surgery for Advanced Endometrial Carcinoma: A Single-Center Retrospective Cohort Study

by Britt Kilkens, Eva Maria Roes, Ingrid Boere, Jan-Willem Mens and Heleen van Beekhuizen

Cancers 2026, 18(10), 1617; https://doi.org/10.3390/cancers18101617 (registering DOI) - 16 May 2026

Abstract

Objectives: Endometrial carcinoma (EC), the most common gynecological malignancy, is associated with unfavorable survival in advanced stages. Treatment strategies now include cytoreductive surgery (CRS) and (neo)adjuvant chemotherapy, but survival rates remain limited. This study evaluates overall survival (OS) and surgical outcomes, including outcomes [...] Read more.

Objectives: Endometrial carcinoma (EC), the most common gynecological malignancy, is associated with unfavorable survival in advanced stages. Treatment strategies now include cytoreductive surgery (CRS) and (neo)adjuvant chemotherapy, but survival rates remain limited. This study evaluates overall survival (OS) and surgical outcomes, including outcomes of CRS and surgical complications, over a 20-year period at the Erasmus MC. Methods: This retrospective cohort study includes women diagnosed with FIGO stage III or IV EC between 2000 and 2020 who received treatment at the Erasmus MC. Data were collected from the Netherlands Comprehensive Cancer Organization and supplemented by medical record reviews. Statistical analyses were conducted to evaluate differences in OS based on FIGO stage, histological type, molecular characteristics, CRS outcome, and type of CRS. Results: A total of 188 patients were included, with a median age of 66 years. Most patients received surgery and additional chemotherapy and radiotherapy. A total of 64 patients (59.3%) underwent primary CRS, and 44 patients (40.7%) underwent interval CRS. Patients with complete CRS had a significant survival advantage over patients with optimal and incomplete CRS (HR 0.56; 95% CI 0.33–0.96, p = 0.036). Comparison between primary and interval CRS revealed no significant difference in OS (HR 1.42; 95% CI 0.82–2.44, p = 0.207). Surgical complications occurred in 33.1% of patients, with infections most common. Two patients died from severe complications. Conclusions: This study highlights the predominant role of surgery in the management of advanced EC. Complete CRS is often achievable and offers significant survival advantage. However, approximately one-third of patients experience surgical complications. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

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13 pages, 387 KB

Open AccessArticle

Single-Nucleotide Polymorphism (SNP) c.73G>A in the UBC9 (E2) SUMO Gene and Breast Cancer Risk in Polish Women

by Hanna Romanowicz, Grzegorz Sychowski, Szymon Kalinowski, Szymon Sypniewski, Oleksandr Zakharin, Marek Zadrożny, Honorata Łukasiewicz, Dariusz Samulak and Beata Smolarz

Cancers 2026, 18(10), 1616; https://doi.org/10.3390/cancers18101616 (registering DOI) - 16 May 2026

Abstract

Introduction: Breast cancer is one of the major killers among malignant conditions worldwide, affecting one out of 10 women in industrialized countries and being the leading cause of cancer-related morbidity and mortality in women. The relationships between risk factors and breast cancer [...] Read more.

Introduction: Breast cancer is one of the major killers among malignant conditions worldwide, affecting one out of 10 women in industrialized countries and being the leading cause of cancer-related morbidity and mortality in women. The relationships between risk factors and breast cancer development are not exactly known. The selection of the UBC9 gene and its c.73G>A polymorphism (rs11553473) in breast cancer studies is justified by the gene’s critical role in sumoylation, its impact on DNA repair, and its association with aggressive tumor characteristics. UBC9 (SUMO-conjugating enzyme) is frequently overexpressed in breast cancer, often 5–8-fold higher than in normal tissues, where it promotes tumor proliferation, invasion, and metastasis, often in a sumoylation-independent manner. Aim: In the present work, the association of polymorphism in the UBC9 genes c.73G>A with breast cancer risk was investigated. Materials and Methods: In the reported study, paraffin-embedded tumor tissue was collected from women with lymph node-negative (n = 59) and lymph node-positive (n = 41) ductal breast carcinoma. Samples from age-matched, cancer-free women (n = 100) served as controls. The genotypes of the UBC9 c.73G>A polymorphism were determined by ASO-PCR methods. Results: In the present work, a significant positive association between the UBC9 c.73G>A G/A genotype and breast cancer is demonstrated. The variant A allele of UBC9 increased breast cancer risk. Some correlation was observed between the genotypes of UBC9 polymorphism and breast cancer invasiveness. A statistically significant increase was observed regarding G/A heterozygote frequency in stage II patients, according to Bloom–Richardson classification. There were no significant differences in genotype distribution among subgroups defined by TNM stage, histological grade, hormone receptor status, or HER-2 expression. Conclusions: In conclusion, the reported study indicates that the polymorphisms of the UBC9 gene may be positively associated with the incidence of breast cancer. However, further research is needed on larger study populations. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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21 pages, 4157 KB

Open AccessArticle

Optimizing Sequential Targeted Therapies in Advanced Renal Cell Carcinoma Using Patient-Derived Orthotopic Xenograft Mouse Avatars

by Amita Bhattarai, Ravan Moret, Xin Zhang, Grace Maresh, Henry Yip, Carl Haupt, Rachel Graham, Maria Latsis, Marc Matrana, Kyle Rose, Stephen Bardot and Li Li

Cancers 2026, 18(10), 1615; https://doi.org/10.3390/cancers18101615 (registering DOI) - 16 May 2026

Abstract

Background/Objectives: Advanced renal cell carcinoma (aRCC) remains incurable, with no established optimal sequence of targeted therapies due to interpatient heterogeneity and acquired resistance. We developed a luciferase-enabled patient-derived orthotopic xenograft (PDOX) avatar platform to evaluate sequential targeted therapies in individualized aRCC models that [...] Read more.

Background/Objectives: Advanced renal cell carcinoma (aRCC) remains incurable, with no established optimal sequence of targeted therapies due to interpatient heterogeneity and acquired resistance. We developed a luciferase-enabled patient-derived orthotopic xenograft (PDOX) avatar platform to evaluate sequential targeted therapies in individualized aRCC models that recapitulate tumor architecture, proliferation, angiogenesis, metastasis, and PD-L1 expression. Methods: Tumor specimens from two renal cell carcinoma (RCC) patients were expanded subcutaneously in NOD/SCID mice, transduced with luciferase/red fluorescent protein (Luc/RFP), and orthotopically implanted into mouse kidneys (KiCa-Pt58: sarcomatoid RCC, pT3aN1M1, Fuhrman grade 4; KiCa-Pt118: clear cell RCC with sarcomatoid component, pT3aNxM0, Fuhrman grade 4, respectively). Tumor growth and metastasis were monitored weekly by bioluminescence imaging (BLI). Mice were randomized into vehicle control or four sequential treatment groups (Everolimus→Sunitinib [E→S], Sunitinib→Everolimus [S→E], Pazopanib→Sunitinib [P→S], Pazopanib→Everolimus [P→E]). Drugs were administered orally three times weekly until resistance (>200% BLI increase), with one switch. At necropsy, tumor burden, ex vivo BLI metastasis, weights, H&E histology, and immunohistochemistry (Ki67, CD44, CD31, PD-L1) were assessed. Results: Two independent experiments were performed. In dosing optimization, PDOX tumors recapitulated parental histology and proliferative indices, mirroring patient trajectories. KiCa-Pt58 (metastatic sarcomatoid RCC; deceased 1-month post-nephrectomy) showed aggressive features: rapid engraftment at low doses, early growth (week 2), and lung metastases in 78% of mice (sacrifice day 34), reflecting a fulminant course. KiCa-Pt118 (non-metastatic; patient recurrence-free >8 years post nephrectomy) exhibited indolent behavior: delayed engraftment requiring higher doses plus lymph node stromal (HK) support, slower growth (week 4), no metastases, and later sacrifice (day 78), consistent with remission. In sequential therapy evaluation, for KiCa-Pt58, P→E yielded greatest reductions in tumor weight (p < 0.01), lung metastases (p < 0.01), Ki67+ proliferation, CD31+ angiogenesis, and PD-L1 expression versus control; E→S and S→E were also effective. For KiCa-Pt118, S→E and P→E reduced tumor burden (p < 0.01) and Ki67⁺ proliferation; S→E lowered CD31 and PD-L1. Conclusions: This RCC PDOX platform faithfully preserves patient-specific biology—including metastatic propensity, engraftment efficiency, growth kinetics, and stromal dependency—while enabling real-time evaluation of sequential targeted therapies. Given the limited number of models tested, these findings provide proof-of-concept for individualized treatment exploration in advanced RCC and support future investigation of rational combinations with immune checkpoint blockade in humanized or immunocompetent systems. Full article

(This article belongs to the Section Cancer Therapy)

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14 pages, 836 KB

Open AccessArticle

Centralized Homologous Recombination Repair Testing in Metastatic Castration-Resistant Prostate Cancer: Real-World Data from a Multicenter Spanish Precision Oncology Program

by Belén Caramelo, Pilar García-Berbel, Sofia del Carmen, Adriana Calapaqui, Luiz Corrêa, Lucia Martinez-Villaseñor, Marta Sotelo, Federico Rojo, Javier Gómez-Román, Ignacio Duran and Javier Freire

Cancers 2026, 18(10), 1614; https://doi.org/10.3390/cancers18101614 (registering DOI) - 16 May 2026

Abstract

Background/Objectives: Determining homologous recombination repair (HRR) status in metastatic castration-resistant prostate cancer (mCRPC) is essential to ensure access to targeted therapies, particularly PARP inhibitors. Yet, variability in testing access and analysis performance exists. This study evaluated feasibility and outcomes of a centralized HRR [...] Read more.

Background/Objectives: Determining homologous recombination repair (HRR) status in metastatic castration-resistant prostate cancer (mCRPC) is essential to ensure access to targeted therapies, particularly PARP inhibitors. Yet, variability in testing access and analysis performance exists. This study evaluated feasibility and outcomes of a centralized HRR testing strategy in Spain for prostate cancer patients. Methods: A total of 1412 formalin-fixed paraffin-embedded (FFPE) tumor samples from mCRPC patients from 89 Spanish institutions within a centralized multicenter molecular testing program were analyzed using a standardized 38-gene-based next-generation sequencing (NGS) assay in a central laboratory (HRR OncoKit, Health in Code, Valencia, Spain), which included five clinically relevant HRR genes: BRCA1, BRCA2, CHEK2, ATM, and CDK12. Results: HRR gene pathogenic or likely pathogenic alterations were identified in 18% (CI 95% = 16–20) of the patients, with BRCA2 being the most frequently altered gene (6%), followed by ATM (5%), CDK12 (4%), BRCA1 (2%), and CHEK2 (1%). Eleven percent had variants of uncertain significance. Only 13% of the samples were rejected due to poor DNA quality, low tumor content or sample age exceeding 5 years, and 2% of the samples analyzed failed since the minimum library technical quality score was not achieved. The average turnaround time for results was 18 ± 3 days. Conclusions: Centralized HRR testing in mCRPC patients in Spain was feasible, efficient and reliable, identifying pathogenic alterations in 18% of the cases, similarly to the prevalence described in the literature. This testing approach facilitates precision medicine by improving the detection of actionable HRR alterations. Full article

(This article belongs to the Section Cancer Biomarkers)

28 pages, 10544 KB

Open AccessArticle

Non-Temperature-Induced Antitumor Effects of Amplitude-Modulated Radiofrequency: Molecular and Functional Synergies with Radiotherapy

by Paraskevi Danai Veltsista, Wolfgang Walther, Sebastian Torke, Andranik Ivanov, Anna Dieper, Dieter Beule, Daniel Zips, Ulrike Stein and Pirus Ghadjar

Cancers 2026, 18(10), 1613; https://doi.org/10.3390/cancers18101613 (registering DOI) - 16 May 2026

Abstract

Background/Objectives: Amplitude-modulated radiofrequency (AMRF) fields have emerged as promising non-temperature-induced strategies in oncology. While conventional hyperthermia (HT) relies on thermal stress, the biological impact of AMRF, particularly in combination with radiotherapy (RT), remains insufficiently characterized. Methods: We assessed RF and AMRF, alone or [...] Read more.

Background/Objectives: Amplitude-modulated radiofrequency (AMRF) fields have emerged as promising non-temperature-induced strategies in oncology. While conventional hyperthermia (HT) relies on thermal stress, the biological impact of AMRF, particularly in combination with radiotherapy (RT), remains insufficiently characterized. Methods: We assessed RF and AMRF, alone or with RT, using phenotypic analyses of proliferation, apoptosis, and necrosis across four cancer cell lines (HT29, SW620, U343, U138). Transcriptomic profiling with Kyoto Encyclopedia of Genes and Genomes (KEGG), GO:BP, and Reactome enrichment was performed in SW620 and U138 cells, selected for their strong phenotypic responses. Results: Across the panel, AMRF was associated with broader cytotoxic responses than RF or HT in most but not all cell lines. AMRF+RT produced the strongest necrotic responses, with cell-line-specific exceptions identified explicitly in the Results (the absence of a significant AMRF+RT apoptotic effect in SW620 and the absence of a significant AMRF+RT necrotic response in U343). In SW620 cells, AMRF was associated with extensive transcriptional reprogramming involving immune modulation, extracellular matrix remodeling, and cell cycle regulation, whereas RF alone showed narrower and delayed effects. In contrast, U138 cells showed elevated apoptosis and necrosis but limited transcriptional changes—a phenotype–transcriptome divergence that points to mechanisms operating downstream of transcription and warrants functional investigation in dedicated follow-up studies. Conclusions: AMRF and AMRF+RT emerge as promising non-temperature-induced anticancer modalities in the cell-line models profiled here, with the pattern of response varying between cell lines. These findings expand the biological impact of RF-based treatments and set the grounds for further investigation in mechanistic and translational studies. Full article

(This article belongs to the Special Issue Feature Papers in Section “Methods and Technologies Development” in 2026)

15 pages, 1074 KB

Open AccessArticle

Risk Factors and Nonlinear Risk Patterns of Prolonged Air Leak After Robot-Assisted Lung Resection for Lung Cancer: A Retrospective Cohort Study

by Hao Xu, Han Zhang and Linyou Zhang

Cancers 2026, 18(10), 1612; https://doi.org/10.3390/cancers18101612 - 15 May 2026

Abstract

Background/Objectives: Prolonged air leak (PAL) remains a common complication after lung resection and may delay postoperative recovery and subsequent treatment. This study aimed to identify clinical factors associated with PAL after robot-assisted thoracic surgery (RATS) and to explore potential nonlinear relationships using restricted [...] Read more.

Background/Objectives: Prolonged air leak (PAL) remains a common complication after lung resection and may delay postoperative recovery and subsequent treatment. This study aimed to identify clinical factors associated with PAL after robot-assisted thoracic surgery (RATS) and to explore potential nonlinear relationships using restricted cubic spline (RCS) modeling. Methods: A retrospective cohort of 1185 patients who underwent RATS for primary lung cancer was analyzed. Multivariable Firth logistic regression was used to identify independent predictors of PAL (≥5 days). A nomogram was constructed based on the final model and internally validated using 1000 bootstrap resamples; its clinical utility was assessed using decision curve analysis. RCS analysis was performed to evaluate potential nonlinear associations. Results: A total of 98 patients (8.3%) developed PAL. Male sex was independently associated with increased PAL risk (OR 3.29, p < 0.001), whereas higher FEV1 was associated with reduced risk (OR 0.50 per 1-L increase, p < 0.001). BMI showed a modest protective effect (OR 0.91, p = 0.01). Age was not significant in the linear model (p = 0.86), but RCS analysis demonstrated a significant nonlinear association, with increased risk at older ages. The nomogram demonstrated moderate discrimination (apparent C-statistic 0.670, optimism-corrected 0.644) and good calibration, with decision curve analysis confirming net clinical benefit over treat-all and treat-none strategies. Conclusions: Male sex and impaired pulmonary function are key predictors of PAL after RATS. Nonlinear modeling revealed complex age-related risk patterns not captured by conventional approaches. The proposed nomogram may assist in preoperative risk stratification and perioperative decision-making. Full article

(This article belongs to the Special Issue Advances in Minimally Invasive Surgery in Thoracic Oncology)

23 pages, 1730 KB

Open AccessReview

Mitochondrial Hijacking and MicroRNA Crosstalk: Cancer Stem Cell-Mediated Immune Evasion and Metabolic Plasticity in the Tumor Microenvironment

by Maziar Ashrafian Bonab, Shahrzad Salehi, Amirreza Aghababaie, Ali Amini, Hoda Alizadeh and Babak Behnam

Cancers 2026, 18(10), 1611; https://doi.org/10.3390/cancers18101611 - 15 May 2026

Abstract

The tumor microenvironment (TME) is a highly adaptive and heterogeneous niche in which cancer stem cells (CSCs) promote immune evasion, metastatic dissemination, and therapy resistance. Among the mechanisms that support this phenotype, mitochondrial hijacking has emerged as a central strategy through which CSCs [...] Read more.

The tumor microenvironment (TME) is a highly adaptive and heterogeneous niche in which cancer stem cells (CSCs) promote immune evasion, metastatic dissemination, and therapy resistance. Among the mechanisms that support this phenotype, mitochondrial hijacking has emerged as a central strategy through which CSCs reprogram immune and stromal cells to favor tumor progression. This review synthesizes current evidence on how CSCs exploit mitochondrial transfer, particularly via tunneling nanotubes (TNTs) and extracellular vesicles (EVs), to impair antitumor immunity and remodel the metastatic niche. CSCs display marked metabolic plasticity, shifting between glycolysis and oxidative phosphorylation (OXPHOS) in response to environmental stress. They exploit this adaptability by transferring mitochondria and mitochondrial components to recipient cells, including tumor-associated macrophages (TAMs) and cytotoxic T cells, thereby disrupting ATP production, increasing oxidative stress, and skewing immune polarization. This mitochondrial hijacking contributes to an immunosuppressive milieu, stabilizes HIF-1α, and enhances PD-L1 expression, ultimately weakening T-cell activity and reinforcing CSC survival. EVs add another layer of regulation by transporting bioactive cargo, including oncogenic microRNAs (miRNAs) and mitomiRs such as miR-21, miR-210, and miR-34a. These molecules modulate mitochondrial gene expression, reshape immune signaling, and reinforce CSC phenotypes through autocrine and paracrine loops. Single-cell and spatial transcriptomic approaches have further revealed metabolic heterogeneity within CSC–immune synapses, identifying “metabolic hotspots” associated with profound immune dysfunction. Therapeutic strategies targeting OXPHOS, EV biogenesis, and miRNA activity are therefore being explored. In parallel, mitochondria-associated proteins such as TSGA10 may also contribute to CSC-driven immunometabolism regulation and deserve further investigation. Targeting downstream heterogeneity is like cutting the branches of a weed. Targeting the upstream mechanisms of mitochondrial hijacking and miRNA crosstalk aims to destroy the root (CSC plasticity) that generates the heterogeneity and drives therapy resistance in the first place. This review highlights mitochondrial hijacking and miRNA-mediated reprogramming as central determinants of CSC-driven immune escape and proposes a framework for precision interventions targeting CSC–immune interactions in metastatic cancer. Full article

(This article belongs to the Special Issue Advances in Cellular Heterogeneity and Plasticity in the Tumor Microenvironment)

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47 pages, 3333 KB

Open AccessReview

miRNA–lncRNA Cross-Regulation Landscape in Cancer: From Molecular Mechanisms to Therapeutic and Diagnostic Applications

by Giuseppe Scafuro, Myriam Karam, Ayesha Khan, Chiara Tammaro, Takehiro Nagatsuka, Anna Grimaldi, Alessia Maria Cossu, Silvia Zappavigna, Michele Caraglia, Gabriella Misso and Michela Falco

Cancers 2026, 18(10), 1610; https://doi.org/10.3390/cancers18101610 - 15 May 2026

Abstract

Background/Objectives: Over the past two decades, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, reshaping the classical view of the genome as predominantly protein-coding. Among them, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play central roles in controlling gene expression [...] Read more.

Background/Objectives: Over the past two decades, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, reshaping the classical view of the genome as predominantly protein-coding. Among them, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play central roles in controlling gene expression at multiple levels. Rather than acting independently, these molecules form complex and interconnected regulatory networks, and their interplay appears particularly relevant in cancer. This review aims to examine the mechanisms underlying miRNA-lncRNA cross-regulation and to explore their functional and clinical implications in tumor biology. Methods: We performed a comprehensive analysis of the current literature focusing on studies investigating miRNA-lncRNA interactions in cancer. Particular attention was given to mechanistic insights, including the competing endogenous RNA (ceRNA) hypothesis, as well as alternative regulatory models involving direct RNA interactions and chromatin-associated processes. Results: miRNA-lncRNA interactions have been associated with cancer progression and therapeutic response across different tumor types, although their mechanisms are highly context-dependent. While the ceRNA hypothesis, based on competition for shared microRNA response elements (MREs), provides a useful framework, it does not fully explain all observed phenomena. Evidence shows that miRNAs can directly regulate lncRNA stability, whereas lncRNAs can influence miRNA biogenesis. Additionally, chromatin-related mechanisms suggest that these interactions extend beyond post-transcriptional regulation. These RNA networks intersect with major oncogenic pathways, including PI3K/AKT/mTOR signaling, hypoxia responses, and epigenetic regulators such as EZH2, thereby affecting key cancer processes such as proliferation, epithelial–mesenchymal transition (EMT), and metabolic reprogramming. From a clinical perspective, the stability of ncRNAs in biological fluids highlights their potential as biomarkers. Combined miRNA-lncRNA signatures may improve diagnostic and prognostic accuracy compared to single markers, although further validation is required. Therapeutic strategies targeting ncRNA networks, such as miRNA mimics, antagomiRs, and lncRNA-directed approaches, are under investigation; however, challenges related to delivery, specificity, and toxicity remain. Conclusions: miRNA-lncRNA cross-regulation represents a complex and multifaceted layer of gene regulation in cancer. A deeper understanding of these interactions could support the development of more accurate diagnostic tools and more effective RNA-based therapeutic strategies, although significant technical and biological challenges still need to be addressed. Full article

(This article belongs to the Special Issue Targeting RNA to Improve Cancer Precision Medicine)

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17 pages, 2811 KB

Open AccessArticle

Efficacy of Spectral-Aided Visual Enhancer in Classification of Esophageal Cancer

by Kok-Yean Koh, Arvind Mukundan, Riya Karmakar, Chaudhary Tirth Atulbhai, Tsung-Hsien Chen, Wei-Chun Weng and Hsiang-Chen Wang

Cancers 2026, 18(10), 1609; https://doi.org/10.3390/cancers18101609 - 15 May 2026

Abstract

Background/Objectives: Esophageal cancer is one of the major global causes of cancer mortality, and the 5-year survival rate remains below 20% because many cases are detected late. In this study, a Spectral-Aided Vision Enhancer (SAVE) algorithm was utilized to convert conventional white-light endoscopic [...] Read more.

Background/Objectives: Esophageal cancer is one of the major global causes of cancer mortality, and the 5-year survival rate remains below 20% because many cases are detected late. In this study, a Spectral-Aided Vision Enhancer (SAVE) algorithm was utilized to convert conventional white-light endoscopic images (WLI) into hyperspectral-like narrow-band imaging (NBI) images for machine-learning classification of Dysplasia, Normal, and Squamous Cell Carcinoma (SCC). Methods: A total of 762 WLI images obtained from Kaohsiung Medical University were augmented to 1074 using the Al bumentations library, employing vertical flipping, horizontal flipping, and rotations. The SAVE conversion pipeline employs a 24-patch Macbeth color checker for calibration, γ-correction, CIE XYZ transformation, and multivariate regression to interpolate spectral bands, yielding an average color difference of 2.79 (CIEDE2000) from true NBI. The training outcomes and performance metrics illustrate the versatility of the machine learning/deep learning models—Random Forest (RF), Support Vector Machine (SVM), and Convolutional Neural Network (CNN)—which were trained and evaluated on both the original WLI and SAVE datasets. Performance metrics were analyzed based on precision, recall, accuracy, and F1-score. Results: The CNN sample achieved an accuracy of 100 percent on SAVE data, compared to 93 percent for WLI. The accuracy of RF improved, with WLI at 91% and SAVE at 96%, while SVM increased from 79% to 84%. These improvements indicate the diagnostically valuable spectral variations that can be amplified with SAVE, resulting in significant enhancements in pre-cancer/SCC sensitivity. Conclusions: The proposed SAVE method demonstrates significant potential for enhancing endoscopic imaging and advancing computer-aided diagnosis in esophageal cancer screening, with applicability in other gastrointestinal imaging scenarios as well. Full article

(This article belongs to the Special Issue Advances in Endoscopic Management of Esophageal Cancer)

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22 pages, 6875 KB

Open AccessArticle

Integrative Multi-Omics Analysis Identifies IL18R1 as a Circulating Prognostic Biomarker for Risk Stratification in Extensive-Stage Small Cell Lung Cancer

by Shengjuan Hu, Sicong Li, Yiyuan Cui, Ying Wang, Luyao Chen, Xiyuan Zhang, Li Hou and Li Feng

Cancers 2026, 18(10), 1608; https://doi.org/10.3390/cancers18101608 - 15 May 2026

Abstract

Background: Small cell lung cancer (SCLC) carries a dismal prognosis with limited biomarkers for risk stratification. This study aimed to identify circulating prognostic biomarkers. Methods: We prioritized SCLC risk-associated genes using Summary-data-based Mendelian Randomization of pQTL/eQTL, differential expression, and weighted gene [...] Read more.

Background: Small cell lung cancer (SCLC) carries a dismal prognosis with limited biomarkers for risk stratification. This study aimed to identify circulating prognostic biomarkers. Methods: We prioritized SCLC risk-associated genes using Summary-data-based Mendelian Randomization of pQTL/eQTL, differential expression, and weighted gene co-expression network analysis. Five machine learning approaches were compared to develop a diagnostic model based on ACE, AGER, and IL18R1, trained on GSE149507 and validated in GSE60052. We conducted single-cell transcriptomic analysis using public datasets (GSE150766 and GSE279570) and peripheral blood mononuclear cells (PBMCs) from our extensive-stage cohort. Finally, prioritizing the lead candidate IL18R1, we enrolled a prospective clinical cohort to assess its prognostic utility. A LASSO–Cox prognostic model incorporating plasma IL18R1 and clinical variables was internally validated (7:3 split) for progression-free survival (PFS) prediction. Results: Integrative multi-omics identified ACE, AGER, and IL18R1 as SCLC-protective genes. Elastic Net machine learning identified a two-gene predictive signature (AGER and IL18R1) with robust diagnostic accuracy. Single-cell RNA sequencing revealed the predominant downregulation of ACE, AGER, and IL18R1 in T cells and alveolar type II cells from SCLC patients. PBMC analysis further supported IL18R1 downregulation in CD8⁺ T cells, NK cells, and dendritic cells. In an independent prospective cohort (n = 300), lower plasma IL18R1 levels were independently associated with shorter PFS (HR = 0.997 per unit increase; 95% CI: 0.995–0.999; and p = 0.003), with time-dependent AUCs of 0.77–0.86. Performance in limited-stage disease was inconsistent and requires further validation. A prognostic model incorporating plasma IL18R1 and 11 clinical parameters stratified patients into distinct risk groups (HR = 5.19), showing a strong discriminative ability in extensive-stage SCLC. Conclusions: We identified ACE, AGER, and IL18R1 as protective factors against SCLC progression. Integration of plasma IL18R1 with clinical parameters provides a prognostic tool for extensive-stage SCLC. Full article

(This article belongs to the Topic Biomarkers of Disease: Discovery and Clinical Applications)

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23 pages, 4124 KB

Open AccessArticle

Tumor Implantation Site of Syngeneic Oral Cancer Models Differentially Induces Site-Dependent Local and Systemic Immunosuppression

by Andrea H. Molina, Gemalene M. Sunga, Shawn Nguyen, Neeraja Dharmaraj, Ratna Veeramachaneni, Roberto Rangel, Jeffrey N. Meyers, Jeffrey D. Hartgerink, Andrew G. Sikora and Simon Young

Cancers 2026, 18(10), 1607; https://doi.org/10.3390/cancers18101607 - 15 May 2026

Abstract

Background/Objectives: Preclinical studies of head and neck squamous cell carcinoma (HNSCC) commonly use subcutaneous heterotopic (flank) tumor models for simplicity; however, orthotopic models may better reflect the native tumor environment. Direct comparisons of the tumor immune microenvironments (TIME) and tumor-draining lymph nodes (tdLNs) [...] Read more.

Background/Objectives: Preclinical studies of head and neck squamous cell carcinoma (HNSCC) commonly use subcutaneous heterotopic (flank) tumor models for simplicity; however, orthotopic models may better reflect the native tumor environment. Direct comparisons of the tumor immune microenvironments (TIME) and tumor-draining lymph nodes (tdLNs) between these models remain limited. Better understanding of site-specific immune differences could improve model selection and interpretation of translational HNSCC studies. Methods: ROC1 tumors were established in murine heterotopic and orthotopic sites, followed by assessment of tumor growth kinetics, survival, and the tumor microenvironment. Immune composition of tumors, blood, tdLNs, and spleen was evaluated at three tumor progression timepoints using multiparameter spectral flow cytometry. Results: Heterotopic and orthotopic tumor models showed similar growth kinetics and survival. Immune profiling revealed increased infiltration of CD3⁺ T-cells, natural killer (NK) cells, and myeloid populations in both models. Heterotopic tumors were enriched in dendritic cells (DCs), plasmacytoid DCs, and monocytic myeloid-derived suppressor cells (M-MDSCs), whereas orthotopic tumors showed increased macrophages, granulocytic MDSCs, and M-MDSCs. Despite temporal variation, both TIMEs were dominated by macrophages, DCs, and CD3⁺ T-cells. Late-stage heterotopic tumors contained more CD4⁺ T-cells. Reduced T-cell cytotoxicity (PD-1, CD107a) and increased immune checkpoint expression across myeloid cells indicated an immunosuppressive TIME. Systemically, effector cells were preserved despite suppressive cell trafficking, and tdLNs in both models exhibited immunosuppressive PD-L1 expression. Conclusions: Heterotopic and orthotopic ROC1 tumors share key immune features, but site-specific differences in the TIME and tdLNs reveal tissue-dependent regulation. These local effects align with systemic changes, supporting global tumor-associated immunosuppression. Full article

(This article belongs to the Special Issue Decoding and Remodeling the Suppressive Tumor Immune Microenvironment in Head and Neck Cancer)

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Graphical abstract

21 pages, 3412 KB

Open AccessArticle

EZH2-Associated Hypermethylated Gene Signature Predicts Immunotherapy Response and Implicates DUSP5 in Tumor-Immune Regulation in Triple-Negative Breast Cancer

by Mingzhan Xue, Sujitha Jeya, Reem Elasad, Sarra Mestiri, Fares Al Ejeh and Mariam Al-Muftah

Cancers 2026, 18(10), 1606; https://doi.org/10.3390/cancers18101606 - 15 May 2026

Abstract

Background/Objectives: Triple-negative breast cancer (TNBC) is a candidate for immune checkpoint blockade; however, current biomarkers remain insufficient to predict therapeutic response or capture tumor-intrinsic mechanisms. Enhancer of Zeste Homolog 2 (EZH2)-mediated epigenetic repression has been implicated in immune evasion, yet the contribution of [...] Read more.

Background/Objectives: Triple-negative breast cancer (TNBC) is a candidate for immune checkpoint blockade; however, current biomarkers remain insufficient to predict therapeutic response or capture tumor-intrinsic mechanisms. Enhancer of Zeste Homolog 2 (EZH2)-mediated epigenetic repression has been implicated in immune evasion, yet the contribution of EZH2-repressed genes to anti-tumor immunity and clinical outcomes in TNBC remains unclear. We aimed to identify EZH2-associated epigenetically repressed genes in TNBC and evaluate their relevance as tumor-intrinsic regulators and potential predictors of immunotherapy outcome. Methods: We performed integrative in silico analyses of The Cancer Genome Atlas (TCGA) breast cancer cohorts to identify EZH2-associated hypermethylated genes in TNBC. A composite 30-gene signature (30GS) was defined based on transcriptional repression and promoter hypermethylation. Associations with clinical outcomes, tumor- and immune-related programs, and therapeutic response were evaluated, with validation in the I-SPY2 cohort and an independent TNBC patient cohort. Results: The 30GS was significantly reduced in TNBC and basal-like tumors and associated with improved clinical outcomes and enrichment of tumor- and immune-related signatures. In the I-SPY2 cohort, the 30GS predicted pathological complete response in patients receiving chemo-immunotherapy (AUC = 0.7377, p = 0.0007). Gene-level analysis identified Dual Specificity Phosphatase 5 (DUSP5) as the gene most consistently associated with immune-related parameters. In an independent TNBC cohort, DUSP5-high tumors demonstrated transcriptional programs enriched for inflammatory, immune-related, and signaling pathways within the NanoString Breast Cancer 360 panel. Conclusions: This study defines an EZH2-associated epigenetic program linked to tumor-intrinsic immune programs in TNBC and identifies DUSP5 as a candidate gene associated with immune-related transcriptional states. Full article

(This article belongs to the Section Cancer Biomarkers)

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11 pages, 1955 KB

Open AccessArticle

P16 DNA Methylation Coupled with Somatic Copy Number Variations in the Development of Gastric Carcinomas

by Ziqian Yang, Jing Zhou, Lewen Deng, Juanli Qiao, Liankun Gu and Dajun Deng

Cancers 2026, 18(10), 1605; https://doi.org/10.3390/cancers18101605 - 15 May 2026

Abstract

Background/Objectives: Tumor suppressor genes are often inactivated by genetic and epigenetic mechanisms. However, whether genetic alterations of these genes, including CDKN2A/P16, are coupled with epigenetic changes in cancer development and progression is unknown. Methods: Freshly frozen gastric carcinoma (GC) samples, [...] Read more.

Background/Objectives: Tumor suppressor genes are often inactivated by genetic and epigenetic mechanisms. However, whether genetic alterations of these genes, including CDKN2A/P16, are coupled with epigenetic changes in cancer development and progression is unknown. Methods: Freshly frozen gastric carcinoma (GC) samples, paired noncancer surgical margin (SM) samples, white blood cell (WBC) samples, and clinicopathological information were collected from 200 patients. The copy number (CN) of the CDKN2A/P16 gene in these samples was determined by a P16-Light assay and normalized to that in white blood cells (WBCs). The DNA methylation level of the P16 promoter in GC and SM samples was determined by a 115 bp P16-specific MethyLight assay. Results: Both the P16 copy number and the DNA methylation level were significantly lower in GC samples than in SM samples (median, 1.94 vs. 2.14, p < 0.001 for P16 CN; 0.0004 vs. 0.0013, p = 0.002 for P16 methylation) and were associated with GC metastasis. The normalized P16 copy number was significantly lower in GCs without vs. with P16 methylation (p = 0.007). Similarly, more P16 somatic copy number deletions (SCNdel) were detected in GCs without vs. with P16 methylation (38.6% vs. 24.1%, p = 0.027). Conclusions: Somatic P16 copy number variations are closely coupled with P16 promoter DNA methylation during GC development. SCNdel and promoter DNA methylation complementarily inactivate P16 in GC development and promote GC metastasis. Full article

(This article belongs to the Section Cancer Metastasis)

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